Cardiovascular Mitochondrial Dysfunction Induced by Cocaine: Biomarkers and Possible Beneficial Effects of Modulators of Oxidative Stress.

PubMed

Graziani, Manuela; Sarti, Paolo; Arese, Marzia; Magnifico, Maria Chiara; Badiani, Aldo; Saso, Luciano

2017-01-01

Cocaine abuse has long been known to cause morbidity and mortality due to its cardiovascular toxic effects. The pathogenesis of the cardiovascular toxicity of cocaine use has been largely reviewed, and the most recent data indicate a fundamental role of oxidative stress in cocaine-induced cardiovascular toxicity, indicating that mitochondrial dysfunction is involved in the mechanisms of oxidative stress. The comprehension of the mechanisms involving mitochondrial dysfunction could help in selecting the most appropriate mitochondria injury biological marker, such as superoxide dismutase-2 activity and glutathionylated hemoglobin. The potential use of modulators of oxidative stress (mitoubiquinone, the short-chain quinone idebenone, and allopurinol) in the treatment of cocaine cardiotoxic effects is also suggested to promote further investigations on these potential mitochondria-targeted antioxidant strategies.

Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models.

PubMed

Biczo, Gyorgy; Vegh, Eszter T; Shalbueva, Natalia; Mareninova, Olga A; Elperin, Jason; Lotshaw, Ethan; Gretler, Sophie; Lugea, Aurelia; Malla, Sudarshan R; Dawson, David; Ruchala, Piotr; Whitelegge, Julian; French, Samuel W; Wen, Li; Husain, Sohail Z; Gorelick, Fred S; Hegyi, Peter; Rakonczay, Zoltan; Gukovsky, Ilya; Gukovskaya, Anna S

2018-02-01

Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca 2+ , mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats. Pancreatitis was induced in C57BL/6J mice (control) and mice deficient in peptidylprolyl isomerase D (cyclophilin D, encoded by Ppid) by administration of L-arginine (also in rats), caerulein, bile acid, or an AP-inducing diet. Parameters of pancreatitis, mitochondrial function, autophagy, ER stress, and lipid metabolism were measured in pancreatic tissue, acinar cells, and isolated mitochondria. Some mice with AP were given trehalose to enhance autophagic efficiency. Human pancreatitis tissues were analyzed by immunofluorescence. Mitochondrial dysfunction in pancreas of mice with AP was induced by either mitochondrial Ca 2+ overload or through a Ca 2+ overload-independent pathway that involved reduced activity of ATP synthase (80% inhibition in pancreatic mitochondria isolated from rats or mice given L-arginine). Both pathways were mediated by cyclophilin D and led to mitochondrial depolarization and fragmentation. Mitochondrial dysfunction caused pancreatic ER stress, impaired autophagy, and deregulation of lipid metabolism. These pathologic responses were abrogated in cyclophilin D-knockout mice. Administration of trehalose largely prevented trypsinogen activation, necrosis, and other parameters of pancreatic injury in mice with L-arginine AP. Tissues from patients with pancreatitis had markers of mitochondrial damage and impaired autophagy, compared with normal pancreas. In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine-induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Mitochondrial Dysfunction in Cancer

PubMed Central

Boland, Michelle L.; Chourasia, Aparajita H.; Macleod, Kay F.

2013-01-01

A mechanistic understanding of how mitochondrial dysfunction contributes to cell growth and tumorigenesis is emerging beyond Warburg as an area of research that is under-explored in terms of its significance for clinical management of cancer. Work discussed in this review focuses less on the Warburg effect and more on mitochondria and how dysfunctional mitochondria modulate cell cycle, gene expression, metabolism, cell viability, and other established aspects of cell growth and stress responses. There is increasing evidence that key oncogenes and tumor suppressors modulate mitochondrial dynamics through important signaling pathways and that mitochondrial mass and function vary between tumors and individuals but the significance of these events for cancer are not fully appreciated. We explore the interplay between key molecules involved in mitochondrial fission and fusion and in apoptosis, as well as in mitophagy, biogenesis, and spatial dynamics of mitochondria and consider how these distinct mechanisms are coordinated in response to physiological stresses such as hypoxia and nutrient deprivation. Importantly, we examine how deregulation of these processes in cancer has knock on effects for cell proliferation and growth. We define major forms of mitochondrial dysfunction and address the extent to which the functional consequences of such dysfunction can be determined and exploited for cancer diagnosis and treatment. PMID:24350057

Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage.

PubMed

Bronner, Denise N; Abuaita, Basel H; Chen, Xiaoyun; Fitzgerald, Katherine A; Nuñez, Gabriel; He, Yongqun; Yin, Xiao-Ming; O'Riordan, Mary X D

2015-09-15

Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1α activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2-dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity. Copyright © 2015 Elsevier Inc. All rights reserved.

Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy

PubMed Central

Tan, Qian; Yan, Xiaoqiong; Song, Lin; Yi, Hongxiang; Li, Ping; Sun, Guobin; Yu, Danfang; Li, Le; Zeng, Zheng; Guo, Zhenli

2017-01-01

Background Inducing mitochondrial dysfunction has been recently demonstrated to be an alternative therapeutic strategy for cancer treatment. Doxycycline is an antibiotic that has been shown to have anti-cancer activities in various cancers by way of targeting mitochondria. In this work, we examined whether doxycycline can be repurposed for glioblastoma treatment. Material/Methods The effects of doxycycline on the growth, survival, and mitochondrial metabolisms of glioblastoma were investigated. The efficacy of a combination of doxycycline with temozolomide was examined using xenograft mouse model in total number of 40 mice. Results Doxycycline targeted glioblastoma cell lines, regardless of their origin, through inhibiting growth and inducing cell death, accompanied by a significant decrease in proliferating cell nuclear antigen (PCNA) and increase in cleaved caspase-3. In addition, doxycycline significantly sensitized glioblastoma cell response to temozolomide in vitro and in vivo. Mechanistically, doxycycline disrupted mitochondrial functions through decreasing mitochondrial membrane potential and mitochondrial respiration. Inducing mitochondrial dysfunctions by using doxycycline led to energy crisis, oxidative stress, and damage as shown by the decreased levels of ATP and the elevated levels of mitochondrial superoxide, intracellular ROS, 8-OHdG, protein carbonylation, and lipid peroxidation. An antioxidant N-acetyl-L-cysteine (NAC) significantly abolished the anti-proliferative and pro-apoptotic effects of doxycycline, demonstrating that doxycycline acts on glioblastoma via inducing oxidative stress. Conclusions In our study, we show that the antibiotic doxycycline is effective in targeting glioblastoma through inducing mitochondrial dysfunctions and oxidative stress. Our work also demonstrated the importance of mitochondrial metabolism in glioblastoma. PMID:28842551

Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy.

PubMed

Tan, Qian; Yan, Xiaoqiong; Song, Lin; Yi, Hongxiang; Li, Ping; Sun, Guobin; Yu, Danfang; Li, Le; Zeng, Zheng; Guo, Zhenlin

2017-08-26

BACKGROUND Inducing mitochondrial dysfunction has been recently demonstrated to be an alternative therapeutic strategy for cancer treatment. Doxycycline is an antibiotic that has been shown to have anti-cancer activities in various cancers by way of targeting mitochondria. In this work, we examined whether doxycycline can be repurposed for glioblastoma treatment. MATERIAL AND METHODS The effects of doxycycline on the growth, survival, and mitochondrial metabolisms of glioblastoma were investigated. The efficacy of a combination of doxycycline with temozolomide was examined using xenograft mouse model in total number of 40 mice. RESULTS Doxycycline targeted glioblastoma cell lines, regardless of their origin, through inhibiting growth and inducing cell death, accompanied by a significant decrease in proliferating cell nuclear antigen (PCNA) and increase in cleaved caspase-3. In addition, doxycycline significantly sensitized glioblastoma cell response to temozolomide in vitro and in vivo. Mechanistically, doxycycline disrupted mitochondrial functions through decreasing mitochondrial membrane potential and mitochondrial respiration. Inducing mitochondrial dysfunctions by using doxycycline led to energy crisis, oxidative stress, and damage as shown by the decreased levels of ATP and the elevated levels of mitochondrial superoxide, intracellular ROS, 8-OHdG, protein carbonylation, and lipid peroxidation. An antioxidant N-acetyl-L-cysteine (NAC) significantly abolished the anti-proliferative and pro-apoptotic effects of doxycycline, demonstrating that doxycycline acts on glioblastoma via inducing oxidative stress. CONCLUSIONS In our study, we show that the antibiotic doxycycline is effective in targeting glioblastoma through inducing mitochondrial dysfunctions and oxidative stress. Our work also demonstrated the importance of mitochondrial metabolism in glioblastoma.

Indian Ginseng (Withania somnifera) supplementation ameliorates oxidative stress and mitochondrial dysfunctions in experimental model of stroke.

PubMed

Sood, Abhilasha; Mehrotra, Arpit; Dhawan, Devinder K; Sandhir, Rajat

2018-04-18

Stroke is an increasingly prevalent clinical condition and second leading cause of death globally. The present study evaluated the therapeutic potential of Indian Ginseng, also known as Withania somnifera (WS), supplementation on middle cerebral artery occlusion (MCAO) induced mitochondrial dysfunctions in experimental model of ischemic stroke. Stroke was induced in animals by occluding the middle cerebral artery, followed by reperfusion injury. Ischemia reperfusion injury resulted in increased oxidative stress indicated by increased reactive oxygen species and protein carbonyl levels; compromised antioxidant system; in terms of reduced superoxide dismutase and catalase activity, along with reduction in GSH levels and the redox ratio, impaired mitochondrial functions and enhanced expression of apoptosis markers. Ischemia reperfusion injury induced mitochondrial dysfunctions in terms of (i) reduced activity of the mitochondrial respiratory chain enzymes, (ii) reduced histochemical staining of complex-II and IV, (iii) reduced in-gel activity of mitochondrial complex-I to V, (iv) mitochondrial structural changes in terms of increased mitochondrial swelling, reduced mitochondrial membrane potential and ultrastructural changes. Additionally, an increase in the activity of caspase-3 and caspase-9 was also observed, along with altered expression of apoptotic proteins Bcl-2 and Bax in MCAO animals. MCAO animals also showed significant impairment in cognitive functions assessed using Y maze test. WS pre-supplementation, on the other hand ameliorated MCAO induced oxidative stress, mitochondrial dysfunctions, apoptosis and cognitive impairments. The results show protective effect of WS pre-supplementation in ischemic stroke and are suggestive of its potential application in stroke management.

Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies - potential role of ER stress pathways.

PubMed

Lightfoot, Adam P; Nagaraju, Kanneboyina; McArdle, Anne; Cooper, Robert G

2015-11-01

Discussion of endoplasmic reticulum (ER) stress pathway activation in idiopathic inflammatory myopathies (IIM), and downstream mechanisms causative of muscle weakness. In IIM, ER stress is an important pathogenic process, but how it causes muscle dysfunction is unknown. We discuss relevant pathways modified in response to ER stress in IIM: reactive oxygen species (ROS) generation and mitochondrial dysfunction, and muscle cytokine (myokine) generation. First, ER stress pathway activation can induce changes in mitochondrial bioenergetics and ROS production. ROS can oxidize cellular components, causing muscle contractile dysfunction and energy deficits. Novel compounds targeting ROS generation and/or mitochondrial dysfunction can improve muscle function in several myopathologies. Second, recent research has demonstrated that skeletal muscle produces multiple myokines. It is suggested that these play a role in causing muscle weakness. Myokines are capable of immune cell recruitment, thus contributing to perturbed muscle function. A characterization of myokines in IIM would clarify their pathogenic role, and so identify new therapeutic targets. ER stress pathway activation is clearly of etiological relevance in IIM. Research to better understand mechanisms of weakness downstream of ER stress is now required, and which may discover new therapeutic targets for nonimmune cell-mediated weakness.

Tempol, a Superoxide Dismutase Mimetic Agent, Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice

PubMed Central

Ahmed, Lamiaa A.; Shehata, Nagwa I.; Abdelkader, Noha F.; Khattab, Mahmoud M.

2014-01-01

Background Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice. Methods and Findings Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg) with or without oral administration of tempol (100 mg/kg/day). Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP) content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I–IV activities and mitochondrial nitric oxide synthase (mNOS) protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma. Conclusion This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction. PMID:25271439

Thymol, a dietary monoterpene phenol abrogates mitochondrial dysfunction in β-adrenergic agonist induced myocardial infarcted rats by inhibiting oxidative stress.

PubMed

Nagoor Meeran, M F; Jagadeesh, G S; Selvaraj, P

2016-01-25

Mitochondrial dysfunction has been suggested to be one of the important pathological events in isoproterenol (ISO), a synthetic catecholamine and β-adrenergic agonist induced myocardial infarction (MI). In this context, we have evaluated the impact of thymol against ISO induced oxidative stress and calcium uniporter malfunction involved in the pathology of mitochondrial dysfunction in rats. Male albino Wistar rats were pre and co-treated with thymol (7.5 mg/kg body weight) daily for 7 days. Isoproterenol (100 mg/kg body weight) was subcutaneously injected into rats on 6th and 7th day to induce MI. To explore the extent of cardiac mitochondrial damage, the activities/levels of cardiac marker enzymes, mitochondrial lipid peroxidation products, antioxidants, lipids, calcium, adenosine triphosphate and multi marker enzymes were evaluated. Isoproterenol induced myocardial infarcted rats showed a significant increase in the activities of cardiac diagnostic markers, heart mitochondrial lipid peroxidation, lipids, calcium, and a significant decrease in the activities/levels of heart mitochondrial superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, isocitrate, malate, α-ketoglutarate and NADH-dehydrogenases, cytochrome-C-oxidase, and adenosine triphosphate. Thymol pre and co-treatment showed near normalized effects on all the biochemical parameters studied. Transmission electron microscopic findings and mitochondrial swelling studies confirmed our biochemical findings. The in vitro study also revealed the potent free-radical scavenging activity of thymol. Thus, thymol attenuates the involvement of ISO against oxidative stress and calcium uniporter malfunction associated with mitochondrial dysfunction in rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD.

PubMed

Lerner, Chad A; Sundar, Isaac K; Rahman, Irfan

2016-12-01

Myriad forms of endogenous and environmental stress disrupt mitochondrial function by impacting critical processes in mitochondrial homeostasis, such as mitochondrial redox system, oxidative phosphorylation, biogenesis, and mitophagy. External stressors that interfere with the steady state activity of mitochondrial functions are generally associated with an increase in reactive oxygen species, inflammatory response, and induction of cellular senescence (inflammaging) potentially via mitochondrial damage associated molecular patterns (DAMPS). Many of these are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations. In this review, we highlight the primary mitochondrial quality control mechanisms that are influenced by oxidative stress/redox system, including role of mitochondria during inflammation and cellular senescence, and how mitochondrial dysfunction contributes to the pathogenesis of COPD and its exacerbations via pathogenic stimuli. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis

PubMed Central

Lowes, D. A.; Webster, N. R.; Murphy, M. P.; Galley, H. F.

2013-01-01

Background Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage. Methods Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines. Results MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001). Conclusions Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis. PMID:23381720

Mitochondrial modulators in experimental Huntington's disease: reversal of mitochondrial dysfunctions and cognitive deficits.

PubMed

Mehrotra, Arpit; Kanwal, Abhinav; Banerjee, Sanjay Kumar; Sandhir, Rajat

2015-06-01

Huntington's disease (HD) is a chronic neurodegenerative condition involving impaired mitochondrial functions. The present study evaluates the therapeutic potential of combined administration of mitochondrial modulators: alpha-lipoic acid and acetyl-l-carnitine on mitochondrial dysfunctions in 3-NP-induced HD. Our results reveal 3-NP administration resulted in compromise of mitochondrial functions in terms of: (1) impaired activity of mitochondrial respiratory chain enzymes, altered cytochrome levels, reduced histochemical staining of complex-II and IV, reduced in-gel activity of complex-I to V, and reduced mRNA expression of respiratory chain complexes; (2) enhanced mitochondrial oxidative stress indicated by increased malondialdehyde, protein carbonyls, reactive oxygen species and nitrite levels, along with decreased Mn-superoxide dismutase and catalase activity; (3) mitochondrial structural changes measured by mitochondrial swelling, reduced mitochondrial membrane potential and ultra-structure changes; (4) increased cytosolic cytochrome c levels, caspase-3 and -9 activity along with altered expression of apoptotic proteins (AIF, Bim, Bad, and Bax); and (5) impaired cognitive functions assessed using Morris water maze and Y-maze. Combination of mitochondrial modulators (alpha-lipoic acid + acetyl-l-carnitine) on the other hand ameliorated 3-NP-induced mitochondrial dysfunctions, oxidative stress, histologic alterations, and behavioral deficits, suggesting their therapeutic efficacy in the management of HD. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of mitochondrial dysfunction and oxidative stress on endogenous levels of coenzyme Q(10) in human cells.

PubMed

Yen, Hsiu-Chuan; Chen, Feng-Yuan; Chen, Shih-Wei; Huang, Yu-Hsiang; Chen, Yun-Ru; Chen, Chih-Wei

2011-01-01

Little is known about the regulation of endogenous CoQ(10) levels in response to mitochondrial dysfunction or oxidative stress although exogenous CoQ(10) has been extensively used in humans. In this study, we first demonstrated that acute treatment of antimycin A, an inhibitor of mitochondrial complex III, and the absence of mitochondrial DNA suppressed CoQ(10) levels in human 143B cells. Because these two conditions also enhanced formation of reactive oxygen species (ROS), we further investigated whether oxidative stress or mitochondrial dysfunction primarily contributed to the decrease of CoQ(10) levels. Results showed that H(2)O(2) augmented CoQ(10) levels, but carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a chemical uncoupler, decreased CoQ(10) levels in 143B cells. However, H(2)O(2) and FCCP both increased mRNA levels of multiple COQ genes for biosynthesis of CoQ(10) . Our findings suggest that ROS induced CoQ(10) biosynthesis, whereas mitochondrial energy deficiency caused secondary suppression of CoQ(10) levels possibly due to impaired import of COQ proteins into mitochondria. Copyright © 2011 Wiley Periodicals, Inc.

Lutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorating mitochondrial disruption and oxidative stress.

PubMed

Nataraj, Jagatheesan; Manivasagam, Thamilarasan; Thenmozhi, Arokiasamy Justin; Essa, Musthafa Mohammed

2016-07-01

Mitochondrial dysfunction and oxidative stress-mediated apoptosis plays an important role in various neurodegenerative diseases including Huntington's disease, Parkinson's disease (PD) and Alzheimer's disease (AD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the most widely used neurotoxin mimics the symptoms of PD by inhibiting mitochondrial complex I that stimulates excessive intracellular reactive oxygen species (ROS) and finally leads to mitochondrial-dependent apoptosis. Lutein, a carotenoid of xanthophyll family, is found abundantly in leafy green vegetables such as spinach, kale and in egg yolk, animal fat and human eye retinal macula. Increasing evidence indicates that lutein has offers benefits against neuronal damages during diabetic retinopathy, ischemia and AD by virtue of its mitochondrial protective, antioxidant and anti-apoptotic properties. Male C57BL/6 mice (23-26 g) were randomized and grouped in to Control, MPTP, and Lutein treated groups. Lutein significantly reversed the loss of nigral dopaminergic neurons by increasing the striatal dopamine level in mice. Moreover, lutein-ameliorated MPTP induced mitochondrial dysfunction, oxidative stress and motor abnormalities. In addition, lutein repressed the MPTP-induced neuronal damage/apoptosis by inhibiting the activation of pro-apoptotic markers (Bax, caspases-3, 8 and 9) and enhancing anti-apoptotic marker (Bcl-2) expressions. Our current results revealed that lutein possessed protection on dopaminergic neurons by enhancing antioxidant defense and diminishing mitochondrial dysfunction and apoptotic death, suggesting the potential benefits of lutein for PD treatment.

Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats

PubMed Central

Apaijai, Nattayaporn; Pintana, Hiranya; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2013-01-01

Background and Purpose Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance. Experimental Approach Male Wistar rats weighing 180–200 g, were fed either a normal diet (20% energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into three subgroups to receive vildagliptin (3 mg·kg−1·day−1), sitagliptin (30 mg·kg−1·day−1) or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function and cardiac mitochondrial function were determined. Key Results Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction and completely restored HRV. Conclusions and Implications Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin-resistant rats. PMID:23488656

Mitochondrial Dysfunction and Oxidative Stress Promote Apoptotic Cell Death in the Striatum via Cytochrome c/Caspase-3 Signaling Cascade Following Chronic Rotenone Intoxication in Rats

PubMed Central

Lin, Tsu-Kung; Cheng, Ching-Hsiao; Chen, Shang-Der; Liou, Chia-Wei; Huang, Chi-Ren; Chuang, Yao-Chung

2012-01-01

Parkinson’s disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration. Evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of different pathways, including free-radical generation and dysfunction of the mitochondrial Complex I activity. In Lewis rats, chronic systemic administration of a specific mitochondrial Complex I inhibitor, rotenone (3 mg/kg/day) produced parkinsonism-like symptoms. Increased oxidized proteins and peroxynitrite, and mitochondrial or cytosol translocation of Bim, Bax or cytochrome c in the striatum was observed after 2–4 weeks of rotenone infusion. After 28 days of systemic rotenone exposure, imunohistochemical staining for tyrosine hydroxylase indicated nigrostriatal dopaminergic neuronal cell degeneration. Characteristic histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were present in the striatal neuronal cell after chronic rotenone intoxication. We conclude that chronic rotenone intoxication may enhance oxidative and nitrosative stress that induces mitochondrial dysfunction and ultrastructural damage, resulting in translocation of Bim and Bax from cytosol to mitochondria that contributes to apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade. PMID:22942730

Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia.

PubMed

McCarthy, Cathal; Kenny, Louise C

2016-09-08

Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates.

Vitamin E confers cytoprotective effects on cardiomyocytes under conditions of heat stress by increasing the expression of metallothionein.

PubMed

Wang, Xiaowu; Dong, Wenpeng; Yuan, Binbin; Yang, Yongchao; Yang, Dongpeng; Lin, Xi; Chen, Changfu; Zhang, Weida

2016-05-01

Heat stress (HS) is commonly used to refer to the heat load that an individual is subjected to due to either metabolic heat, or environmental factors, including high temperatures and high humidity levels. HS has been reported to affect and even damage the functioning of various organs; overexposure to high temperatures and high humidity may lead to accidental deaths. It has been suggested that the cardiovascular system is primarily targeted by exposure to HS conditions; the HS-induced dysfunction of cardiomyocytes, which is characterized by mitochondrial dysfunction, may result in the development of cardiovascular diseases. The excessive production of reactive oxygen species (ROS) also participates in mitochondrial dysfunction. However, effective methods for the prevention and treatment of mitochondrial and cardiovascular dysfunction induced by exposure to HS are lacking. In the present study, we hypothesized that vitamin E (VE), an antioxidant, is capable of preventing oxidative stress and mitochondrial injury in cardiomyocytes induced by exposure to HS. The results revealed that pre‑treatment with VE increased the expression of metallothionein (MT), which has previously been reported to confer cytoprotective effects, particularly on the cardiovascular system. Pre-treatment with VE restored mitochondrial function in cardiomyocytes under conditions of HS by increasing the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), and by increasing adenosine triphosphate (ATP) levels. Furthermore, pre-treatment with VE decreased the production of ROS, which was induced by exposure to HS and thus exerted antioxidant effects. In addition, pre-treatment with VE attenuated oxidative stress induced by exposure to HS, as demonstrated by the increased levels of antioxidant enzymes [superoxide dismutase (SOD) and glutathione (GSH)], and by the decreased levels of markers of oxidative injury [malondialdehyde (MDA) and lactate dehydrogenase (LDH)]. Taken together, these findings suggest that pre-treatment with VE can prevent mitochondrial dysfunction and oxidative stress in cardiomyocytes induced by exposure to HS, by increasing the expression of MT.

Early Mitochondrial Adaptations in Skeletal Muscle to Diet-Induced Obesity Are Strain Dependent and Determine Oxidative Stress and Energy Expenditure But Not Insulin Sensitivity

PubMed Central

Sena, Sandra; Sloan, Crystal; Tebbi, Ali; Han, Yong Hwan; O'Neill, Brian T.; Cooksey, Robert C.; Jones, Deborah; Holland, William L.; McClain, Donald A.; Abel, E. Dale

2012-01-01

This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake. PMID:22510273

Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease.

PubMed

Yan, Michael H; Wang, Xinglong; Zhu, Xiongwei

2013-09-01

Alzheimer disease (AD) and Parkinson disease (PD) are the two most common age-related neurodegenerative diseases characterized by prominent neurodegeneration in selective neural systems. Although a small fraction of AD and PD cases exhibit evidence of heritability, among which many genes have been identified, the majority are sporadic without known causes. Molecular mechanisms underlying neurodegeneration and pathogenesis of these diseases remain elusive. Convincing evidence demonstrates oxidative stress as a prominent feature in AD and PD and links oxidative stress to the development of neuronal death and neural dysfunction, which suggests a key pathogenic role for oxidative stress in both AD and PD. Notably, mitochondrial dysfunction is also a prominent feature in these diseases, which is likely to be of critical importance in the genesis and amplification of reactive oxygen species and the pathophysiology of these diseases. In this review, we focus on changes in mitochondrial DNA and mitochondrial dynamics, two aspects critical to the maintenance of mitochondrial homeostasis and function, in relationship with oxidative stress in the pathogenesis of AD and PD. Copyright © 2012 Elsevier Inc. All rights reserved.

Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease

PubMed Central

Yan, Michael H.; Wang, Xinglong; Zhu, Xiongwei

2013-01-01

Alzheimer disease (AD) and Parkinson disease (PD) are the two most common age-related neurodegenerative diseases characterized by prominent neurodegeneration in selective neural systems. Although a small fraction of AD and PD cases exhibit evidence of heritability, among which many genes have been identified, the majority are sporadic without known causes. Molecular mechanisms underlying neurodegeneration and pathogenesis of these diseases remain elusive. Convincing evidence demonstrates oxidative stress as a prominent feature in AD and PD and links oxidative stress to the development of neuronal death and neural dysfunction, which suggests a key pathogenic role for oxidative stress in both AD and PD. Notably, mitochondrial dysfunction is also a prominent feature in these diseases, which is likely to be of critical importance in the genesis and amplification of reactive oxygen species and the pathophysiology of these diseases. In this review, we focus on changes in mitochondrial DNA and mitochondrial dynamics, two aspects critical to the maintenance of mitochondrial homeostasis and function, in relationship with oxidative stress in the pathogenesis of AD and PD. PMID:23200807

Thyroid hormone-induced oxidative stress.

PubMed

Venditti, P; Di Meo, S

2006-02-01

Hypermetabolic state in hyperthyroidism is associated with tissue oxidative injury. Available data indicate that hyperthyroid tissues exhibit an increased ROS and RNS production. The increased mitochondrial ROS generation is a side effect of the enhanced level of electron carriers, by which hyperthyroid tissues increase their metabolic capacity. Investigations of antioxidant defence system have returned controversial results. Moreover, other thyroid hormone-linked biochemical changes increase tissue susceptibility to oxidative challenge, which exacerbates the injury and dysfunction they suffer under stressful conditions. Mitochondria, as a primary target for oxidative stress, might account for hyperthyroidism linked tissue dysfunction. This is consistent with the inverse relationship found between functional recovery of ischemic hyperthyroid hearts and mitochondrial oxidative damage and respiration impairment. However, thyroid hormone-activated mitochondrial mechanisms provide protection against excessive tissue dysfunction, including increased expression of uncoupling proteins, proteolytic enzymes and transcriptional coactivator PGC-1, and stimulate opening of permeability transition pores.

Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity.

PubMed

Arruda, Ana Paula; Pers, Benedicte M; Parlakgül, Güneş; Güney, Ekin; Inouye, Karen; Hotamisligil, Gökhan S

2014-12-01

Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, whereas downregulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering or calcium transport, respectively, improves mitochondrial oxidative capacity and glucose metabolism in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes.

Autophagy of Mitochondria: A Promising Therapeutic Target for Neurodegenerative Disease

PubMed Central

Kamat, Pradip K.; Kalani, Anuradha; Kyles, Philip; Tyagi, Suresh C.; Tyagi, Neetu

2014-01-01

The autophagic process is the only known mechanism for mitochondrial turnover and it has been speculated that dysfunction of autophagy may result in mitochondrial error and cellular stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is associated with cellular oxidative stress and its impact on neuro-degeneration. This impaired autophagic function may be considered as a possible mechanism in the pathogenesis of several neurodegenerative disorders including: Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington disease (HD). It can be suggested that autophagy dysfunction along with oxidative stress are considered main events in neurodegenerative disorders. New therapeutic approaches have now begun to target mitochondria as a potential drug target. This review discusses evidence supporting the notion that oxidative stress and autophagy are intimately associated with neurodegenerative disease pathogenesis. This review also explores new approaches that can prevent mitochondrial dysfunction, improve neurodegenerative etiology, and also offer possible cures to the aforementioned neurodegenerative diseases. PMID:24807843

Inhibition of nuclear factor-κB signal by pyrrolidine dithiocarbamate alleviates lipopolysaccharide-induced acute lung injury

PubMed Central

Yang, Hongfu; Sun, Rongqing; Ma, Ning; Liu, Qilong; Sun, Xiaoge; Zi, Panpan; Wang, Junsheng; Chao, Ke; Yu, Lei

2017-01-01

This study mainly studied the effect of inhibition of nuclear factor-κB (NF-κB) signal by pyrrolidine dithiocarbamate (PDTC) on lipopolysaccharide (LPS)-induced inflammatory response, oxidative stress, and mitochondrial dysfunction in a murine acute lung injury model. The results showed that LPS exposure activated NF-κB and its upstream proteins and caused lung inflammation, oxidative stress, and mitochondrial dysfunction in mice. While inhibition of NF-κB by PDTC adminstration alleviated LPS-induced generation of lymphocytes, IL-1β, and TNF-α. Malondialdehyde, a common oxidative product, was markedly reduced after PDTC treatment in LPS-challenged mice. Furthermore, PDTC alleviated LPS-induced mitochondrial dysfunction via improving ATP synthesis and uncoupling protein 2 expression. In conclusion, inhibition of NF-κB by PDTC alleviated LPS-induced acute lung injury via maintaining inflammatory status, oxidative balance, and mitochondrial function in mice. PMID:28521300

Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines

PubMed Central

Rose, S; Frye, R E; Slattery, J; Wynne, R; Tippett, M; Melnyk, S; James, S J

2014-01-01

There is an increasing recognition that mitochondrial dysfunction is associated with autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction and how mitochondrial abnormalities might interact with other physiological disturbances such as oxidative stress. Reserve capacity is a measure of the ability of the mitochondria to respond to physiological stress. In this study, we demonstrate, for the first time, that lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) have an abnormal mitochondrial reserve capacity before and after exposure to reactive oxygen species (ROS). Ten (44%) of 22 AD LCLs exhibited abnormally high reserve capacity at baseline and a sharp depletion of reserve capacity when challenged with ROS. This depletion of reserve capacity was found to be directly related to an atypical simultaneous increase in both proton-leak respiration and adenosine triphosphate-linked respiration in response to increased ROS in this AD LCL subgroup. In this AD LCL subgroup, 48-hour pretreatment with N-acetylcysteine, a glutathione precursor, prevented these abnormalities and improved glutathione metabolism, suggesting a role for altered glutathione metabolism associated with this type of mitochondrial dysfunction. The results of this study suggest that a significant subgroup of AD children may have alterations in mitochondrial function, which could render them more vulnerable to a pro-oxidant microenvironment as well as intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxins. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors. PMID:24690598

Altered mitochondrial function and oxidative stress in leukocytes of anorexia nervosa patients.

PubMed

Victor, Victor M; Rovira-Llopis, Susana; Saiz-Alarcon, Vanessa; Sangüesa, Maria C; Rojo-Bofill, Luis; Bañuls, Celia; Falcón, Rosa; Castelló, Raquel; Rojo, Luis; Rocha, Milagros; Hernández-Mijares, Antonio

2014-01-01

Anorexia nervosa is a common illness among adolescents and is characterised by oxidative stress. The effects of anorexia on mitochondrial function and redox state in leukocytes from anorexic subjects were evaluated. A multi-centre, cross-sectional case-control study was performed. Our study population consisted of 20 anorexic patients and 20 age-matched controls, all of which were Caucasian women. Anthropometric and metabolic parameters were evaluated in the study population. To assess whether anorexia nervosa affects mitochondrial function and redox state in leukocytes of anorexic patients, we measured mitochondrial oxygen consumption, membrane potential, reactive oxygen species production, glutathione levels, mitochondrial mass, and complex I and III activity in polymorphonuclear cells. Mitochondrial function was impaired in the leukocytes of the anorexic patients. This was evident in a decrease in mitochondrial O2 consumption (P<0.05), mitochondrial membrane potential (P<0.01) and GSH levels (P<0.05), and an increase in ROS production (P<0.05) with respect to control subjects. Furthermore, a reduction of mitochondrial mass was detected in leukocytes of the anorexic patients (P<0.05), while the activity of mitochondrial complex I (P<0.001), but not that of complex III, was found to be inhibited in the same population. Oxidative stress is produced in the leukocytes of anorexic patients and is closely related to mitochondrial dysfunction. Our results lead us to propose that the oxidative stress that occurs in anorexia takes place at mitochondrial complex I. Future research concerning mitochondrial dysfunction and oxidative stress should aim to determine the physiological mechanism involved in this effect and the physiological impact of anorexia.

MitoTEMPO Prevents Oxalate Induced Injury in NRK-52E Cells via Inhibiting Mitochondrial Dysfunction and Modulating Oxidative Stress

PubMed Central

Yu, Xiao; Liu, Jihong

2017-01-01

As one of the major risks for urolithiasis, hyperoxaluria can be caused by genetic defect or dietary intake. And high oxalate induced renal epithelial cells injury is related to oxidative stress and mitochondrial dysfunction. Here, we investigated whether MitoTEMPO, a mitochondria-targeted antioxidant, could protect against oxalate mediated injury in NRK-52E cells via inhibiting mitochondrial dysfunction and modulating oxidative stress. MitoSOX Red was used to determine mitochondrial ROS (mtROS) production. Mitochondrial membrane potential (Δψm) and quantification of ATP synthesis were measured to evaluate mitochondrial function. The protein expression of Nox4, Nox2, and p22 was also detected to explore the effect of oxalate and MitoTEMPO on NADPH oxidase. Our results revealed that pretreatment with MitoTEMPO significantly inhibited oxalate induced lactate dehydrogenase (LDH) and malondialdehyde (MDA) release and decreased oxalate induced mtROS generation. Further, MitoTEMPO pretreatment restored disruption of Δψm and decreased ATP synthesis mediated by oxalate. In addition, MitoTEMPO altered the protein expression of Nox4 and p22 and decreased the protein expression of IL-6 and osteopontin (OPN) induced by oxalate. We concluded that MitoTEMPO may be a new candidate to protect against oxalate induced kidney injury as well as urolithiasis. PMID:28116040

Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis

PubMed Central

Daehn, Ilse; Casalena, Gabriella; Zhang, Taoran; Shi, Shaolin; Fenninger, Franz; Barasch, Nicholas; Yu, Liping; D’Agati, Vivette; Schlondorff, Detlef; Kriz, Wilhelm; Haraldsson, Borje; Bottinger, Erwin P.

2014-01-01

Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS. PMID:24590287

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

PubMed Central

Bavli, Danny; Prill, Sebastian; Ezra, Elishai; Levy, Gahl; Cohen, Merav; Vinken, Mathieu; Vanfleteren, Jan; Jaeger, Magnus; Nahmias, Yaakov

2016-01-01

Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liver-on-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology. PMID:27044092

Mitochondria and heart failure.

PubMed

Murray, Andrew J; Edwards, Lindsay M; Clarke, Kieran

2007-11-01

Energetic abnormalities in cardiac and skeletal muscle occur in heart failure and correlate with clinical symptoms and mortality. It is likely that the cellular mechanism leading to energetic failure involves mitochondrial dysfunction. Therefore, it is crucial to elucidate the causes of mitochondrial myopathy, in order to improve cardiac and skeletal muscle function, and hence quality of life, in heart failure patients. Recent studies identified several potential stresses that lead to mitochondrial dysfunction in heart failure. Chronically elevated plasma free fatty acid levels in heart failure are associated with decreased metabolic efficiency and cellular insulin resistance. Tissue hypoxia, resulting from low cardiac output and endothelial impairment, can lead to oxidative stress and mitochondrial DNA damage, which in turn causes dysfunction and loss of mitochondrial mass. Therapies aimed at protecting mitochondrial function have shown promise in patients and animal models with heart failure. Despite current therapies, which provide substantial benefit to patients, heart failure remains a relentlessly progressive disease, and new approaches to treatment are necessary. Novel pharmacological agents are needed that optimize substrate metabolism and maintain mitochondrial integrity, improve oxidative capacity in heart and skeletal muscle, and alleviate many of the clinical symptoms associated with heart failure.

Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: therapeutic potential of mitochondrially-targeted antioxidants

PubMed Central

Mukhopadhyay, Partha; Horváth, Bėla; Zsengellėr, Zsuzsanna; Bátkai, Sándor; Cao, Zongxian; Kechrid, Malek; Holovac, Eileen; Erdėlyi, Katalin; Tanchian, Galin; Liaudet, Lucas; Stillman, Isaac E.; Joseph, Joy; Kalyanaraman, Balaraman; Pacher, Pál

2012-01-01

Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia-reperfusion (I/R) injury, however its exact role and its spatial-temporal relationship with inflammation are elusive. Herein we explored the spatial-temporal relationship of oxidative/nitrative stress and inflammatory response during the course of hepatic I/R and the possible therapeutic potential of mitochondrial-targeted antioxidants, using a mouse model of segmental hepatic ischemia-reperfusion injury. Hepatic I/R was characterized by early (at 2 hours of reperfusion) mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute pro-inflammatory response (TNF-α, MIP-1αCCL3, MIP-2/CXCL2) without inflammatory cell infiltration, followed by marked neutrophil infiltration and more pronounced secondary wave of oxidative/nitrative stress in the liver (starting from 6 hours of reperfusion and peaking at 24 hours). Mitochondrially-targeted antioxidants, MitoQ or Mito-CP, dose-dependently attenuated I/R-induced liver dysfunction, the early and delayed oxidative and nitrative stress response (HNE/carbonyl adducts, malondialdehyde, 8-OHdG, and 3-nitrotyrosine formation), mitochondrial and histopathological injury/dysfunction, as well as delayed inflammatory cell infiltration and cell death. Mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with hepatic I/R, which may be targeted by novel antioxidants for therapeutic advantage. PMID:22683818

Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I.

PubMed

Rodrigues, Marília Danyelle Nunes; Seminotti, Bianca; Zanatta, Ângela; de Mello Gonçalves, Aline; Bellaver, Bruna; Amaral, Alexandre Umpierrez; Quincozes-Santos, André; Goodman, Stephen Irwin; Woontner, Michael; Souza, Diogo Onofre; Wajner, Moacir

2017-08-01

Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh +/+ ) and glutaryl-CoA dehydrogenase knockout (Gcdh -/- ) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh +/+ and Gcdh -/- mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFα levels, IL1-β and NF-ƙB) in unstimulated astrocytes obtained from these mice. Gcdh -/- mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh +/+ astrocytes. A higher inflammatory response (TNFα, IL1-β and NF-ƙB) was also observed in Gcdh -/- mice astrocytes. These data indicate a higher susceptibility of Gcdh -/- cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients.

Renal Oxidative Stress Induced by Long-Term Hyperuricemia Alters Mitochondrial Function and Maintains Systemic Hypertension

PubMed Central

Cristóbal-García, Magdalena; García-Arroyo, Fernando E.; Arellano-Buendía, Abraham S.; Madero, Magdalena; Rodríguez-Iturbe, Bernardo; Pedraza-Chaverrí, José; Zazueta, Cecilia; Johnson, Richard J.; Sánchez Lozada, Laura-Gabriela

2015-01-01

We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident. PMID:25918583

Cellular stress induced by resazurin leads to autophagy and cell death via production of reactive oxygen species and mitochondrial impairment.

PubMed

Erikstein, Bjarte S; Hagland, Hanne R; Nikolaisen, Julie; Kulawiec, Mariola; Singh, Keshav K; Gjertsen, Bjørn T; Tronstad, Karl J

2010-10-15

Mitochondrial bioenergetics and reactive oxygen species (ROS) often play important roles in cellular stress mechanisms. In this study we investigated how these factors are involved in the stress response triggered by resazurin (Alamar Blue) in cultured cancer cells. Resazurin is a redox reactive compound widely used as reporter agent in assays of cell biology (e.g. cell viability and metabolic activity) due to its colorimetric and fluorimetric properties. In order to investigate resazurin-induced stress mechanisms we employed cells affording different metabolic and regulatory phenotypes. In HL-60 and Jurkat leukemia cells resazurin caused mitochondrial disintegration, respiratory dysfunction, reduced proliferation, and cell death. These effects were preceded by a burst of ROS, especially in HL-60 cells which were also more sensitive and contained autophagic vesicles. Studies in Rho(0) cells (devoid of mitochondrial DNA) indicated that the stress response does not depend on the rates of mitochondrial respiration. The anti-proliferative effect of resazurin was confirmed in native acute myelogenous leukemia (AML) blasts. In conclusion, the data suggest that resazurin triggers cellular ROS production and thereby initiates a stress response leading to mitochondrial dysfunction, reduced proliferation, autophagy, and cell degradation. The ability of cells to tolerate this type of stress may be important in toxicity and chemoresistance. © 2010 Wiley-Liss, Inc.

Effects of Astragalus Polysaccharides on Dysfunction of Mitochondrial Dynamics Induced by Oxidative Stress.

PubMed

Huang, Yan-Feng; Lu, Lu; Zhu, Da-Jian; Wang, Ming; Yin, Yi; Chen, De-Xiu; Wei, Lian-Bo

2016-01-01

This paper studied the chronic fatigue induced by excessive exercise and the restoration effects of Astragalus polysaccharides (APS) on mitochondria. In vivo, we found that excessive exercise could cause oxidative stress statue which led to morphological and functional changes of mitochondria. The changes, including imbalance between mitochondria fusion-fission processes, activation of mitophagy, and decrease of PGC-1α expression, could be restored by APS. We further confirmed in vitro, and what is more, we found that APS may ameliorate mitochondrial dysfunction through Sirt1 pathway. Based on the results, we may figure out part of the molecular mechanism of mitochondrial amelioration by APS.

The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway.

PubMed

Hu, Qiongyuan; Ren, Jianan; Li, Guanwei; Wu, Jie; Wu, Xiuwen; Wang, Gefei; Gu, Guosheng; Ren, Huajian; Hong, Zhiwu; Li, Jieshou

2018-03-14

Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to the early phase of I/R injury and amplify the inflammatory response. MitoQ is a mitochondrially targeted antioxidant that exerts protective effects following I/R injury. In the present study, we aimed to determine whether and how MitoQ protects intestinal epithelial cells (IECs) from I/R injury. In both in vivo and in vitro studies, we found that MitoQ pretreatment downregulated I/R-induced oxidative stress and stabilized the intestinal barrier, as evidenced by MitoQ-treated I/R mice exhibiting attenuated intestinal hyperpermeability, inflammatory response, epithelial apoptosis, and tight junction damage compared to controls. Mechanistically, I/R elevated mitochondrial 8-hydroxyguanine content, reduced mitochondrial DNA (mtDNA) copy number and mRNA transcription levels, and induced mitochondrial disruption in IECs. However, MitoQ pretreatment dramatically inhibited these deleterious effects. mtDNA depletion alone was sufficient to induce apoptosis and mitochondrial dysfunction of IECs. Mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription, was significantly reduced during I/R injury, a phenomenon that was prevented by MitoQ treatment. Furthermore, we observed that thee protective properties of MitoQ were affected by upregulation of cellular antioxidant genes, including HO-1, NQO-1, and γ-GCLC. Transfection with Nrf2 siRNA in IECs exposed to hypoxia/reperfusion conditions partially blocked the effects of MitoQ on mtDNA damage and mitochondrial oxidative stress. In conclusion, our data suggest that MitoQ exerts protective effect on I/R-induced intestinal barrier dysfunction.

Melanocortin 4 Receptor Activation Attenuates Mitochondrial Dysfunction in Skeletal Muscle of Diabetic Rats.

PubMed

Zhang, Hao-Hao; Liu, Jiao; Qin, Gui-Jun; Li, Xia-Lian; Du, Pei-Jie; Hao, Xiao; Zhao, Di; Tian, Tian; Wu, Jing; Yun, Meng; Bai, Yan-Hui

2017-11-01

A previous study has confirmed that the central melanocortin system was able to mediate skeletal muscle AMP-activated protein kinase (AMPK) activation in mice fed a high-fat diet, while activation of the AMPK signaling pathway significantly induced mitochondrial biogenesis. Our hypothesis was that melanocortin 4 receptor (MC4R) was involved in the development of skeletal muscle injury in diabetic rats. In this study, we treated diabetic rats intracerebroventricularly with MC4R agonist R027-3225 or antagonist SHU9119, respectively. Then, we measured the production of reactive oxygen species (ROS), the levels of malondialdehyde (MDA) and glutathione (GSH), the mitochondrial DNA (mtDNA) content and mitochondrial biogenesis, and the protein levels of p-AMPK, AMPK, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), sirtuin 1 (SIRT1), and manganese superoxide dismutase (MnSOD) in the skeletal muscle of diabetic rats. The results showed that there was significant skeletal muscle injury in the diabetic rats along with serious oxidative stress and decreased mitochondrial biogenesis. Treatment with R027-3225 reduced oxidative stress and induced mitochondrial biogenesis in skeletal muscle, and also activated the AMPK-SIRT1-PGC-1α signaling pathway. However, diabetic rats injected with MC4R antagonist SHU9119 showed an aggravated oxidative stress and mitochondrial dysfunction in skeletal muscle. In conclusion, our results revealed that MC4R activation was able to attenuate oxidative stress and mitochondrial dysfunction in skeletal muscle induced by diabetes partially through activating the AMPK-SIRT1-PGC-1α signaling pathway. J. Cell. Biochem. 118: 4072-4079, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells

PubMed Central

Caballano-Infantes, Estefania; Terron-Bautista, José; Beltrán-Povea, Amparo; Cahuana, Gladys M; Soria, Bernat; Nabil, Hajji; Bedoya, Francisco J; Tejedo, Juan R

2017-01-01

Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies. PMID:28289506

Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells.

PubMed

Caballano-Infantes, Estefania; Terron-Bautista, José; Beltrán-Povea, Amparo; Cahuana, Gladys M; Soria, Bernat; Nabil, Hajji; Bedoya, Francisco J; Tejedo, Juan R

2017-02-26

Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca 2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.

Lycopene Prevents Amyloid [Beta]-Induced Mitochondrial Oxidative Stress and Dysfunctions in Cultured Rat Cortical Neurons.

PubMed

Qu, Mingyue; Jiang, Zheng; Liao, Yuanxiang; Song, Zhenyao; Nan, Xinzhong

2016-06-01

Brains affected by Alzheimer's disease (AD) show a large spectrum of mitochondrial alterations at both morphological and genetic level. The causal link between β-amyloid (Aβ) and mitochondrial dysfunction has been established in cellular models of AD. We observed previously that lycopene, a member of the carotenoid family of phytochemicals, could counteract neuronal apoptosis and cell damage induced by Aβ and other neurotoxic substances, and that this neuroprotective action somehow involved the mitochondria. The present study aims to investigate the effects of lycopene on mitochondria in cultured rat cortical neurons exposed to Aβ. It was found that lycopene attenuated Aβ-induced oxidative stress, as evidenced by the decreased intracellular reactive oxygen species generation and mitochondria-derived superoxide production. Additionally, lycopene ameliorated Aβ-induced mitochondrial morphological alteration, opening of the mitochondrial permeability transition pores and the consequent cytochrome c release. Lycopene also improved mitochondrial complex activities and restored ATP levels in Aβ-treated neuron. Furthermore, lycopene prevented mitochondrial DNA damages and improved the protein level of mitochondrial transcription factor A in mitochondria. Those results indicate that lycopene protects mitochondria against Aβ-induced damages, at least in part by inhibiting mitochondrial oxidative stress and improving mitochondrial function. These beneficial effects of lycopene may account for its protection against Aβ-induced neurotoxicity.

Bisphenol A induces oxidative stress and mitochondrial dysfunction in lymphoblasts from children with autism and unaffected siblings.

PubMed

Kaur, Kulbir; Chauhan, Ved; Gu, Feng; Chauhan, Abha

2014-11-01

Autism is a behaviorally defined neurodevelopmental disorder. Although there is no single identifiable cause for autism, roles for genetic and environmental factors have been implicated in autism. Extensive evidence suggests increased oxidative stress and mitochondrial dysfunction in autism. In this study, we examined whether bisphenol A (BPA) is an environmental risk factor for autism by studying its effects on oxidative stress and mitochondrial function in the lymphoblasts. When lymphoblastoid cells from autistic subjects and age-matched unaffected sibling controls were exposed to BPA, there was an increase in the generation of reactive oxygen species (ROS) and a decrease in mitochondrial membrane potential in both groups. A further subdivision of the control group into two subgroups-unaffected nontwin siblings and twin siblings-showed significantly higher ROS levels without any exposure to BPA in the unaffected twin siblings compared to the unaffected nontwin siblings. ROS levels were also significantly higher in the autism vs the unaffected nontwin siblings group. The effect of BPA on three important mtDNA genes-NADH dehydrogenase 1, NADH dehydrogenase 4, and cytochrome b-was analyzed to observe any changes in the mitochondria after BPA exposure. BPA induced a significant increase in the mtDNA copy number in the lymphoblasts from the unaffected siblings group and in the unaffected twin siblings group vs the unaffected nontwin siblings. In all three genes, the mtDNA increase was seen in 70% of the subjects. These results suggest that BPA exposure results in increased oxidative stress and mitochondrial dysfunction in the autistic subjects as well as the age-matched sibling control subjects, particularly unaffected twin siblings. Therefore, BPA may act as an environmental risk factor for autism in genetically susceptible children by inducing oxidative stress and mitochondrial dysfunction. Copyright © 2014 Elsevier Inc. All rights reserved.

Utility of Periodontal exploration in patients with Fibromyalgia

PubMed Central

Santos-García, Rocío; Sánchez-Domínguez, Benito; Cordero, Mario D.; Rios-Santos, José V.; Jaramillo-Santos, María R.; Climent, Mariano H.

2012-01-01

Objetive: Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology, which affects predominantly women. Mitochondrial alteration could have a role in the pathophysilogical mechanisms of inflammatory conditions as FM and periodontitis. The aim of the present study was assay the relationship between both diseases and mitochondrial dysfunction. Patient and Methods: We study the presence of periodontitis in twelve patients diagnosed of FM and mitochondrial dysfunction described. The diagnosis of FM was established according to ACR criteria and clinical symptoms were evaluated using the Fibromyalgia Impact Questionnaire (FIQ) and Beck Depression Inventory (BDI). Results: Only one patients of twelve included and agreed to participate in the study were diagnosed with periodontitis. Conclusions: Pending studies with larger numbers of patients, we can conclude that mitochondrial dysfunction in FM is a itself event not related with periodontitis. Periodontitis could be considered a exclusion criterion in all studies about mitochondrial dysfunction in patients. Key words:Peridontitis, fibromyalgia, mitocondrial dysfunction, oxidative stress. PMID:24558523

KM-34, a Novel Antioxidant Compound, Protects against 6-Hydroxydopamine-Induced Mitochondrial Damage and Neurotoxicity.

PubMed

Fonseca-Fonseca, Luis Arturo; Nuñez-Figueredo, Yanier; Sánchez, Jeney Ramírez; Guerra, Maylin Wong; Ochoa-Rodríguez, Estael; Verdecia-Reyes, Yamila; Hernádez, René Delgado; Menezes-Filho, Noelio J; Costa, Teresa Cristina Silva; de Santana, Wagno Alcântara; Oliveira, Joana L; Segura-Aguilar, Juan; da Silva, Victor Diogenes Amaral; Costa, Silva Lima

2018-01-02

The etiology of Parkinson's disease is not completely understood and is believed to be multifactorial. Neuronal disorders associated to oxidative stress and mitochondrial dysfunction are widely considered major consequences. The aim of this study was to investigate the effect of the synthetic arylidenmalonate derivative 5-(3,4-dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (KM-34), in oxidative stress and mitochondrial dysfunction induced by 6-hydroxydopamine (6-OHDA). Pretreatment (2 h) with KM-34 (1 and 10 μM) markedly attenuated 6-OHDA-induced PC12 cell death in a concentration-dependent manner. KM-34 also inhibited H 2 O 2 generation, mitochondrial swelling, and membrane potential dissipation after 6-OHDA-induced mitochondrial damage. In vivo, KM-34 treatment (1 and 2 mg/Kg) reduced percentage of asymmetry (cylinder test) and increased the vertical exploration (open field) with respect to untreated injured animals; KM-34 also reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in substantia nigra pars compacta. These results demonstrate that KM-34 present biological effects associated to mitoprotection and neuroprotection in vitro, moreover, glial response and neuroprotection in SNpc in vivo. We suggest that KM-34 could be a putative neuroprotective agent for inhibiting the progressive neurodegenerative disease associated to oxidative stress and mitochondrial dysfunction.

p53-PGC-1α Pathway Mediates Oxidative Mitochondrial Damage and Cardiomyocyte Necrosis Induced by Monoamine Oxidase-A Upregulation: Role in Chronic Left Ventricular Dysfunction in Mice

PubMed Central

Villeneuve, Christelle; Guilbeau-Frugier, Céline; Sicard, Pierre; Lairez, Olivier; Ordener, Catherine; Duparc, Thibaut; De Paulis, Damien; Couderc, Bettina; Spreux-Varoquaux, Odile; Tortosa, Florence; Garnier, Anne; Knauf, Claude; Valet, Philippe; Borchi, Elisabetta; Nediani, Chiara; Gharib, Abdallah; Ovize, Michel; Delisle, Marie-Bernadette; Mialet-Perez, Jeanne

2013-01-01

Abstract Aims: Oxidative stress and mitochondrial dysfunction participate together in the development of heart failure (HF). mRNA levels of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that produces hydrogen peroxide (H2O2), increase in several models of cardiomyopathies. Therefore, we hypothesized that an increase in cardiac MAO-A could cause oxidative stress and mitochondrial damage, leading to cardiac dysfunction. In the present study, we evaluated the consequences of cardiac MAO-A augmentation on chronic oxidative damage, cardiomyocyte survival, and heart function, and identified the intracellular pathways involved. Results: We generated transgenic (Tg) mice with cardiac-specific MAO-A overexpression. Tg mice displayed cardiac MAO-A activity levels similar to those found in HF and aging. As expected, Tg mice showed a significant decrease in the cardiac amounts of the MAO-A substrates serotonin and norepinephrine. This was associated with enhanced H2O2 generation in situ and mitochondrial DNA oxidation. As a consequence, MAO-A Tg mice demonstrated progressive loss of cardiomyocytes by necrosis and ventricular failure, which were prevented by chronic treatment with the MAO-A inhibitor clorgyline and the antioxidant N-acetyl-cystein. Interestingly, Tg hearts exhibited p53 accumulation and downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial function. This was concomitant with cardiac mitochondrial ultrastructural defects and ATP depletion. In vitro, MAO-A adenovirus transduction of neonatal cardiomyocytes mimicked the results in MAO-A Tg mice, triggering oxidative stress-dependent p53 activation, leading to PGC-1α downregulation, mitochondrial impairment, and cardiomyocyte necrosis. Innovation and Conclusion: We provide the first evidence that MAO-A upregulation in the heart causes oxidative mitochondrial damage, p53-dependent repression of PGC-1α, cardiomyocyte necrosis, and chronic ventricular dysfunction. Antioxid. Redox Signal. 18, 5–18. PMID:22738191

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

PubMed Central

Liao, Yajin; Dong, Yuan; Cheng, Jinbo

2017-01-01

The mitochondrial calcium uniporter (MCU)—a calcium uniporter on the inner membrane of mitochondria—controls the mitochondrial calcium uptake in normal and abnormal situations. Mitochondrial calcium is essential for the production of adenosine triphosphate (ATP); however, excessive calcium will induce mitochondrial dysfunction. Calcium homeostasis disruption and mitochondrial dysfunction is observed in many neurodegenerative disorders. However, the role and regulatory mechanism of the MCU in the development of these diseases are obscure. In this review, we summarize the role of the MCU in controlling oxidative stress-elevated mitochondrial calcium and its function in neurodegenerative disorders. Inhibition of the MCU signaling pathway might be a new target for the treatment of neurodegenerative disorders. PMID:28208618

Capybara Oil Improves Hepatic Mitochondrial Dysfunction, Steatosis, and Inflammation in a Murine Model of Nonalcoholic Fatty Liver Disease.

PubMed

Marinho, Polyana C; Vieira, Aline B; Pereira, Priscila G; Rabelo, Kíssila; Ciambarella, Bianca T; Nascimento, Ana L R; Cortez, Erika; Moura, Aníbal S; Guimarães, Fernanda V; Martins, Marco A; Barquero, Gonzalo; Ferreira, Rodrigo N; de Carvalho, Jorge J

2018-01-01

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of liver dysfunction worldwide and is commonly associated with obesity. Evidences suggest that NAFLD might be a mitochondrial disease, which contributes to the hepatic steatosis, oxidative stress, cytokine release, and cell death. Capybara oil (CO) is a rich source of polyunsaturated fatty acids (PUFA), which is known to improve inflammation and oxidative stress. In order to determine the effects of CO on NAFLD, C57Bl/6 mice were divided into 3 groups and fed a high-fat diet (HFD) (NAFLD group and NAFLD + CO group) or a control diet (CG group) during 16 weeks. The CO (1.5 g/kg/daily) was administered by gavage during the last 4 weeks of the diet protocol. We evaluated plasma liver enzymes, hepatic steatosis, and cytokine expression in liver as well as hepatocyte ultrastructural morphology and mitochondrial function. CO treatment suppressed hepatic steatosis, attenuated inflammatory response, and decreased plasma alanine aminotransferase (ALT) in mice with NAFLD. CO was also capable of restoring mitochondrial ultrastructure and function as well as balance superoxide dismutase and catalase levels. Our findings indicate that CO treatment has positive effects on NAFLD improving mitochondrial dysfunction, steatosis, acute inflammation, and oxidative stress.

High-fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production

PubMed Central

Ruggiero, Christine; Ehrenshaft, Marilyn; Cleland, Ellen

2011-01-01

Obesity and metabolic syndrome are associated with an increased risk for several diabetic complications, including diabetic nephropathy and chronic kidney diseases. Oxidative stress and mitochondrial dysfunction are often proposed mechanisms in various organs in obesity models, but limited data are available on the kidney. Here, we fed a lard-based high-fat diet to mice to investigate structural changes, cellular and subcellular oxidative stress and redox status, and mitochondrial biogenesis and function in the kidney. The diet induced characteristic changes, including glomerular hypertrophy, fibrosis, and interstitial scarring, which were accompanied by a proinflammatory transition. We demonstrate evidence for oxidative stress in the kidney through 3-nitrotyrosine and protein radical formation on high-fat diet with a contribution from iNOS and NOX-4 as well as increased generation of mitochondrial oxidants on carbohydrate- and lipid-based substrates. The increased H2O2 emission in the mitochondria suggests altered redox balance and mitochondrial ROS generation, contributing to the overall oxidative stress. No major derailments were observed in respiratory function or biogenesis, indicating preserved and initially improved bioenergetic parameters and energy production. We suggest that, regardless of the oxidative stress events, the kidney developed an adaptation to maintain normal respiratory function as a possible response to an increased lipid overload. These findings provide new insights into the complex role of oxidative stress and mitochondrial redox status in the pathogenesis of the kidney in obesity and indicate that early oxidative stress-related changes, but not mitochondrial bioenergetic dysfunction, may contribute to the pathogenesis and development of obesity-linked chronic kidney diseases. PMID:21386058

Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

PubMed Central

He, Quan; Harris, Nicole; Ren, Jun; Han, Xianlin

2014-01-01

Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress. PMID:25247053

Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro.

PubMed

Casalena, Gabriela; Krick, Stefanie; Daehn, Ilse; Yu, Liping; Ju, Wenjun; Shi, Shaolin; Tsai, Su-yi; D'Agati, Vivette; Lindenmeyer, Maja; Cohen, Clemens D; Schlondorff, Detlef; Bottinger, Erwin P

2014-06-01

Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17(+/+) wild-type (WT) and Mpv17(-/-) knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo. Copyright © 2014 the American Physiological Society.

SIRT3 protects hepatocytes from oxidative injury by enhancing ROS scavenging and mitochondrial integrity

USDA-ARS?s Scientific Manuscript database

Evidences of oxidative stress and mitochondrial dysfunction have been recognized in most of clinical and experimental liver diseases. SIRT3, a member of NAD+-dependent deacetylases, is mainly localized in mitochondria. So far, the role of SIRT3 in protecting hepatocytes against oxidative stress rema...

Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders.

PubMed

Islam, Md Torequl

2017-01-01

Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.

Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

PubMed Central

Kaludercic, Nina; Carpi, Andrea; Nagayama, Takahiro; Sivakumaran, Vidhya; Zhu, Guangshuo; Lai, Edwin W.; Bedja, Djahida; De Mario, Agnese; Chen, Kevin; Gabrielson, Kathleen L.; Lindsey, Merry L.; Pacak, Karel; Takimoto, Eiki; Shih, Jean C.; Kass, David A.; Di Lisa, Fabio

2014-01-01

Abstract Aims: Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function. Results: In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B−/−) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics. Innovation: Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function. Conclusion: Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria. Antioxid. Redox Signal. 20, 267–280. PMID:23581564

Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy

PubMed Central

Mukhopadhyay, Partha; Horváth, Béla; Zsengellér, Zsuzsanna; Zielonka, Jacek; Tanchian, Galin; Holovac, Eileen; Kechrid, Malek; Patel, Vivek; Stillman, Isaac E.; Parikh, Samir M.; Joseph, Joy; Kalyanaraman, Balaraman; Pacher, Pál

2011-01-01

Cisplatin is a widely used anti-neoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show that mitochondrial dysfunction is not only a feature of cisplatin nephrotoxicity, but that targeted delivery of superoxide dismutase mimetics to mitochondria largely prevents the renal effects of cisplatin. Cisplatin induced renal oxidative stress, deterioration of mitochondrial structure and function, an intense inflammatory response, histopathological injury, and renal dysfunction. A single systemic dose of mitochondrially-targeted antioxidants, MitoQ or Mito-CP, dose-dependently prevented cisplatin-induced renal dysfunction. Mito-CP also prevented mitochondrial injury and dysfunction, renal inflammation, and tubular injury and apoptosis. Despite being broadly renoprotective against cisplatin, Mito-CP did not diminish cisplatin’s anti-neoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Since similar compounds appear to be safe in humans, mitochondrially-targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity. PMID:22120494

Oxidative stress treatment for clinical trials in neurodegenerative diseases.

PubMed

Ienco, Elena Caldarazzo; LoGerfo, Annalisa; Carlesi, Cecilia; Orsucci, Daniele; Ricci, Giulia; Mancuso, Michelangelo; Siciliano, Gabriele

2011-01-01

Oxidative stress is a metabolic condition arising from imbalance between the production of potentially reactive oxygen species and the scavenging activities. Mitochondria are the main providers but also the main scavengers of cell oxidative stress. The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative diseases is well documented. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. Despite this evidence, human experience with antioxidant neuroprotectants has generally been negative with regards to the clinical progress of disease, with unclear results in biochemical assays. Here we review the antioxidant approaches performed so far in neurodegenerative diseases and the future challenges in modern medicine.

Oxidative stress and mitochondrial dysfunction in Kindler syndrome.

PubMed

Zapatero-Solana, Elisabeth; García-Giménez, Jose Luis; Guerrero-Aspizua, Sara; García, Marta; Toll, Agustí; Baselga, Eulalia; Durán-Moreno, Maria; Markovic, Jelena; García-Verdugo, Jose Manuel; Conti, Claudio J; Has, Cristina; Larcher, Fernando; Pallardó, Federico V; Del Rio, Marcela

2014-12-21

Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease. Patient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy. Patient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state. This is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.

Sodium valproate induces mitochondrial respiration dysfunction in HepG2 in vitro cell model.

PubMed

Komulainen, Tuomas; Lodge, Tiffany; Hinttala, Reetta; Bolszak, Maija; Pietilä, Mika; Koivunen, Peppi; Hakkola, Jukka; Poulton, Joanna; Morten, Karl J; Uusimaa, Johanna

2015-05-04

Sodium valproate (VPA) is a potentially hepatotoxic antiepileptic drug. Risk of VPA-induced hepatotoxicity is increased in patients with mitochondrial diseases and especially in patients with POLG1 gene mutations. We used a HepG2 cell in vitro model to investigate the effect of VPA on mitochondrial activity. Cells were incubated in glucose medium and mitochondrial respiration-inducing medium supplemented with galactose and pyruvate. VPA treatments were carried out at concentrations of 0-2.0mM for 24-72 h. In both media, VPA caused decrease in oxygen consumption rates and mitochondrial membrane potential. VPA exposure led to depleted ATP levels in HepG2 cells incubated in galactose medium suggesting dysfunction in mitochondrial ATP production. In addition, VPA exposure for 72 h increased levels of mitochondrial reactive oxygen species (ROS), but adversely decreased protein levels of mitochondrial superoxide dismutase SOD2, suggesting oxidative stress caused by impaired elimination of mitochondrial ROS and a novel pathomechanism related to VPA toxicity. Increased cell death and decrease in cell number was detected under both metabolic conditions. However, immunoblotting did not show any changes in the protein levels of the catalytic subunit A of mitochondrial DNA polymerase γ, the mitochondrial respiratory chain complexes I, II and IV, ATP synthase, E3 subunit dihydrolipoyl dehydrogenase of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and glutathione peroxidase. Our results show that VPA inhibits mitochondrial respiration and leads to mitochondrial dysfunction, oxidative stress and increased cell death, thus suggesting an essential role of mitochondria in VPA-induced hepatotoxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Ursolic acid improves domoic acid-induced cognitive deficits in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Dong-mei; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, Jiangsu Province; Lu, Jun, E-mail: lu-jun75@163.com

Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitivemore » deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.« less

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening.

PubMed

Yin, Xueyao; Zheng, Fenping; Pan, Qianqian; Zhang, Saifei; Yu, Dan; Xu, Zhiye; Li, Hong

2015-12-01

Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 μmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction. © 2015 Society for Endocrinology.

Glutamate Signaling and Mitochondrial Dysfunction in Models of Parkinson’s Disease

DTIC Science & Technology

2014-03-01

stages of PD, an elevation in synaptically released glutamate leads to persistent activation of NMDARs that synergizes with Cav1 calcium channels to...neurons is attributable to activity -dependent calcium entry through Cav1 channels, resulting in mitochondrial oxidant stress. Although this mechanism...glutamate leads to persistent activation of NMDARs that synergizes with Cav1 calcium channels to significantly increase mitochondrial oxidant stress and

Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies

PubMed Central

d'Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V.; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

2014-01-01

Beyond the disorders recognized as mitochondrial diseases, abnormalities in function and/or ultrastructure of mitochondria have been reported in several unrelated pathologies. These encompass ageing, malformations, and a number of genetic or acquired diseases, as diabetes and cardiologic, haematologic, organ-specific (e.g., eye or liver), neurologic and psychiatric, autoimmune, and dermatologic disorders. The mechanistic grounds for mitochondrial dysfunction (MDF) along with the occurrence of oxidative stress (OS) have been investigated within the pathogenesis of individual disorders or in groups of interrelated disorders. We attempt to review broad-ranging pathologies that involve mitochondrial-specific deficiencies or rely on cytosol-derived prooxidant states or on autoimmune-induced mitochondrial damage. The established knowledge in these subjects warrants studies aimed at elucidating several open questions that are highlighted in the present review. The relevance of OS and MDF in different pathologies may establish the grounds for chemoprevention trials aimed at compensating OS/MDF by means of antioxidants and mitochondrial nutrients. PMID:24876913

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

PubMed Central

Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

2015-01-01

The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

Antibiotic tigecycline enhances cisplatin activity against human hepatocellular carcinoma through inducing mitochondrial dysfunction and oxidative damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Jun; Song, Meijun; Zhou, Mi

Targeting mitochondrial metabolism has been recently demonstrated to be a promising therapeutic strategy for the treatment of various cancer. In this work, we demonstrate that antibiotic tigecycline is selectively against hepatocellular carcinoma (HCC) through inducing mitochondrial dysfunction and oxidative damage. Tigecycline is more effective in inhibiting proliferation and inducing apoptosis of HCC than normal liver cells. Importantly, tigecycline significantly enhances the inhibitory effects of chemotherapeutic drug cisplatin in HCC in vitro and in vivo. Mechanistically, tigecycline specifically inhibits mitochondrial translation as shown by the decreased protein levels of Cox-1 and -2 but not Cox-4 or Grp78, and increased mRNA levels of Cox-1more » and -2 but not Cox-4 in HCC cells exposed to tigecycline. In addition, tigecycline significantly induces mitochondrial dysfunction in HCC cells via decreasing mitochondrial membrane potential, complex I and IV activities, mitochondrial respiration and ATP levels. Tigecycline also increases levels of mitochondrial superoxide, hydrogen peroxide and ROS levels. Consistent with oxidative stress, oxidative damage on DNA, protein and lipid are also observed in tigecycline-treated cells. Importantly, antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of tigecycline, suggesting that oxidative stress is required for the action of tigecycline in HCC cells. We further show that HCC cells have higher level of mitochondrial biogenesis than normal liver cells which might explain the different sensitivity to tigecycline between HCC and normal liver cells. Our work is the first to demonstrate that tigecycline is a promising candidate for HCC treatment and highlight the therapeutic value of targeting mitochondrial metabolism in HCC. - Highlights: • Tigecycline selectively targets HCC in vitro and in vivo. • Tigecycline enhances HCC cell response to chemotherapeutic drug. • Tigecycline inhibits mitochondrial translation and functions in HCC cells. • Tigecycline induces oxidative stress and damage in HCC cells. • Mitochondrial biogenesis and respiration is higher in HCC than normal liver cells.« less

Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats.

PubMed

Akude, Eli; Zherebitskaya, Elena; Chowdhury, Subir K Roy; Smith, Darrell R; Dobrowsky, Rick T; Fernyhough, Paul

2011-01-01

Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons. Alternative pathways involving polyol pathway activity appear to contribute to raised ROS in axons of diabetic neurons under high glucose concentration.

A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress.

PubMed

Chaudhari, Namrata; Talwar, Priti; Parimisetty, Avinash; Lefebvre d'Hellencourt, Christian; Ravanan, Palaniyandi

2014-01-01

Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress.

Coenzyme Q{sub 10} and alpha-tocopherol protect against amitriptyline toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cordero, Mario D.; Dpto. Citologia e Histologia Normal y Patologica, Facultad de Medicina. Universidad de Sevilla. 41009 Sevilla; Moreno-Fernandez, Ana Maria

Since amitriptyline is a very frequently prescribed antidepressant drug, it is not surprising that amitriptyline toxicity is relatively common. Amitriptyline toxic systemic effects include cardiovascular, autonomous nervous, and central nervous systems. To understand the mechanisms of amitriptyline toxicity we studied the cytotoxic effects of amitriptyline treatment on cultured primary human fibroblasts and zebrafish embryos, and the protective role of coenzyme Q{sub 10} and alpha-tocopherol, two membrane antioxidants. We found that amitriptyline treatment induced oxidative stress and mitochondrial dysfunction in primary human fibroblasts. Mitochondrial dysfunction in amitriptyline treatment was characterized by reduced expression levels of mitochondrial proteins and coenzyme Q{sub 10},more » decreased NADH:cytochrome c reductase activity, and a drop in mitochondrial membrane potential. Moreover, and as a consequence of these toxic effects, amitriptyline treatment induced a significant increase in apoptotic cell death activating mitochondrial permeability transition. Coenzyme Q{sub 10} and alpha-tocopherol supplementation attenuated ROS production, lipid peroxidation, mitochondrial dysfunction, and cell death, suggesting that oxidative stress affecting cell membrane components is involved in amitriptyline cytotoxicity. Furthermore, amitriptyline-dependent toxicity and antioxidant protection were also evaluated in zebrafish embryos, a well established vertebrate model to study developmental toxicity. Amitriptyline significantly increased embryonic cell death and apoptosis rate, and both antioxidants provided a significant protection against amitriptyline embryotoxicity.« less

Mitochondrial dysfunction-associated OPA1 cleavage contributes to muscle degeneration: preventative effect of hydroxytyrosol acetate.

PubMed

Wang, X; Li, H; Zheng, A; Yang, L; Liu, J; Chen, C; Tang, Y; Zou, X; Li, Y; Long, J; Liu, J; Zhang, Y; Feng, Z

2014-11-13

Mitochondrial dysfunction contributes to the development of muscle disorders, including muscle wasting, muscle atrophy and degeneration. Despite the knowledge that oxidative stress closely interacts with mitochondrial dysfunction, the detailed mechanisms remain obscure. In this study, tert-butylhydroperoxide (t-BHP) was used to induce oxidative stress on differentiated C2C12 myotubes. t-BHP induced significant mitochondrial dysfunction in a time-dependent manner, accompanied by decreased myosin heavy chain (MyHC) expression at both the mRNA and protein levels. Consistently, endogenous reactive oxygen species (ROS) overproduction triggered by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation inhibitor, was accompanied by decreased membrane potential and decreased MyHC protein content. However, the free radical scavenger N-acetyl-L-cysteine (NAC) efficiently reduced the ROS level and restored MyHC content, suggesting a close association between ROS and MyHC expression. Meanwhile, we found that both t-BHP and FCCP promoted the cleavage of optic atrophy 1 (OPA1) from the long form into short form during the early stages. In addition, the ATPase family gene 3-like 2, a mitochondrial inner membrane protease, was also markedly increased. Moreover, OPA1 knockdown in myotubes was accompanied by decreased MyHC content, whereas NAC failed to prevent FCCP-induced MyHC decrease with OPA1 knockdown, suggesting that ROS might affect MyHC content by modulating OPA1 cleavage. In addition, hydroxytyrosol acetate (HT-AC), an important compound in virgin olive oil, could significantly prevent t-BHP-induced mitochondrial membrane potential and cell viability loss in myotubes. Specifically, HT-AC inhibited t-BHP-induced OPA1 cleavage and mitochondrial morphology changes, accompanied by improvement on mitochondrial oxygen consumption capacity, ATP productive potential and activities of mitochondrial complex I, II and V. Moreover, both t-BHP- and FCCP-induced MyHC decrease was sufficiently inhibited by HT-AC. Taken together, our data provide evidence indicating that mitochondrial dysfunction-associated OPA1 cleavage may contribute to muscle degeneration, and olive oil compounds could be effective nutrients for preventing the development of muscle disorders.

CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation.

PubMed

Gan, Xueqi; Zhang, Ling; Liu, Beilei; Zhu, Zhuoli; He, Yuting; Chen, Junsheng; Zhu, Junfei; Yu, Haiyang

2018-04-20

Bone is a dynamic organ, the bone-forming osteoblasts and bone-resorbing osteoclasts form the physiological basis of bone remodeling process. During pathological process of numerous inflammatory diseases, these two aspects are uncoupled and the balance is usually tipped in favor of bone destruction. Evidence suggests that the inflammatory destruction of bone is mainly attributed to oxidative stress and is closely related to mitochondrial dysfunction. The mechanisms underlying osteogenic dysfunction in inflammation still need further investigation. Reactive oxygen species (ROS) is associated with mitochondrial dysfunction and cellular damage. Here, we reported an unexplored role of cyclophilin D (CypD), the major modulator of mitochondrial permeability transition pore (mPTP), and the CypD-mPTP axis in inflammation-induced mitochondrial dysfunction and bone damage. And the protective effects of knocking down CypD by siRNA interference or the addition of cyclosporin A (CsA), an inhibitor of CypD, were evidenced by rescued mitochondrial function and osteogenic function of osteoblast under tumor necrosis factor-α (TNF-α) treatment. These findings provide new insights into the role of CypD-mPTP-dependent mitochondrial pathway in the inflammatory bone injury. The protective effect of CsA or other moleculars affecting the mPTP formation may hold promise as a potential novel therapeutic strategy for inflammation-induced bone damage via mitochondrial pathways.

The Measurement of Reversible Redox Dependent Post-translational Modifications and Their Regulation of Mitochondrial and Skeletal Muscle Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kramer, Philip A.; Duan, Jicheng; Qian, Wei-Jun

Mitochondrial oxidative stress is a common feature of skeletal myopathies across multiple conditions; however, the mechanism by which it contributes to skeletal muscle dysfunction remains controversial. Oxidative damage to proteins, lipids, and DNA has received the most attention, yet an important role for reversible redox post-translational modifications (PTMs) in pathophysiology is emerging. The possibility that these PTMs can exert dynamic control of muscle function implicates them as a mechanism contributing to skeletal muscle dysfunction in chronic disease. Herein, we discuss the significance of thiol-based redox dependent modifications to mitochondrial, myofibrillar and excitation-contraction (EC) coupling proteins with an emphasis on howmore » these changes could alter skeletal muscle performance under chronically stressed conditions. A major barrier to a better mechanistic understanding of the role of reversible redox PTMs in muscle function is the technical challenges associated with accurately measuring the changes of site-specific redox PTMs. Here we will critically review current approaches with an emphasis on sample preparation artifacts, quantitation, and specificity. Despite these challenges, the ability to accurately quantify reversible redox PTMs is critical to understanding the mechanisms by which mitochondrial oxidative stress contributes to skeletal muscle dysfunction in chronic diseases.« less

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

PubMed Central

Bueno, Marta; Lai, Yen-Chun; Romero, Yair; Brands, Judith; St. Croix, Claudette M.; Kamga, Christelle; Corey, Catherine; Herazo-Maya, Jose D.; Sembrat, John; Lee, Janet S.; Duncan, Steve R.; Rojas, Mauricio; Shiva, Sruti; Chu, Charleen T.; Mora, Ana L.

2014-01-01

Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress. We found that impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Knockdown of PINK1 expression in lung epithelial cells resulted in mitochondria depolarization and expression of profibrotic factors. Moreover, young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. Our data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung. PMID:25562319

A milk-based wolfberry preparation prevents prenatal stress-induced cognitive impairment of offspring rats, and inhibits oxidative damage and mitochondrial dysfunction in vitro.

PubMed

Feng, Zhihui; Jia, Haiqun; Li, Xuesen; Bai, Zhuanli; Liu, Zhongbo; Sun, Lijuan; Zhu, Zhongliang; Bucheli, Peter; Ballèvre, Olivier; Wang, Junkuan; Liu, Jiankang

2010-05-01

Lycium barbarum (Fructus Lycii, Wolfberry, or Gouqi) belongs to the Solanaceae. The red-colored fruits of L. barbarum have been used for a long time as an ingredient in Chinese cuisine and brewing, and also in traditional Chinese herbal medicine for improving health. However, its effects on cognitive function have not been well studied. In the present study, prevention of a milk-based wolfberry preparation (WP) on cognitive dysfunction was tested in a prenatal stress model with rats and the antioxidant mechanism was tested by in vitro experiments. We found that prenatal stress caused a significant decrease in cognitive function (Morris water maze test) in female offspring. Pretreatment of the mother rats with WP significantly prevented the prenatal stress-induced cognitive dysfunction. In vitro studies showed that WP dose-dependently scavenged hydroxyl and superoxide radicals (determined by an electron spin resonance spectrometric assay), and inhibited FeCl(2)/ascorbic acid-induced dysfunction in brain tissue and tissue mitochondria, including increases in reactive oxygen species and lipid peroxidation and decreases in the activities of complex I, complex II, and glutamate cysteine ligase. These results suggest that dietary supplementation with WP may be an effective strategy for preventing the brain oxidative mitochondrial damage and cognitive dysfunction associated with prenatal stress.

Perspectives of drug-based neuroprotection targeting mitochondria.

PubMed

Procaccio, V; Bris, C; Chao de la Barca, J M; Oca, F; Chevrollier, A; Amati-Bonneau, P; Bonneau, D; Reynier, P

2014-05-01

Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

MITOCHONDRIA-TARGETED ANTIOXIDANTS FOR TREATMENT OF PARKINSON’S DISEASE: PRECLINICAL AND CLINICAL OUTCOMES

PubMed Central

Jin, Huajun; Kanthasamy, Arthi; Ghosh, Anamitra; Anantharam, Vellareddy; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G.

2013-01-01

Parkinson’s disease (PD) is a progressive neurodegenerative disease in the elderly, and no cure or disease-modifying therapies exist. Several lines of evidence suggest that mitochondrial dysfunction and oxidative stress have a central role in the dopaminergic neurodegeneration of PD. In this context, mitochondria-targeted therapies that improve mitochondrial function may have great promise in the prevention and treatment of PD. In this review, we discuss the recent developments in mitochondria-targeted antioxidants and their potential beneficial effects as a therapy for ameliorating mitochondrial dysfunction in PD. PMID:24060637

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by beta-amyloid peptide.

PubMed

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, W E

2010-05-01

beta-Amyloid peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Abeta-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Abeta and on neurite outgrowth in PC12 cells were investigated. Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Abeta(1-42). Similar protective effects against Abeta(1-42) were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Abeta load was markedly diminished in the brain of those animals after treatment with piracetam. Abeta production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Abeta-induced mitochondrial dysfunction and Abeta-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Abeta on brain function.

Mitochondrial Dysfunction in Parkinson's Disease: Pathogenesis and Neuroprotection

PubMed Central

Mounsey, Ross B.; Teismann, Peter

2011-01-01

Mitochondria are vitally important organelles involved in an array of functions. The most notable is their prominent role in energy metabolism, where they generate over 90% of our cellular energy in the form of ATP through oxidative phosphorylation. Mitochondria are involved in various other processes including the regulation of calcium homeostasis and stress response. Mitochondrial complex I impairment and subsequent oxidative stress have been identified as modulators of cell death in experimental models of Parkinson's disease (PD). Identification of specific genes which are involved in the rare familial forms of PD has further augmented the understanding and elevated the role mitochondrial dysfunction is thought to have in disease pathogenesis. This paper provides a review of the role mitochondria may play in idiopathic PD through the study of experimental models and how genetic mutations influence mitochondrial activity. Recent attempts at providing neuroprotection by targeting mitochondria are described and their progress assessed. PMID:21234411

C-Phycocyanin Confers Protection against Oxalate-Mediated Oxidative Stress and Mitochondrial Dysfunctions in MDCK Cells

PubMed Central

Farooq, Shukkur M.; Boppana, Nithin B.; Asokan, Devarajan; Sekaran, Shamala D.; Shankar, Esaki M.; Li, Chunying; Gopal, Kaliappan; Bakar, Sazaly A.; Karthik, Harve S.; Ebrahim, Abdul S.

2014-01-01

Oxalate toxicity is mediated through generation of reactive oxygen species (ROS) via a process that is partly dependent on mitochondrial dysfunction. Here, we investigated whether C-phycocyanin (CP) could protect against oxidative stress-mediated intracellular damage triggered by oxalate in MDCK cells. DCFDA, a fluorescence-based probe and hexanoyl-lysine adduct (HEL), an oxidative stress marker were used to investigate the effect of CP on oxalate-induced ROS production and membrane lipid peroxidation (LPO). The role of CP against oxalate-induced oxidative stress was studied by the evaluation of mitochondrial membrane potential by JC1 fluorescein staining, quantification of ATP synthesis and stress-induced MAP kinases (JNK/SAPK and ERK1/2). Our results revealed that oxalate-induced cells show markedly increased ROS levels and HEL protein expression that were significantly decreased following pre-treatment with CP. Further, JC1 staining showed that CP pre-treatment conferred significant protection from mitochondrial membrane permeability and increased ATP production in CP-treated cells than oxalate-alone-treated cells. In addition, CP treated cells significantly decreased the expression of phosphorylated JNK/SAPK and ERK1/2 as compared to oxalate-alone-treated cells. We concluded that CP could be used as a potential free radical-scavenging therapeutic strategy against oxidative stress-associated diseases including urolithiasis. PMID:24691130

Glia Maturation Factor Dependent Inhibition of Mitochondrial PGC-1α Triggers Oxidative Stress-Mediated Apoptosis in N27 Rat Dopaminergic Neuronal Cells.

PubMed

Selvakumar, Govindhasamy Pushpavathi; Iyer, Shankar S; Kempuraj, Duraisamy; Raju, Murugesan; Thangavel, Ramasamy; Saeed, Daniyal; Ahmed, Mohammad Ejaz; Zahoor, Harris; Raikwar, Sudhanshu P; Zaheer, Smita; Zaheer, Asgar

2018-01-30

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting over five million individuals worldwide. The exact molecular events underlying PD pathogenesis are still not clearly known. Glia maturation factor (GMF), a neuroinflammatory protein in the brain plays an important role in the pathogenesis of PD. Mitochondrial dysfunctions and oxidative stress trigger apoptosis leading to dopaminergic neuronal degeneration in PD. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α or PPARGC-α) acts as a transcriptional co-regulator of mitochondrial biogenesis and energy metabolism by controlling oxidative phosphorylation, antioxidant activity, and autophagy. In this study, we found that incubation of immortalized rat dopaminergic (N27) neurons with GMF influences the expression of peroxisome PGC-1α and increases oxidative stress, mitochondrial dysfunction, and apoptotic cell death. We show that incubation with GMF reduces the expression of PGC-1α with concomitant decreases in the mitochondrial complexes. Besides, there is increased oxidative stress and depolarization of mitochondrial membrane potential (MMP) in these cells. Further, GMF reduces tyrosine hydroxylase (TH) expression and shifts Bax/Bcl-2 expression resulting in release of cytochrome-c and increased activations of effector caspase expressions. Transmission electron microscopy analyses revealed alteration in the mitochondrial architecture. Our results show that GMF acts as an important upstream regulator of PGC-1α in promoting dopaminergic neuronal death through its effect on oxidative stress-mediated apoptosis. Our current data suggest that GMF is a critical risk factor for PD and suggest that it could be explored as a potential therapeutic target to inhibit PD progression.

A Molecular Web: Endoplasmic Reticulum Stress, Inflammation, and Oxidative Stress

PubMed Central

Chaudhari, Namrata; Talwar, Priti; Parimisetty, Avinash; Lefebvre d’Hellencourt, Christian; Ravanan, Palaniyandi

2014-01-01

Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress. PMID:25120434

Mitochondrial dysfunction in brain cortex mitochondria of STZ-diabetic rats: effect of l-Arginine.

PubMed

Ortiz, M Del Carmen; Lores-Arnaiz, Silvia; Albertoni Borghese, M Florencia; Balonga, Sabrina; Lavagna, Agustina; Filipuzzi, Ana Laura; Cicerchia, Daniela; Majowicz, Monica; Bustamante, Juanita

2013-12-01

Mitochondrial dysfunction has been implicated in many diseases, including diabetes. It is well known that oxygen free radical species are produced endogenously by mitochondria, and also nitric oxide (NO) by nitric oxide synthases (NOS) associated to mitochondrial membranes, in consequence these organelles constitute main targets for oxidative damage. The aim of this study was to analyze mitochondrial physiology and NO production in brain cortex mitochondria of streptozotocin (STZ) diabetic rats in an early stage of diabetes and the potential effect of L-arginine administration. The diabetic condition was characterized by a clear hyperglycaemic state with loose of body weight after 4 days of STZ injection. This hyperglycaemic state was associated with mitochondrial dysfunction that was evident by an impairment of the respiratory activity, increased production of superoxide anion and a clear mitochondrial depolarization. In addition, the alteration in mitochondrial physiology was associated with a significant decrease in both NO production and nitric oxide synthase type I (NOS I) expression associated to the mitochondrial membranes. An increased level of thiobarbituric acid-reactive substances (TBARS) in brain cortex homogenates from STZ-diabetic rats indicated the presence of lipid peroxidation. L-arginine treatment to diabetic rats did not change blood glucose levels but significantly ameliorated the oxidative stress evidenced by lower TBARS and a lower level of superoxide anion. This effect was paralleled by improvement of mitochondrial respiratory function and a partial mitochondrial repolarization.In addition, the administration of L-arginine to diabetic rats prevented the decrease in NO production and NOSI expression. These results could indicate that exogenously administered L-arginine may have beneficial effects on mitochondrial function, oxidative stress and NO production in brain cortex mitochondria of STZ-diabetic rats.

Oxidative Stress Induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort

PubMed Central

Rose, Shannon; Frye, Richard E.; Slattery, John; Wynne, Rebecca; Tippett, Marie; Pavliv, Oleksandra; Melnyk, Stepan; James, S. Jill

2014-01-01

There is increasing recognition that mitochondrial dysfunction is associated with the autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction or how mitochondrial abnormalities might interact with other physiological disturbances associated with autism, such as oxidative stress. In the current study we used respirometry to examine reserve capacity, a measure of the mitochondrial ability to respond to physiological stress, in lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) as well as age and gender-matched control LCLs. We demonstrate, for the first time, that LCLs derived from children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases intracellular reactive oxygen species (ROS). Specifically, the AD LCLs exhibit a higher reserve capacity at baseline and a sharper depletion of reserve capacity when ROS exposure is increased, as compared to control LCLs. Detailed investigation indicated that reserve capacity abnormalities seen in AD LCLs were the result of higher ATP-linked respiration and maximal respiratory capacity at baseline combined with a marked increase in proton leak respiration as ROS was increased. We further demonstrate that these reserve capacity abnormalities are driven by a subgroup of eight (32%) of 25 AD LCLs. Additional investigation of this subgroup of AD LCLs with reserve capacity abnormalities revealed that it demonstrated a greater reliance on glycolysis and on uncoupling protein 2 to regulate oxidative stress at the inner mitochondria membrane. This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxicants. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors. PMID:24416410

Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis

PubMed Central

Matyas, Csaba; Varga, Zoltan V.; Mukhopadhyay, Partha; Paloczi, Janos; Lajtos, Tamas; Erdelyi, Katalin; Nemeth, Balazs T.; Nan, Mintong; Hasko, Gyorgy; Gao, Bin

2016-01-01

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. PMID:27106042

Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis.

PubMed

Matyas, Csaba; Varga, Zoltan V; Mukhopadhyay, Partha; Paloczi, Janos; Lajtos, Tamas; Erdelyi, Katalin; Nemeth, Balazs T; Nan, Mintong; Hasko, Gyorgy; Gao, Bin; Pacher, Pal

2016-06-01

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. Copyright © 2016 the American Physiological Society.

Role of mitochondrial dysfunction in renal fibrosis promoted by hypochlorite-modified albumin in a remnant kidney model and protective effects of antioxidant peptide SS-31.

PubMed

Zhao, Hao; Liu, Yan-Jun; Liu, Zong-Rui; Tang, Dong-Dong; Chen, Xiao-Wen; Chen, Yi-Hua; Zhou, Ru-Ning; Chen, Si-Qi; Niu, Hong-Xin

2017-06-05

Oxidative stress aggravates renal fibrosis, a pathway involved in almost all forms of chronic kidney disease (CKD). However, the underlying mechanism involved in the pathogenesis of renal oxidative stress has not been completely elucidated. In this study, we explored the role and mechanism of hypochlorite-modified albumin (HOCl-alb) in mediating oxidative stress and fibrotic response in a remnant-kidney rat model. Five-sixths nephrectomy (5/6 NX) was performed on the rats and then the animals were randomly assigned to intravenous treatment with either vehicle alone, or HOCl-rat serum albumin (RSA) in the presence or absence of SS-31 (administered intraperitoneally). A sham-operation control group was set up concurrently. Compared with the control group, 5/6 NX animals displayed marked mitochondrial (mt) dysfunction, as evidenced by decrease of mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and manganese superoxide dismutase (MnSOD) activity, release of cytochrome C (Cyto C) from mitochondria to the cytoplasm, and increase of mitochondrial reactive oxygen species in renal tissues. They also displayed increased levels of HOCl-alb in both plasma and renal tissues. These changes were accompanied by accumulation of extracellular matrix, worsened proteinuria, deteriorated renal function, and a marked increase of macrophage infiltration along with up-regulation of monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-β1 expression. HOCl-alb challenge further exacerbated the above biological effects in 5/6 NX animals, but these adverse effects were prevented by administration of SS-31, a mitochondrial targeted antioxidant peptide. These data suggest that accumulation of HOCl-alb may promote renal inflammation and fibrosis, probably related to mitochondrial oxidative stress and dysfunction and that the mitochondrial targeted peptide SS-31 might be a novel therapy for renal fibrosis and chronic renal failure (CRF). Copyright © 2017 Elsevier B.V. All rights reserved.

Mitochondrial Dysfunction and Its Relationship with mTOR Signaling and Oxidative Damage in Autism Spectrum Disorders.

PubMed

Yui, Kunio; Sato, Atsushi; Imataka, George

2015-01-01

Mitochondria are organelles that play a central role in processes related to cellular viability, such as energy production, cell growth, cell death via apoptosis, and metabolism of reactive oxygen species (ROS). We can observe behavioral abnormalities relevant to autism spectrum disorders (ASDs) and their recovery mediated by the mTOR inhibitor rapamycin in mouse models. In Tsc2(+/-) mice, the transcription of multiple genes involved in mTOR signaling is enhanced, suggesting a crucial role of dysregulated mTOR signaling in the ASD model. This review proposes that the mTOR inhibitor may be useful for the pharmacological treatment of ASD. This review offers novel insights into mitochondrial dysfunction and the related impaired glutathione synthesis and lower detoxification capacity. Firstly, children with ASD and concomitant mitochondrial dysfunction have been reported to manifest clinical symptoms similar to those of mitochondrial disorders, and it therefore shows that the clinical manifestations of ASD with a concomitant diagnosis of mitochondrial dysfunction are likely due to these mitochondrial disorders. Secondly, the adenosine triphosphate (ATP) production/oxygen consumption pathway may be a potential candidate for preventing mitochondrial dysfunction due to oxidative stress, and disruption of ATP synthesis alone may be related to impaired glutathione synthesis. Finally, a decrease in total antioxidant capacity may account for ASD children who show core social and behavioral impairments without neurological and somatic symptoms.

Assessment of hepatoprotective and nephroprotective potential of withaferin A on bromobenzene-induced injury in Swiss albino mice: possible involvement of mitochondrial dysfunction and inflammation.

PubMed

Vedi, Mahima; Sabina, Evan Prince

2016-10-01

Bromobenzene is a well-known environmental toxin which causes liver and kidney damage through CYP450-mediated bio-activation to generate reactive metabolites and, consequently, oxidative stress. The present study aimed to evaluate the possible protective role of withaferin A against bromobenzene-induced liver and kidney damage in mice. Withaferin A (10 mg/kg) was administered orally to the mice for 8 days before intragastric intubation of bromobenzene (10 mmol/kg). As results of this experiment, the levels of liver and kidney functional markers, lipid peroxidation, and cytokines (TNF-α and IL-1β) presented an increase and there was a decrease in anti-oxidant activity in the bromobenzene-treated group of mice. Pre-treatment with withaferin A not only significantly decreased the levels of liver and kidney functional markers and cytokines but also reduced oxidative stress, as evidenced by improved anti-oxidant status. In addition, the mitochondrial dysfunction shown through the decrease in the activities of mitochondrial enzymes and imbalance in the Bax/Bcl-2 expression in the livers and kidneys of bromobenzene-treated mice was effectively prevented by pre-administration of withaferin A. These results validated our conviction that bromobenzene caused liver and kidney damage via mitochondrial pathway and withaferin A provided significant protection against it. Thus, withaferin A may have possible usage in clinical liver and kidney diseases in which oxidative stress and mitochondrial dysfunction may be existent.

Garlic activates SIRT-3 to prevent cardiac oxidative stress and mitochondrial dysfunction in diabetes.

PubMed

Sultana, Md Razia; Bagul, Pankaj K; Katare, Parameshwar B; Anwar Mohammed, Soheb; Padiya, Raju; Banerjee, Sanjay K

2016-11-01

Cardiac complications are major contributor in the mortality of diabetic people. Mitochondrial dysfunctioning is a crucial contributor for the cardiac complications in diabetes, and SIRT-3 remains the major mitochondrial deacetylase. We hypothesized whether garlic has any role on SIRT-3 to prevent mitochondrial dysfunction in diabetic heart. Rats with developed hyperglycemia after STZ injection were divided into two groups; diabetic (Dia) and diabetic+garlic (Dia+Garl). Garlic was administered at a dose of 250mg/kg/day, orally for four weeks. An additional group was maintained to evaluate the effect of raw garlic administration on control rat heart. We have observed altered functioning of cardiac mitochondrial enzymes involved in metabolic pathways, and increased levels of cardiac ROS with decreased activity of catalase and SOD in diabetic rats. Cardiac mRNA expression of TFAM, PGC-1α, and CO1 was also altered in diabetes. In addition, reduced levels of electron transport chain complexes that observed in Dia group were normalized with garlic administration. This indicates the presence of increased oxidative stress with mitochondrial dysfunctioning in diabetic heart. We have observed reduced activity of SIRT3 and increased acetylation of MnSOD. Silencing SIRT-3 in cells also revealed the same. However, administration of garlic improved the SIRT-3 and MnSOD activity, by deacetylating MnSOD. Increased SOD activity was correlated with reduced levels of ROS in garlic-administered rat hearts. Collectively, our results provide an insight into garlic's protection to T1DM heart through activation of SIRT3-MnSOD pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Chronic aerobic exercise training attenuates aortic stiffening and endothelial dysfunction through preserving aortic mitochondrial function in aged rats.

PubMed

Gu, Qi; Wang, Bing; Zhang, Xiao-Feng; Ma, Yan-Ping; Liu, Jian-Dong; Wang, Xiao-Ze

2014-08-01

Aging leads to large vessel arterial stiffening and endothelial dysfunction, which are important determinants of cardiovascular risk. The aim of present work was to assess the effects of chronic aerobic exercise training on aortic stiffening and endothelial dysfunction in aged rats and investigate the underlying mechanism about mitochondrial function. Chronic aerobic exercise training attenuated aortic stiffening with age marked by reduced collagen concentration, increased elastin concentration and reduced pulse wave velocity (PWV), and prevented aging-related endothelial dysfunction marked by improved endothelium-mediated vascular relaxation of aortas in response to acetylcholine. Chronic aerobic exercise training abated oxidative stress and nitrosative stress in aortas of aged rats. More importantly, we found that chronic aerobic exercise training in old rats preserved aortic mitochondrial function marked by reduced reactive oxygen species (ROS) formation and mitochondrial swelling, increased ATP formation and mitochondrial DNA content, and restored activities of complexes I and III and electron-coupling capacity between complexes I and III and between complexes II and III. In addition, it was found that chronic aerobic exercise training in old rats enhanced protein expression of uncoupling protein 2 (UCP-2), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), manganese superoxide dismutase (Mn-SOD), aldehyde dehydrogenase 2 (ALDH-2), prohibitin (PHB) and AMP-activated kinase (AMPK) phosphorylation in aortas. In conclusion, chronic aerobic exercise training preserved mitochondrial function in aortas, which, at least in part, explained the aorta-protecting effects of exercise training in aging. Copyright © 2014 Elsevier Inc. All rights reserved.

Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness

PubMed Central

Shetty, Geetha A.; Hattiangady, Bharathi; Upadhya, Dinesh; Bates, Adrian; Attaluri, Sahithi; Shuai, Bing; Kodali, Maheedhar; Shetty, Ashok K.

2017-01-01

Memory and mood dysfunction are the key symptoms of Gulf war illness (GWI), a lingering multi-symptom ailment afflicting >200,000 veterans who served in the Persian Gulf War-1. Research probing the source of the disease has demonstrated that concomitant exposures to anti-nerve gas agent pyridostigmine bromide (PB), pesticides, and war-related stress are among the chief causes of GWI. Indeed, exposures to GWI-related chemicals (GWIR-Cs) and mild stress in animal models cause memory and mood impairments alongside reduced neurogenesis and chronic low-level inflammation in the hippocampus. In the current study, we examined whether exposure to GWIR-Cs and stress causes chronic changes in the expression of genes related to increased oxidative stress, mitochondrial dysfunction, and inflammation in the hippocampus. We also investigated whether GWI is linked with chronically increased activation of Nrf2 (a master regulator of antioxidant response) in the hippocampus, and inflammation and enhanced oxidative stress at the systemic level. Adult male rats were exposed daily to low-doses of PB and pesticides (DEET and permethrin), in combination with 5 min of restraint stress for 4 weeks. Analysis of the hippocampus performed 6 months after the exposure revealed increased expression of many genes related to oxidative stress response and/or antioxidant activity (Hmox1, Sepp1, and Srxn1), reactive oxygen species metabolism (Fmo2, Sod2, and Ucp2) and oxygen transport (Ift172 and Slc38a1). Furthermore, multiple genes relevant to mitochondrial respiration (Atp6a1, Cox6a1, Cox7a2L, Ndufs7, Ndufv1, Lhpp, Slc25a10, and Ucp1) and neuroinflammation (Nfkb1, Bcl6, Csf2, IL6, Mapk1, Mapk3, Ngf, N-pac, and Prkaca) were up-regulated, alongside 73–88% reduction in the expression of anti-inflammatory genes IL4 and IL10, and nuclear translocation and increased expression of Nrf2 protein. These hippocampal changes were associated with elevated levels of pro-inflammatory cytokines and chemokines (Tnfa, IL1b, IL1a, Tgfb, and Fgf2) and lipid peroxidation byproduct malondialdehyde in the serum, suggesting the presence of an incessant systemic inflammation and elevated oxidative stress. These results imply that chronic oxidative stress, inflammation, and mitochondrial dysfunction in the hippocampus, and heightened systemic inflammation and oxidative stress likely underlie the persistent memory and mood dysfunction observed in GWI. PMID:28659758

Downregulation of peroxiredoxin-3 by hydrophobic bile acid induces mitochondrial dysfunction and cellular senescence in human trophoblasts

PubMed Central

Wu, Wei-Bin; Menon, Ramkumar; Xu, Yue-Ying; Zhao, Jiu-Ru; Wang, Yan-Lin; Liu, Yuan; Zhang, Hui-Juan

2016-01-01

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder characterised by raised bile acids in foetal-maternal circulation, which threatens perinatal health. During the progression of ICP, the effect of oxidative stress is underscored. Peroxiredoxin-3 (PRDX3) is a mitochondrial antioxidant enzyme that is crucial to balance intracellular oxidative stress. However, the role of PRDX3 in placental trophoblast cells under ICP is not fully understood. We demonstrated that the level of PRDX3 was downregulated in ICP placentas as well as bile acids–treated trophoblast cells and villous explant in vitro. Toxic levels of bile acids and PRDX3 knockdown induced oxidative stress and mitochondrial dysfunction in trophoblast cells. Moreover, silencing of PRDX3 in trophoblast cell line HTR8/SVneo induced growth arrest and cellular senescence via activation of p38-mitogen-activated protein kinase (MAPK) and induction of p21WAF1/CIP and p16INK4A. Additionally, enhanced cellular senescence, determined by senescence-associated beta-galactosidase staining, was obviously attenuated by p38-MAPK inhibitor SB203580. Our data determined that exposure to bile acid decreased PRDX3 level in human trophoblasts. PRDX3 protected trophoblast cells against mitochondrial dysfunction and cellular senescence induced by oxidative stress. Our results suggest that decreased PRDX3 by excessive bile acids in trophoblasts plays a critical role in the pathogenesis and progression of ICP. PMID:27958341

Mitochondrial Dysfunction in Retinal Diseases

PubMed Central

Barot, Megha; Gokulgandhi, Mitan R.; Mitra, Ashim K.

2015-01-01

The mitochondrion is a vital intracellular organelle for retinal cell function and survival. There is growing confirmation to support an association between mitochondrial dysfunction and a number of retinal degenerations. Investigations have also unveiled mitochondrial genomic instability as one of the contributing factors for age-related retinal pathophysiology. This review highlights the role of mitochondrial dysfunction originating from oxidative stress in the etiology of retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration (AMD). Moreover, mitochondrial DNA (mtDNA) damage associated with AMD due to susceptibility of mtDNA to oxidative damage and failure of mtDNA repair pathways is also highlighted in this review. The susceptibility of neural retina and retinal pigment epithelium (RPE) mitochondria to oxidative damage with ageing appears to be a major factor in retinal degeneration. It thus appears that the mitochondrion is a weak link in the antioxidant defenses of retinal cells. In addition, failure of mtDNA repair pathways can also specifically contribute towards pathogenesis of AMD. This review will further summarize the prospective role of mitochondria targeting therapeutic agents for the treatment of retinal disease. Mitochondria based drug targeting to diminish oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of various retinal degenerative diseases. PMID:21978133

Mitochondrial dysfunction in retinal diseases.

PubMed

Barot, Megha; Gokulgandhi, Mitan R; Mitra, Ashim K

2011-12-01

The mitochondrion is a vital intracellular organelle for retinal cell function and survival. There is growing confirmation to support an association between mitochondrial dysfunction and a number of retinal degenerations. Investigations have also unveiled mitochondrial genomic instability as one of the contributing factors for age-related retinal pathophysiology. This review highlights the role of mitochondrial dysfunction originating from oxidative stress in the etiology of retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration (AMD). Moreover, mitochondrial DNA (mtDNA) damage associated with AMD due to susceptibility of mtDNA to oxidative damage and failure of mtDNA repair pathways is also highlighted in this review. The susceptibility of neural retina and retinal pigment epithelium (RPE) mitochondria to oxidative damage with ageing appears to be a major factor in retinal degeneration. It thus appears that the mitochondrion is a weak link in the antioxidant defenses of retinal cells. In addition, failure of mtDNA repair pathways can also specifically contribute towards pathogenesis of AMD. This review will further summarize the prospective role of mitochondria targeting therapeutic agents for the treatment of retinal disease. Mitochondria based drug targeting to diminish oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of various retinal degenerative diseases.

Neuroprotective effect of asiatic acid on rotenone-induced mitochondrial dysfunction and oxidative stress-mediated apoptosis in differentiated SH-SYS5Y cells.

PubMed

Nataraj, Jagatheesan; Manivasagam, Thamilarasan; Justin Thenmozhi, Arokiasamy; Essa, Musthafa Mohamed

2017-07-01

Parkinson's disease (PD) is a chronic neurodegenerative disease, manifested due to the loss of dopaminergic neurons, which ultimately leads to impaired movement in elderly populations. The pathogenesis of PD is associated with numerous factors including oxidative stress, mitochondrial dysfunction and apoptosis. There is no effective therapy available to cure or halt the progression of this disease still now. Asiatic acid (AA) is a triterpene extracted from Centella asiatica has been reported as an antioxidant and anti-inflammatory agent, that offers neuroprotection against glutamate toxicity. Therefore, in this study, we have investigated the effect of AA in a rotenone (an inhibitor of mitochondrial complex I) induced in vitro model of PD. Following the exposure of SH-SY5Y cells to rotenone, there was a marked overproduction of ROS, mitochondrial dysfunction (as indexed by the decrease in mitochondrial membrane potential) and apoptosis (Hoechst and dual staining, comet assay; expressions of pro-apoptotic and anti-apoptotic indices). Pre-treatment with AA reversed these changes might be due to its antioxidant, mitoprotective and anti-apoptotic properties. However further extensive studies on in vivo models of PD are warranted to prove AA neuroprotective effect before entering into the clinical trial.

Melatonin and human mitochondrial diseases

PubMed Central

Sharafati-Chaleshtori, Reza; Shirzad, Hedayatollah; Rafieian-Kopaei, Mahmoud; Soltani, Amin

2017-01-01

Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function. Melatonin increases the permeability of membranes and is the stimulator of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also acts as an inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes. Melatonin has been shown to retard aging and inhibit neurodegenerative disorders, ischemia/reperfusion, septic shock, diabetes, cancer, and other complications related to oxidative stress. The purpose of the current study, other than introducing melatonin, was to present the recent findings on clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, gastrointestinal diseases, and diseases related to brain function. PMID:28400824

Improved mitochondrial function underlies the protective effect of pirfenidone against tubulointerstitial fibrosis in 5/6 nephrectomized rats.

PubMed

Chen, Jun-Feng; Liu, Hong; Ni, Hai-Feng; Lv, Lin-Li; Zhang, Ming-Hui; Zhang, Ai-Hua; Tang, Ri-Ning; Chen, Ping-Sheng; Liu, Bi-Cheng

2013-01-01

Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex Ι inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells.

PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease

PubMed Central

Mouton-Liger, Francois; Jacoupy, Maxime; Corvol, Jean-Christophe; Corti, Olga

2017-01-01

Parkinson's disease (PD) is one of the most frequent neurodegenerative disease caused by the preferential, progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta. PD is characterized by a multifaceted pathological process involving protein misfolding, mitochondrial dysfunction, neuroinflammation and metabolism deregulation. The molecular mechanisms governing the complex interplay between the different facets of this process are still unknown. PARK2/Parkin and PARK6/PINK1, two genes responsible for familial forms of PD, act as a ubiquitous core signaling pathway, coupling mitochondrial stress to mitochondrial surveillance, by regulating mitochondrial dynamics, the removal of damaged mitochondrial components by mitochondria-derived vesicles, mitophagy, and mitochondrial biogenesis. Over the last decade, PINK1/Parkin-dependent mitochondrial quality control emerged as a pleiotropic regulatory pathway. Loss of its function impinges on a number of physiological processes suspected to contribute to PD pathogenesis. Its role in the regulation of innate immunity and inflammatory processes stands out, providing compelling support to the contribution of non-cell-autonomous immune mechanisms in PD. In this review, we illustrate the central role of this multifunctional pathway at the crossroads between mitochondrial stress, neuroinflammation and metabolism. We discuss how its dysfunction may contribute to PD pathogenesis and pinpoint major unresolved questions in the field. PMID:28507507

Improved Mitochondrial Function Underlies the Protective Effect of Pirfenidone against Tubulointerstitial Fibrosis in 5/6 Nephrectomized Rats

PubMed Central

Chen, Jun-Feng; Liu, Hong; Ni, Hai-Feng; Lv, Lin-Li; Zhang, Ming-Hui; Zhang, Ai-Hua; Tang, Ri-Ning; Chen, Ping-Sheng; Liu, Bi-Cheng

2013-01-01

Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex Ι inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells. PMID:24349535

Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury

PubMed Central

Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Ban, Tae Hyun; Jang, In-Ae; Yoon, Hye Eun; Park, Cheol Whee; Chang, Yoon Sik

2018-01-01

Background. Two important issues in the aging kidney are mitochondrial dysfunction and oxidative stress. An Nrf2 activator, resveratrol, is known to have various effects. Resveratrol may prevent inflammation and oxidative stress by activating Nrf2 and SIRT1 signaling. We examined whether resveratrol could potentially ameliorate the cellular condition, such as renal injury due to cellular oxidative stress and mitochondrial dysfunction caused by aging. Methods. Male 18-month-old C57BL/6 mice were used. Resveratrol (40 mg/kg) was administered to aged mice for 6 months. We compared histological changes, oxidative stress, and aging-related protein expression in the kidney between the resveratrol-treated group (RSV) and the control group (cont). We performed experiments using small-interfering RNAs (siRNAs) for Nrf2 and SIRT1 in cultured HK2 cells. Results. Resveratrol improved renal function, proteinuria, histological changes and inflammation in aging mice. Also, expression of Nrf2-HO-1-NOQ-1 signaling and SIRT1-AMPK-PGC-1α signaling was increased in the RSV group. Transfection with Nrf2 and SIRT1 siRNA prevented resveratrol-induced anti-oxidative effect in HK2 cells in media treated with H2O2. Conclusions. Activation of the Nrf2 and SIRT1 signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Pharmacological targeting of Nrf2 signaling molecules may reduce the pathologic changes of aging in the kidney. PMID:29326403

Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction

PubMed Central

Qu, Kai; Shen, Nai-ying; Xu, Xin-sen; Su, Hai-bo; Wei, Ji-chao; Tai, Ming-hui; Meng, Fan-di; Zhou, Lei; Zhang, Yue-lang; Liu, Chang

2013-01-01

Aim: To elucidate the molecular mechanisms underlying the immunosuppressive effects of emodin isolated from Rheum palmatum L. Methods: Human T cells were isolated from the peripheral venous blood of 10 healthy adult donors. Cell viability was analyzed with MTT assay. AO/EB and Annexin V/PI staining and DNA damage assay were used to detect cell apoptosis. Fluorescence staining was used to detect the levels of ROS, the mitochondrial membrane potential and intracellular Ca2+. Colorimetry was used to detect the levels of MDA and total SOD and GSH/GSSG ratio. The expression and activity of caspase-3, -4, and -9 were detected with Western blotting and a fluorometric assay. Western blotting was also used to detect the expression of Bcl-2, Bax, cytochrome C, and endoplasmic reticulum (ER) markers. Results: Emodin (1, 10, and 100 μmol/L) inhibited the growth of human T cells and induced apoptosis in dose- and time dependent manners. Emodin triggered ER stress and significantly elevated intracellular free Ca2+ in human T cells. It also disrupted mitochondrial membrane potential, and increased cytosolic level of cytochrome C, and the levels of activated cleavage fragments of caspase-3, -4, and -9 in human T cells. Furthermore, emodin significantly increased the levels of ROS and MDA, inhibited both SOD level and GSH/GSSG ratio in human T cells, whereas co-incubation with the ROS scavenger N-acetylcysteine (NAC, 20 μmol/L) almost completely blocked emodin-induced ER stress and mitochondrial dysfunction in human T cells, and decreased the caspase cascade-mediated apoptosis. Conclusion: Emodin exerts immunosuppressive actions at least partly by inducing apoptosis of human T cells, which is triggered by ROS-mediated ER stress and mitochondrial dysfunction. PMID:23811723

Hepatocellular toxicity of oxalicumone A via oxidative stress injury and mitochondrial dysfunction in healthy human liver cells.

PubMed

Shi, Si; Yao, Limei; Guo, Kunbin; Wang, Xiangyu; Wang, Qi; Li, Weirong

2018-01-01

The marine‑derived oxalicumone A (POA) has been demonstrated as a potent anti‑tumor bioactive agent for a variety of human carcinoma, but to the best of our knowledge, remains to be evaluated in healthy liver cells. As many drugs distribute preferentially in the liver, the present study aimed to investigate the effects of POA on apoptosis, oxidative stress and mitochondrial function in L‑02 healthy liver cells. A Cell‑Counting kit‑8 assay demonstrated that POA inhibits the proliferation of L‑02 cells in a dose‑ and time‑dependent manner. Furthermore, POA induced apoptosis by increasing the percentage of cells in early apoptosis and the sub‑G1 cell cycle, along with causing S‑phase arrest in L‑02 cells. Additionally, POA activated caspase 3, increased the protein expression levels of Fas ligand and B‑cell lymphoma X‑associated protein, and decreased the expression of the anti‑apoptotic protein B‑cell lymphoma 2. POA additionally reduced the content of GSH and the activity of superoxide dismutase, elevated malondialdehyde and nitric oxide levels, increased reactive oxygen species production and the levels of alanine aminotransferase and aspartate aminotransferase, which suggested that POA induced lipid peroxidation injury in L‑02 cells and that oxidative stress serves an important role. Furthermore, POA caused alternations of mitochondrial function, including an abrupt depletion of adenosine triphosphate synthesis, mitochondrial permeability transition pore opening and depletion of mitochondrial membrane potential in L‑02 cells. These data suggested that POA exerts cytotoxicity, at least in part, by inducing oxidative stress, mitochondrial dysfunction, and eventually apoptosis. Changes in mitochondrial function and oxidative stress by POA may therefore be critical in POA‑induced toxicity in L‑02 cells.

Ammonia-induced mitochondrial dysfunction and energy metabolism disturbances in isolated brain and liver mitochondria, and the effect of taurine administration: relevance to hepatic encephalopathy treatment

PubMed Central

Niknahad, Hossein; Jamshidzadeh, Akram; Zarei, Mahdi; Ommati, Mohammad Mehdi

2017-01-01

Introduction Ammonia-induced oxidative stress, mitochondrial dysfunction, and energy crisis are known as some the major mechanisms of brain injury in hepatic encephalopathy (HE). Hyperammonemia also affects the liver and hepatocytes. Therefore, targeting mitochondria seems to be a therapeutic point of intervention in the treatment of HE. Taurine is an abundant amino acid in the human body. Several biological functions including the mitochondrial protective properties are attributed to this amino acid. The aim of this study is to evaluate the effect of taurine administration on ammonia-induced mitochondrial dysfunction. Material and methods Isolated mice liver and brain mitochondria were exposed to different concentrations of ammonia (1, 5, 10, and 20 mM) and taurine (1, 5, and 10 mM), and several mitochondrial indices were assessed. Results It was found that ammonia inhibited mitochondrial dehydrogenases activity caused collapse of mitochondrial membrane potential (MMP), induced mitochondrial swelling (MPP), and increased reactive oxygen species (ROS) in isolated liver and brain mitochondria. Furthermore, a significant amount of lipid peroxidation (LPO), along with glutathione (GSH) and ATP depletion, was detected in ammonia exposed mitochondria. Taurine administration (5 and 10 mM) mitigated ammonia-induced mitochondrial dysfunction. Conclusions The current investigation demonstrates that taurine is instrumental in preserving brain and liver mitochondrial function in a hyperammonemic environment. The data suggest taurine as a potential protective agent with a therapeutic capability against hepatic encephalopathy and hyperammonemia. PMID:29062904

Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis.

PubMed

Schröder, Torsten; Kucharczyk, David; Bär, Florian; Pagel, René; Derer, Stefanie; Jendrek, Sebastian Torben; Sünderhauf, Annika; Brethack, Ann-Kathrin; Hirose, Misa; Möller, Steffen; Künstner, Axel; Bischof, Julia; Weyers, Imke; Heeren, Jörg; Koczan, Dirk; Schmid, Sebastian Michael; Divanovic, Senad; Giles, Daniel Aaron; Adamski, Jerzy; Fellermann, Klaus; Lehnert, Hendrik; Köhl, Jörg; Ibrahim, Saleh; Sina, Christian

2016-04-01

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mt(FVB/N) mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8). At baseline conditions, C57BL/6J-mt(FVB/N) mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mt(FVB/N) mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH.

Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis

PubMed Central

Schröder, Torsten; Kucharczyk, David; Bär, Florian; Pagel, René; Derer, Stefanie; Jendrek, Sebastian Torben; Sünderhauf, Annika; Brethack, Ann-Kathrin; Hirose, Misa; Möller, Steffen; Künstner, Axel; Bischof, Julia; Weyers, Imke; Heeren, Jörg; Koczan, Dirk; Schmid, Sebastian Michael; Divanovic, Senad; Giles, Daniel Aaron; Adamski, Jerzy; Fellermann, Klaus; Lehnert, Hendrik; Köhl, Jörg; Ibrahim, Saleh; Sina, Christian

2016-01-01

Objective Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. Methods To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mtFVB/N mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8). Results At baseline conditions, C57BL/6J-mtFVB/N mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mtFVB/N mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. Conclusions We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH. PMID:27069868

Tetrahydrocannabinol induces brain mitochondrial respiratory chain dysfunction and increases oxidative stress: a potential mechanism involved in cannabis-related stroke.

PubMed

Wolff, Valérie; Schlagowski, Anna-Isabel; Rouyer, Olivier; Charles, Anne-Laure; Singh, François; Auger, Cyril; Schini-Kerth, Valérie; Marescaux, Christian; Raul, Jean-Sébastien; Zoll, Joffrey; Geny, Bernard

2015-01-01

Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities V max (complexes I, III, and IV activities), V succ (complexes II, III, and IV activities), V tmpd (complex IV activity), together with mitochondrial coupling (V max/V 0), were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H2O2) production, measured with Amplex Red. THC significantly decreased V max (-71%; P < 0.0001), V succ (-65%; P < 0.0001), and V tmpd (-3.5%; P < 0.001). Mitochondrial coupling (V max/V 0) was also significantly decreased after THC exposure (1.8±0.2 versus 6.3±0.7; P < 0.001). Furthermore, THC significantly enhanced H2O2 production by cerebral mitochondria (+171%; P < 0.05) and mitochondrial free radical leak was increased from 0.01±0.01 to 0.10±0.01% (P < 0.001). Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patient's vulnerability to stroke.

Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy.

PubMed

Cikankova, Tereza; Sigitova, Ekaterina; Zverova, Martina; Fisar, Zdenek; Raboch, Jiri; Hroudova, Jana

2017-01-01

Exact pathophysiological mechanisms of bipolar disorder have not been sufficiently clarified. We review the evidence of mitochondrial dysfunctions on the relation between both disease and pharmacotherapy. Mitochondria produce the most of energy-rich molecules of adenosine triphosphate (ATP), apart from energy production they are involved in other functions: regulation of free radicals, antioxidant defenses, lipid peroxidation, calcium metabolism and participate in the intrinsic pathway of apoptosis. According to increasing evidence dysfunctions of mitochondria are associated with affective disorders, a hypothesis of impaired mitochondrial functions has been proposed in bipolar disorder pathogenesis. Mitochondrial DNA mutations and/or polymorphisms, impaired phospholipid metabolism and glycolytic shift, decrease in ATP production, increased oxidative stress and changes of intracellular calcium are concerned in mood disorders and effects of mood stabilizers. Recent studies have also provided data about the positive effects of chronic treatment by mood stabilizers on mitochondrial functions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

EFFECTS OF THE ORGANOCHLORINE PESTICIDE METHOXYCHLOR ON DOPAMINE METABOLITES AND TRANSPORTERS IN THE MOUSE BRAIN

PubMed Central

Schuh, Rosemary A.; Richardson, Jason R.; Gupta, Rupesh K.; Flaws, Jodi A.; Fiskum, Gary

2009-01-01

Pesticide exposure has been suggested as an increased risk factor in developing Parkinson’s disease (PD). While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days. Following treatment, we observed a dose-related increase in protein carbonyl levels in non-synaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16–31%), which were accompanied by decreased levels of the dopamine transporter (DAT; 35–48%) and the vesicular monoamine transporter 2 (VMAT2; 21–44%). Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggests that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly-exposed populations. PMID:19459224

Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Areti, Aparna; Komirishetty, Prashanth; Kumar, Ash

Oxaliplatin use as chemotherapeutic agent is frequently limited by cumulative neurotoxicity which may compromise quality of life. Reports relate this neurotoxic effect to oxidative stress and mitochondrial dysfunction in peripheral nerves and dorsal root ganglion (DRG). Carvedilol is an antihypertensive drug, has also been appreciated for its antioxidant and mitoprotective properties. Carvedilol co-treatment did not reduce the anti-tumor effects of oxaliplatin in human colon cancer cells (HT-29), but exhibited free radical scavenging activity against oxaliplatin-induced oxidative stress in neuronal cells (Neuro-2a). Hence, the present study was designed to investigate the effect of carvedilol in the experimental model of oxaliplatin-induced peripheralmore » neuropathy (OIPN) in Sprague-Dawley rats. Oxaliplatin reduced the sensory nerve conduction velocity and produced the thermal and mechanical nociception. Carvedilol significantly (P < 0.001) attenuated these functional and sensorimotor deficits. It also counteracted oxidative/nitrosative stress by reducing the levels of nitrotyrosine and improving the mitochondrial superoxide dismutase expression in both sciatic nerve and DRG tissues. It improved the mitochondrial function and prevented the oxaliplatin-induced alteration in mitochondrial membrane potential in sciatic nerve thus prevented loss of intra epidermal nerve fiber density in the foot pads. Together the results prompt the use of carvedilol along with chemotherapy with oxaliplatin to prevent the peripheral neuropathy. - Graphical abstract: Schematic representation neuroprotective mechanisms of carvedilol in oxaliplatin-induced peripheral neuropathy. - Highlights: • Oxaliplatin-induced mitochondrial dysfunction causes neurotoxicity. • Mitochondrial dysfunction leads to bioenergetic and functional deficits. • Carvedilol alleviated oxaliplatin-induced behavioural and functional changes. • Targeting mitochondria with carvedilol attenuated neuropathic pain.« less

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis.

PubMed

Maestraggi, Quentin; Lebas, Benjamin; Clere-Jehl, Raphaël; Ludes, Pierre-Olivier; Chamaraux-Tran, Thiên-Nga; Schneider, Francis; Diemunsch, Pierre; Geny, Bernard; Pottecher, Julien

2017-01-01

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Association of cultured myotubes and fasting plasma metabolite profiles with mitochondrial dysfunction in type 2 diabetes subjects.

PubMed

Abu Bakar, Mohamad Hafizi; Sarmidi, Mohamad Roji

2017-08-22

Accumulating evidence implicates mitochondrial dysfunction-induced insulin resistance in skeletal muscle as the root cause for the greatest hallmarks of type 2 diabetes (T2D). However, the identification of specific metabolite-based markers linked to mitochondrial dysfunction in T2D has not been adequately addressed. Therefore, we sought to identify the markers-based metabolomics for mitochondrial dysfunction associated with T2D. First, a cellular disease model was established using human myotubes treated with antimycin A, an oxidative phosphorylation inhibitor. Non-targeted metabolomic profiling of intracellular-defined metabolites on the cultured myotubes with mitochondrial dysfunction was then determined. Further, a targeted MS-based metabolic profiling of fasting blood plasma from normal (n = 32) and T2D (n = 37) subjects in a cross-sectional study was verified. Multinomial logical regression analyses for defining the top 5% of the metabolites within a 95% group were employed to determine the differentiating metabolites. The myotubes with mitochondrial dysfunction exhibited insulin resistance, oxidative stress and inflammation with impaired insulin signalling activities. Four metabolic pathways were found to be strongly associated with mitochondrial dysfunction in the cultured myotubes. Metabolites derived from these pathways were validated in an independent pilot investigation of the fasting blood plasma of healthy and diseased subjects. Targeted metabolic analysis of the fasting blood plasma with specific baseline adjustment revealed 245 significant features based on orthogonal partial least square discriminant analysis (PLS-DA) with a p-value < 0.05. Among these features, 20 significant metabolites comprised primarily of branched chain and aromatic amino acids, glutamine, aminobutyric acid, hydroxyisobutyric acid, pyroglutamic acid, acylcarnitine species (acetylcarnitine, propionylcarnitine, dodecenoylcarnitine, tetradecenoylcarnitine hexadecadienoylcarnitine and oleylcarnitine), free fatty acids (palmitate, arachidonate, stearate and linoleate) and sphingomyelin (d18:2/16:0) were identified as predictive markers for mitochondrial dysfunction in T2D subjects. The current study illustrates how cellular metabolites provide potential signatures associated with the biochemical changes in the dysregulated body metabolism of diseased subjects. Our finding yields additional insights into the identification of robust biomarkers for T2D associated with mitochondrial dysfunction in cultured myotubes.

Atrazine Triggers Mitochondrial Dysfunction and Oxidative Stress in Quail ( Coturnix C. coturnix) Cerebrum via Activating Xenobiotic-Sensing Nuclear Receptors and Modulating Cytochrome P450 Systems.

PubMed

Lin, Jia; Zhao, Hua-Shan; Qin, Lei; Li, Xue-Nan; Zhang, Cong; Xia, Jun; Li, Jin-Long

2018-06-14

The residues from the widely used broad-spectrum environmental herbicide, atrazine (ATR), result in the exposure of nontarget organisms and persist as a global major public health hazard. ATR is neurotoxic and may cause adverse health effects in mammals, birds, and fishes. Nevertheless, the molecular mechanism of ATR induced neurotoxicity remains unclear. To assess the molecular mechanisms of ATR-induced cerebral toxicity through potential oxidative damage, quail were treated with ATR by oral gavage administration at doses of 0, 50, 250, and 500 mg/kg body weight daily for 45 days. Markedly, increases in the amount of swelling of neuronal cells, the percentage of mean damaged mitochondria, mitochondrial malformation, and mitochondrial vacuolar degeneration as well as decreases in the mitochondrial cristae and mitochondrial volume density were observed by light and electron microscopy in the cerebrum of quail. ATR induced toxicities in the expression of mitochondrial function-related genes and promoted oxidative damage, as indicated by effects on oxidative stress indices. These results indicated that ATR exposure can cause neurological disorders and cerebral injury. ATR may initiate apoptosis by activating Bcl-2, Bax, and Caspase3 protein expression but failed to induce autophagy (LC3B has not cleaved to LC3BI/II). Furthermore, ATR induced CYP-related enzymes metabolism disorders by activating the nuclear xenobiotic receptors response (NXRs including AHR, CAR, and PXR) and increased expression of several CYP isoforms (including CYP1B1 and CYP2C18) and thereby producing mitochondrial dysfunction. In this study, we observed ATR exposure resulted in oxidative stress and mitochondrial dysfunction by activating the NXR response and interfering the CYP450s homeostasis in quail cerebrum that supported the molecular mechanism of ATR induced cerebrum toxicity. In conclusion, these results provided new evidence on molecular mechanism of ATR induced neurotoxicity.

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence.

PubMed

Tai, Haoran; Wang, Zhe; Gong, Hui; Han, Xiaojuan; Zhou, Jiao; Wang, Xiaobo; Wei, Xiawei; Ding, Yi; Huang, Ning; Qin, Jianqiong; Zhang, Jie; Wang, Shuang; Gao, Fei; Chrzanowska-Lightowlers, Zofia M; Xiang, Rong; Xiao, Hengyi

2017-01-02

Macroautophagy/autophagy has profound implications for aging. However, the true features of autophagy in the progression of aging remain to be clarified. In the present study, we explored the status of autophagic flux during the development of cell senescence induced by oxidative stress. In this system, although autophagic structures increased, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence and the activity of lysosomal proteolytic enzymes all decreased in senescent cells, indicating impaired autophagic flux with lysosomal dysfunction. The influence of autophagy activity on senescence development was confirmed by both positive and negative autophagy modulators; and MTOR-dependent autophagy activators, rapamycin and PP242, efficiently suppressed cellular senescence through a mechanism relevant to restoring autophagic flux. By time-phased treatment of cells with the antioxidant N-acetylcysteine (NAC), the mitochondria uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and ambroxol, a reagent with the effect of enhancing lysosomal enzyme maturation, we found that mitochondrial dysfunction plays an initiating role, while lysosomal dysfunction is more directly responsible for autophagy impairment and senescence. Interestingly, the effect of rapamycin on autophagy flux is linked to its role in functional revitalization of both mitochondrial and lysosomal functions. Together, this study demonstrates that autophagy impairment is crucial for oxidative stress-induced cell senescence, thus restoring autophagy activity could be a promising way to retard senescence.

Hyperammonaemia‐induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress

PubMed Central

Davuluri, Gangarao; Allawy, Allawy; Thapaliya, Samjhana; Rennison, Julie H.; Singh, Dharmvir; Kumar, Avinash; Sandlers, Yana; Van Wagoner, David R.; Flask, Chris A.; Hoppel, Charles; Kasumov, Takhar

2016-01-01

Key points Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia.We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD+/NADH ratio and ATP content.During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids.Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell‐permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content.Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS. Abstract Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non‐hepatic ammonia disposal. Non‐hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α‐ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD+/NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell‐permeable ester of α‐ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia‐induced mitochondrial dysfunction is a novel therapeutic approach. PMID:27558544

A specific amino acid formula prevents alcoholic liver disease in rodents.

PubMed

Tedesco, Laura; Corsetti, Giovanni; Ruocco, Chiara; Ragni, Maurizio; Rossi, Fabio; Carruba, Michele O; Valerio, Alessandra; Nisoli, Enzo

2018-05-01

Chronic alcohol consumption promotes mitochondrial dysfunction, oxidative stress, defective protein metabolism, and fat accumulation in hepatocytes (liver steatosis). Inadequate amino acid metabolism is worsened by protein malnutrition, frequently present in alcohol-consuming patients, with reduced circulating branched-chain amino acids (BCAAs). Here we asked whether dietary supplementation with a specific amino acid mixture, enriched in BCAAs (BCAAem) and able to promote mitochondrial function in muscle of middle-aged rodents, would prevent mitochondrial dysfunction and liver steatosis in Wistar rats fed on a Lieber-DeCarli ethanol (EtOH)-containing liquid diet. Supplementation of BCAAem, unlike a mixture based on the amino acid profile of casein, abrogated the EtOH-induced fat accumulation, mitochondrial impairment, and oxidative stress in liver. These effects of BCAAem were accompanied by normalization of leucine, arginine, and tryptophan levels, which were reduced in liver of EtOH-consuming rats. Moreover, although the EtOH exposure of HepG2 cells reduced mitochondrial DNA, mitochondrial transcription factors, and respiratory chain proteins, the BCAAem but not casein-derived amino acid supplementation halted this mitochondrial toxicity. Nicotinamide adenine dinucleotide levels and sirtuin 1 (Sirt1) expression, as well as endothelial nitric oxide (eNOS) and mammalian/mechanistic target of rapamycin (mTOR) signaling pathways, were downregulated in the EtOH-exposed HepG2 cells. BCAAem reverted these molecular defects and the mitochondrial dysfunction, suggesting that the mitochondrial integrity obtained with the amino acid supplementation could be mediated through a Sirt1-eNOS-mTOR pathway. Thus a dietary activation of the mitochondrial biogenesis and function by a specific amino acid supplement protects against the EtOH toxicity and preserves the liver integrity in mammals. NEW & NOTEWORTHY Dietary supplementation of a specific amino acid formula prevents both fat accumulation and mitochondrial dysfunction in hepatocytes of alcohol-consuming rats. These effects are accompanied also by increased expression of anti-reactive oxygen species genes. The amino acid-protective effects likely reflect activation of sirtuin 1-endothelial nitric oxide synthase-mammalian target of rapamycin pathway able to regulate the cellular energy balance of hepatocytes exposed to chronic, alcoholic damage.

The Membrane-Bound NAC Transcription Factor ANAC013 Functions in Mitochondrial Retrograde Regulation of the Oxidative Stress Response in Arabidopsis[C][W

PubMed Central

De Clercq, Inge; Vermeirssen, Vanessa; Van Aken, Olivier; Vandepoele, Klaas; Murcha, Monika W.; Law, Simon R.; Inzé, Annelies; Ng, Sophia; Ivanova, Aneta; Rombaut, Debbie; van de Cotte, Brigitte; Jaspers, Pinja; Van de Peer, Yves; Kangasjärvi, Jaakko; Whelan, James; Van Breusegem, Frank

2013-01-01

Upon disturbance of their function by stress, mitochondria can signal to the nucleus to steer the expression of responsive genes. This mitochondria-to-nucleus communication is often referred to as mitochondrial retrograde regulation (MRR). Although reactive oxygen species and calcium are likely candidate signaling molecules for MRR, the protein signaling components in plants remain largely unknown. Through meta-analysis of transcriptome data, we detected a set of genes that are common and robust targets of MRR and used them as a bait to identify its transcriptional regulators. In the upstream regions of these mitochondrial dysfunction stimulon (MDS) genes, we found a cis-regulatory element, the mitochondrial dysfunction motif (MDM), which is necessary and sufficient for gene expression under various mitochondrial perturbation conditions. Yeast one-hybrid analysis and electrophoretic mobility shift assays revealed that the transmembrane domain–containing NO APICAL MERISTEM/ARABIDOPSIS TRANSCRIPTION ACTIVATION FACTOR/CUP-SHAPED COTYLEDON transcription factors (ANAC013, ANAC016, ANAC017, ANAC053, and ANAC078) bound to the MDM cis-regulatory element. We demonstrate that ANAC013 mediates MRR-induced expression of the MDS genes by direct interaction with the MDM cis-regulatory element and triggers increased oxidative stress tolerance. In conclusion, we characterized ANAC013 as a regulator of MRR upon stress in Arabidopsis thaliana. PMID:24045019

Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.

PubMed

Gioscia-Ryan, Rachel A; LaRocca, Thomas J; Sindler, Amy L; Zigler, Melanie C; Murphy, Michael P; Seals, Douglas R

2014-06-15

Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice

PubMed Central

Gioscia-Ryan, Rachel A; LaRocca, Thomas J; Sindler, Amy L; Zigler, Melanie C; Murphy, Michael P; Seals, Douglas R

2014-01-01

Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD. PMID:24665093

The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.

PubMed

Fukunaga, Kohji; Shinoda, Yasuharu; Tagashira, Hideaki

2015-01-01

Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection.

PubMed

Sahu, Bidya Dhar; Tatireddy, Srujana; Koneru, Meghana; Borkar, Roshan M; Kumar, Jerald Mahesh; Kuncha, Madhusudana; Srinivas, R; Shyam Sunder, R; Sistla, Ramakrishna

2014-05-15

Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney. Copyright © 2014 Elsevier Inc. All rights reserved.

Accumulation of exogenous amyloid-beta peptide in hippocampal mitochondria causes their dysfunction: a protective role for melatonin.

PubMed

Rosales-Corral, Sergio; Acuna-Castroviejo, Dario; Tan, Dun Xian; López-Armas, Gabriela; Cruz-Ramos, José; Munoz, Rubén; Melnikov, Valery G; Manchester, Lucien C; Reiter, Russel J

2012-01-01

Amyloid-beta (Aβ) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.

Accumulation of Exogenous Amyloid-Beta Peptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin

PubMed Central

Rosales-Corral, Sergio; Acuna-Castroviejo, Dario; Tan, Dun Xian; López-Armas, Gabriela; Cruz-Ramos, José; Munoz, Rubén; Melnikov, Valery G.; Manchester, Lucien C.; Reiter, Russel J.

2012-01-01

Amyloid-beta (Aβ) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance. PMID:22666521

Damaging Effects of Bisphenol A on the Kidney and the Protection by Melatonin: Emerging Evidences from In Vivo and In Vitro Studies

PubMed Central

Peerapanyasut, Wachirasek

2018-01-01

This study investigates the effects of bisphenol A (BPA) contamination on the kidney and the possible protection by melatonin in experimental rats and isolated mitochondrial models. Rats exposed to BPA (50, 100, and 150 mg/kg, i.p.) for 5 weeks demonstrated renal damages as evident by increased serum urea and creatinine and decreased creatinine clearance, together with the presence of proteinuria and glomerular injuries in a dose-dependent manner. These changes were associated with increased lipid peroxidation and decreased antioxidant glutathione and superoxide dismutase. Mitochondrial dysfunction was also evident as indicated by increased reactive oxygen species production, decreased membrane potential change, and mitochondrial swelling. Coadministration of melatonin resulted in the reversal of all the changes caused by BPA. Studies using isolated mitochondria showed that BPA incubation produced dose-dependent impairment in mitochondrial function. Preincubation with melatonin was able to sustain mitochondrial function and architecture and decreases oxidative stress upon exposure to BPA. The findings indicated that BPA is capable of acting directly on the kidney mitochondria, causing mitochondrial oxidative stress, dysfunction, and subsequently, leading to whole organ damage. Emerging evidence further suggests the protective benefits of melatonin against BPA nephrotoxicity, which may be mediated, in part, by its ability to diminish oxidative stress and maintain redox equilibrium within the mitochondria. PMID:29670679

Parkin and PINK1 functions in oxidative stress and neurodegeneration.

PubMed

Barodia, Sandeep K; Creed, Rose B; Goldberg, Matthew S

2017-07-01

Loss-of-function mutations in the genes encoding Parkin and PINK1 are causally linked to autosomal recessive Parkinson's disease (PD). Parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial-targeted kinase, function together in a common pathway to remove dysfunctional mitochondria by autophagy. Presumably, deficiency for Parkin or PINK1 impairs mitochondrial autophagy and thereby increases oxidative stress due to the accumulation of dysfunctional mitochondria that release reactive oxygen species. Parkin and PINK1 likely have additional functions that may be relevant to the mechanisms by which mutations in these genes cause neurodegeneration, such as regulating inflammation, apoptosis, or dendritic morphogenesis. Here we briefly review what is known about functions of Parkin and PINK1 related to oxidative stress and neurodegeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

Importance of mitochondrial calcium uniporter in high glucose-induced endothelial cell dysfunction.

PubMed

Chen, Wei; Yang, Jie; Chen, Shuhua; Xiang, Hong; Liu, Hengdao; Lin, Dan; Zhao, Shaoli; Peng, Hui; Chen, Pan; Chen, Alex F; Lu, Hongwei

2017-11-01

Mitochondrial Ca 2+ overload is implicated in hyperglycaemia-induced endothelial cell dysfunction, but the key molecular events responsible remain unclear. We examined the involvement of mitochondrial calcium uniporter, which mediates mitochondrial Ca 2+ uptake, in endothelial cell dysfunction resulting from high-glucose treatment. Human umbilical vein endothelial cells were exposed to various glucose concentrations and to high glucose (30 mM) following mitochondrial calcium uniporter inhibition or activation with ruthenium red and spermine, respectively. Subsequently, mitochondrial calcium uniporter and mitochondrial calcium uniporter regulator 1 messenger RNA and protein expression was measured by real-time polymerase chain reaction and western blotting. Ca 2+ concentrations were analysed by laser confocal microscopy, and cytoplasmic and mitochondrial oxidative stress was detected using 2',7'-dichlorofluorescein diacetate and MitoSOX Red, respectively. Apoptosis was assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, and a wound-healing assay was performed using an in vitro model. High glucose markedly upregulated mitochondrial calcium uniporter and mitochondrial calcium uniporter regulator 1 messenger RNA expression, as well as protein production, in a dose- and time-dependent manner with a maximum effect demonstrated at 72 h and 30 mM glucose concentration. Moreover, high-glucose treatment significantly raised both mitochondrial and cytoplasmic Ca 2+ and reactive oxygen species levels, increased apoptosis and compromised wound healing (all p < 0.05). These effects were enhanced by spermine and completely negated by ruthenium red, which are known to activate and inhibit mitochondrial calcium uniporter, respectively. Mitochondrial calcium uniporter plays an important role in hyperglycaemia-induced endothelial cell dysfunction and may constitute a therapeutic target to reduce vascular complications in diabetes.

Ginsenoside Re protects against phencyclidine-induced behavioral changes and mitochondrial dysfunction via interactive modulation of glutathione peroxidase-1 and NADPH oxidase in the dorsolateral cortex of mice.

PubMed

Tran, The-Vinh; Shin, Eun-Joo; Dang, Duy-Khanh; Ko, Sung Kwon; Jeong, Ji Hoon; Nah, Seung-Yeol; Jang, Choon-Gon; Lee, Yu Jeung; Toriumi, Kazuya; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2017-12-01

We investigated whether ginsenoside Re (Re) modulates phencyclidine (PCP)-induced sociability deficits and recognition memory impairments to extend our recent finding. We examined the role of GPx-1 gene in the pharmacological activity of Re against mitochondrial dysfunction induced by PCP in the dorsolateral cortex of mice. Since mitochondrial oxidative stress activates NADPH oxidase (PHOX), we applied PHOX inhibitor apocynin for evaluating interactive modulation between GPx-1 and PHOX against PCP neurotoxicity. Sociability deficits and recognition memory impairments induced by PCP were more pronounced in GPx-1 knockout (KO) than in wild type (WT) mice. PCP-induced mitochondrial oxidative stress, mitochondrial dysfunction, and membrane translocation of p47phox were more evident in GPx-1 KO than in WT. Re treatment significantly attenuated PCP-induced neurotoxic changes. Re also significantly attenuated PCP-induced sociability deficits and recognition memory impairments. The attenuation by Re was comparable to that by apocynin. The attenuation was more obvious in GPx-1 KO than in WT. Importantly, apocynin did not show any additional positive effects on the neuroprotective activity of Re, indicating that PHOX is a molecular target for therapeutic activity of Re. Our results suggest that Re requires interactive modulation between GPx activity and PHOX (p47phox) to exhibit neuroprotective potentials against PCP insult. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration

PubMed Central

Guo, Xing; Disatnik, Marie-Helene; Monbureau, Marie; Shamloo, Mehrdad; Mochly-Rosen, Daria; Qi, Xin

2013-01-01

Huntington’s disease (HD) is the result of expression of a mutated Huntingtin protein (mtHtt), and is associated with a variety of cellular dysfunctions including excessive mitochondrial fission. Here, we tested whether inhibition of excessive mitochondrial fission prevents mtHtt-induced pathology. We developed a selective inhibitor (P110-TAT) of the mitochondrial fission protein dynamin-related protein 1 (DRP1). We found that P110-TAT inhibited mtHtt-induced excessive mitochondrial fragmentation, improved mitochondrial function, and increased cell viability in HD cell culture models. P110-TAT treatment of fibroblasts from patients with HD and patients with HD with iPS cell–derived neurons reduced mitochondrial fragmentation and corrected mitochondrial dysfunction. P110-TAT treatment also reduced the extent of neurite shortening and cell death in iPS cell–derived neurons in patients with HD. Moreover, treatment of HD transgenic mice with P110-TAT reduced mitochondrial dysfunction, motor deficits, neuropathology, and mortality. We found that p53, a stress gene involved in HD pathogenesis, binds to DRP1 and mediates DRP1-induced mitochondrial and neuronal damage. Furthermore, P110-TAT treatment suppressed mtHtt-induced association of p53 with mitochondria in multiple HD models. These data indicate that inhibition of DRP1-dependent excessive mitochondrial fission with a P110-TAT–like inhibitor may prevent or slow the progression of HD. PMID:24231356

Increased mitochondrial matrix directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria

PubMed Central

Bhattacharya, Arunabh; Lustgarten, Michael; Shi, Yun; Liu, Yuhong; Jang, Youngmok C; Pulliam, Daniel; Jernigan, Amanda L; Van Remmen, Holly

2013-01-01

Previous studies have shown that muscle atrophy is associated with mitochondrial dysfunction and an increased rate of mitochondrial reactive oxygen species production. We recently demonstrated that fatty acid hydroperoxides (FA-OOH) are significantly elevated in mitochondria isolated from atrophied muscles. The purpose of the current study is to determine whether FA-OOH can alter skeletal muscle mitochondrial function. We found that FA-OOH (at low micromolar concentrations) induces mitochondrial dysfunction assessed by decrease in the rate of ATP production, oxygen consumption and activity of respiratory chain complexes I and III. Using methods to distinguish superoxide release towards the matrix and inter-membrane space, we demonstrate that FA-OOH significantly elevates oxidative stress in the mitochondrial matrix (and not the inter-membrane space) with complex I as the major site of superoxide production (most likely from a site upstream of the ubiquinone binding site but downstream from the flavin binding site-the iron sulfur clusters). Our results are the first to indicate that FA-OOH’s are important modulators of mitochondrial function and oxidative stress in skeletal muscle mitochondria and may play an important role in muscle atrophies that are associated with increased generation of FA-OOH’s, e.g., denervation-induced muscle atrophy. PMID:21172427

Mitochondrial Genetic Background Modulates Bioenergetics and Susceptibility to Acute Cardiac Volume – Overload

PubMed Central

Fetterman, Jessica L.; Zelickson, Blake R.; Johnson, Larry W.; Moellering, Douglas R.; Westbrook, David G.; Pompilius, Melissa; Sammy, Melissa J.; Johnson, Michelle; Dunham-Snary, Kimberly J.; Cao, Xuemei; Bradley, Wayne E.; Zhang, Jinju; Wei, Chih-Chang; Chacko, Balu; Schurr, Theodore G.; Kesterson, Robert A.; Dell’Italia, Louis J.; Darley-Usmar, Victor M.; Welch, Danny R.; Ballinger, Scott W.

2013-01-01

Synopsis Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mitochondrial DNA (mtDNA) sequence variation contributes to disease susceptibility. In this study we present a novel animal model of mtDNA polymorphisms, the mitochondrial nuclear exchange mouse (MNX), in which the mtDNA from C3H/HeN mouse has been inserted onto the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harboring the C57/BL6J mtDNA generate more reactive oxygen species (ROS) and have a higher mitochondrial membrane potential relative to those having the C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the “mitochondrial paradigm” for the development of disease susceptibility, and show that the mtDNA modulates, cellular bioenergetics, mitochondrial reactive oxygen species generation and susceptibility to cardiac stress. PMID:23924350

Mechanisms of MDMA (Ecstasy)-Induced Oxidative Stress, Mitochondrial Dysfunction, and Organ Damage

PubMed Central

Song, Byoung-Joon; Moon, Kwan-Hoon; Upreti, Vijay V.; Eddington, Natalie D.; Lee, Insong J.

2010-01-01

Despite numerous reports about the acute and sub-chronic toxicities caused by MDMA (3,4-methylenedioxymethamphetamine, ecstasy), the underlying mechanism of organ damage is poorly understood. The aim of this review is to present an update of the mechanistic studies on MDMA-mediated organ damage partly caused by increased oxidative/nitrosative stress. Because of the extensive reviews on MDMA-mediated oxidative stress and tissue damage, we specifically focus on the mechanisms and consequences of oxidative-modifications of mitochondrial proteins, leading to mitochondrial dysfunction. We briefly describe a method to systematically identify oxidatively-modified mitochondrial proteins in control and MDMA-exposed rats by using biotin-N-maleimide (biotin-NM) as a sensitive probe for oxidized proteins. We also describe various applications and advantages of this Cys-targeted proteomics method and alternative approaches to overcome potential limitations of this method in studying oxidized proteins from MDMA-exposed tissues. Finally we discuss the mechanism of synergistic drug-interaction between MDMA and other abused substances including alcohol (ethanol) as well as application of this redox-based proteomics method in translational studies for developing effective preventive and therapeutic agents against MDMA-induced organ damage. PMID:20420575

Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction

PubMed Central

Mikhed, Yuliya; Daiber, Andreas; Steven, Sebastian

2015-01-01

The prevalence of cardiovascular diseases is significantly increased in the older population. Risk factors and predictors of future cardiovascular events such as hypertension, atherosclerosis, or diabetes are observed with higher frequency in elderly individuals. A major determinant of vascular aging is endothelial dysfunction, characterized by impaired endothelium-dependent signaling processes. Increased production of reactive oxygen species (ROS) leads to oxidative stress, loss of nitric oxide (•NO) signaling, loss of endothelial barrier function and infiltration of leukocytes to the vascular wall, explaining the low-grade inflammation characteristic for the aged vasculature. We here discuss the importance of different sources of ROS for vascular aging and their contribution to the increased cardiovascular risk in the elderly population with special emphasis on mitochondrial ROS formation and oxidative damage of mitochondrial DNA. Also the interaction (crosstalk) of mitochondria with nicotinamide adenosine dinucleotide phosphate (NADPH) oxidases is highlighted. Current concepts of vascular aging, consequences for the development of cardiovascular events and the particular role of ROS are evaluated on the basis of cell culture experiments, animal studies and clinical trials. Present data point to a more important role of oxidative stress for the maximal healthspan (healthy aging) than for the maximal lifespan. PMID:26184181

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia.

PubMed

Ábrigo, Johanna; Elorza, Alvaro A; Riedel, Claudia A; Vilos, Cristian; Simon, Felipe; Cabrera, Daniel; Estrada, Lisbell; Cabello-Verrugio, Claudio

2018-01-01

Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.

Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

PubMed

Woodman, Andrew G; Mah, Richard; Keddie, Danae; Noble, Ronan M N; Panahi, Sareh; Gragasin, Ferrante S; Lemieux, Hélène; Bourque, Stephane L

2018-06-01

Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups (-54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron-deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ-dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

Impaired mitochondria and intracellular calcium transients in the salivary glands of obese rats.

PubMed

Ittichaicharoen, Jitjiroj; Apaijai, Nattayaporn; Tanajak, Pongpan; Sa-Nguanmoo, Piangkwan; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-04-01

Long-term consumption of a high-fat diet (HFD) causes not only obese-insulin resistance, but is also associated with mitochondrial dysfunction in several organs. However, the effect of obese-insulin resistance on salivary glands has not been investigated. We hypothesized that obese-insulin resistance induced by HFD impaired salivary gland function by reducing salivation, increasing inflammation, and fibrosis, as well as impairing mitochondrial function and calcium transient signaling. Male Wistar rats (200-220 g) were fed either a ND or an HFD (n = 8/group) for 16 weeks. At the end of week 16, salivary flow rates, metabolic parameters, and plasma oxidative stress were determined. Rats were then sacrificed and submandibular glands were removed to determine inflammation, fibrosis, apoptosis, mitochondrial function and dynamics, and intracellular calcium transient signaling. Long-term consumption of an HFD caused obese-insulin resistance and increased oxidative stress, fibrosis, inflammation, and apoptosis in the salivary glands. In addition, impaired mitochondrial function, as indicated by increased mitochondrial reactive oxygen species, mitochondrial membrane depolarization, and mitochondrial swelling in salivary glands and impaired intracellular calcium regulation, as indicated by a reduced intracellular calcium transient rising rate, decay rates, and amplitude of salivary acinar cells, were observed in HFD-fed rats. However, salivary flow rate and level of aquaporin 5 protein were not different between both groups. Although HFD consumption did not affect salivation, it caused obese-insulin resistance, leading to pathophysiological alteration of salivary glands, including impaired intracellular calcium transients, increased oxidative stress and inflammation, and salivary mitochondrial dysfunction.

Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial.

PubMed

Dai, Yuk-Ling; Luk, Ting-Hin; Yiu, Kai-Hang; Wang, Mei; Yip, Pandora M C; Lee, Stephen W L; Li, Sheung-Wai; Tam, Sidney; Fong, Bonnie; Lau, Chu-Pak; Siu, Chung-Wah; Tse, Hung-Fat

2011-06-01

Coronary artery disease (CAD) is associated with endothelial dysfunction and mitochondrial dysfunction (MD). The aim of this study was to investigate whether co-enzyme Q10 (CoQ) supplementation, which is an obligatory coenzyme in the mitochondrial respiratory transport chain, can reverse MD and improve endothelial function in patients with ischaemic left ventricular systolic dysfunction (LVSD). We performed a randomized, double-blind, placebo-controlled trial to determine the effects of CoQ supplement (300 mg/day, n=28) vs. placebo (controls, n=28) for 8 weeks on brachial flow-mediated dilation (FMD) in patients with ischaemic LVSD(left ventricular ejection fraction <45%). Mitochondrial function was determined by plasma lactate/pyruvate ratio (LP ratio). After 8 weeks, CoQ-treated patients had significant increases in plasma CoQ concentration (treatment effect 2.20 μg/mL, P<0.001) and FMD (treatment effect 1.51%, P=0.03); and decrease in LP ratio (treatment effect -2.46, P=0.03) compared with controls. However, CoQ treatment did not alter nitroglycerin-mediated dilation, blood pressure, blood levels of fasting glucose, haemoglobin A1c, lipid profile, high-sensitivity C-reactive protein and oxidative stress as determined by serum superoxide dismutase and 8-isoprostane (all P>0.05). Furthermore, the reduction in LP ratio significantly correlated with improvement in FMD (r=-0.29, P=0.047). In patients with ischaemic LVSD, 8 weeks supplement of CoQ improved mitochondrial function and FMD; and the improvement of FMD correlated with the change in mitochondrial function, suggesting that CoQ improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Penghao; Xie, Qihai; Wei, Tong

Objective: Obesity-induced vascular dysfunction is related to chronic low-grade systemic inflammation. Recent studies indicate that NLRP3, a multiprotein complex formed by NOD-like receptor (NLR) family members, is a key component mediating internal sterile inflammation, but the role in obesity-related vascular dysfunction is largely unknown. In the present study, we investigate whether NLRP3 activation is involved in vascular inflammation in obese Otsuka Long-Evans Tokushima Fatty rats (OLETF). Methods and results: Male OLETF with their control Long-Evans Tokushima Otsuka rats (LETO) were studied at 3 and 12 months of age. Aortic relaxation in response to acetylcholine decreased gradually with age in bothmore » strains, with early and persistent endothelium dysfunction in obese OLETF compared with age-matched LETO controls. These changes are associated with parallel changes of aortic endothelial nitric oxide synthase (eNOS) content, macrophage accumulation and intimal thickening. NLRP3 increased in OLETF rats compared to LETO. Consistent with inflammasome activation, the conversion of procaspase-1 to cleaved and activated forms as well as IL-1β markedly increased in OLETF rats. Additionally, we observed increased expression of dynamin-related protein-1 (Drp1) and decreased fusion-relative protein optic atropy-1(OPA1). Altered mitochondrial dynamics was associated with elevated oxidative stress level in OLETF aortas. Conclusions: These results demonstrate that obesity seems to accelerate endothelial dysfunction in OLETFs via the activation of NLRP3 and mitochondrial dysfunction. - Highlights: • NLRP3 is involved in obesity-induced vascular dysfunction. • Impaired mitochondrial dynamics may have been linked to mitochondrial defect and inflammasome activation. • Obesity seems to accelerate vascular dysfunction via NLRP3 activation and mitochondrial dysfunction.« less

Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa: a novel role of mitochondrial aconitase oxidation.

PubMed

Maity, Pallab; Bindu, Samik; Dey, Sumanta; Goyal, Manish; Alam, Athar; Pal, Chinmay; Mitra, Kalyan; Bandyopadhyay, Uday

2009-01-30

We have investigated the role of mitochondria on the development of indomethacin (a non-steroidal anti-inflammatory drug)-induced gastric mucosal apoptosis and associated gastropathy in rat. Transmission electron microscopic studies indicate that indomethacin damages mitochondrial ultrastructure and causes mitochondrial dysfunction as evident from decreased stage-3 respiration, dehydrogenase activity, and transmembrane potential (DeltaPsi(m)). Mitochondrial pathology is associated with increased generation of intra-mitochondrial-reactive oxygen species, such as O(2)(*), H(2)O(2) and *OH, leading to oxidative stress. O(2)(*) is the most effective to damage mitochondrial aconitase, leading to the release of iron from its iron-sulfur cluster. The released iron, by interacting with intra-mitochondrial H(2)O(2), forms *OH. Immunoprecipitation of mitochondrial aconitase and subsequent Western immunoblotting indicate carbonylation of aconitase along with the loss of activity in vivo after indomethacin treatment. The release of iron has been documented by fluorescence imaging of mucosal cells by using Phen Green SK, a specific probe for chelatable iron. Interestingly, intra-mitochondrial *OH generation is crucial for the development of mitochondrial pathology and activation of mitochondrial death pathway by indomethacin. Scavenging of *OH by dimethyl sulfoxide or alpha-phenyl-n-tert-butylnitrone, a spin-trap, prevents indomethacin-induced mitochondrial ultrastructural changes, oxidative stress, collapse of DeltaPsi(m), and mitochondrial dysfunction. The scavengers also restore indomethacin-induced activation of caspase-9 and caspase-3 to block mitochondrial pathway of apoptosis and gastric mucosal damage. This study, thus, reveals the critical role of O(2)(*)-mediated mitochondrial aconitase inactivation to release intra-mitochondrial iron, which by generating *OH promotes gastric mucosal cell apoptosis and gastropathy during indomethacin treatment.

Mitigating peroxynitrite mediated mitochondrial dysfunction in aged rat brain by mitochondria-targeted antioxidant MitoQ.

PubMed

Maiti, Arpan Kumar; Spoorthi, B C; Saha, Nimai Chandra; Panigrahi, Ashis Kumar

2018-05-17

Although reactive oxygen species mediated oxidative stress is a well-documented mechanism of aging, recent evidences indicate involvement of nitrosative stress in the same. As mitochondrial dysfunction is considered as one of the primary features of aging, the present study was designed to understand the involvement of nitrosative stress by studying the impact of a mitochondria-targeted antioxidant MitoQ, a peroxynitrite (ONOO - ) scavenger, on mitochondrial functions. Four groups of rats were included in this study: Group I: Young-6 months (-MitoQ), Group II: Aged-22 months (- MitoQ), Group III: Young-6 months (+ MitoQ), Group IV: Aged-22 months (+ MitoQ). The rats belonging to group III and IV were treated with oral administration of MitoQ (500 μM) daily through drinking water for 5 weeks. MitoQ efficiently suppressed synaptosomal lipid peroxidation and protein oxidation accompanied by diminution of nitrite production and protein bound 3-nitrotyrosine. MitoQ normalized enhanced caspase 3 and 9 activities in aged rat brains and efficiently reversed ONOO - mediated mitochondrial complex I and IV inhibition, restored mitochondrial ATP production and lowered mitochondrial membrane potential loss. To ascertain these findings, a mitochondrial in vitro model (iron/ascorbate) was used involving different free radical scavengers and anti-oxidants. MitoQ provided better protection compared to mercaptoethylguanidine, N-nitro-L-arginine-methyl ester and superoxide dismutase establishing the predominancy of ONOO - in the process compared to • NO and O 2 •- . These results clearly highlight the involvement of nitrosative stress in aging process with MitoQ having therapeutic potential to fight against ONOO - mediated aging deficits.

Dysfunction of mitochondrial dynamics in the brains of scrapie-infected mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Hong-Seok; Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang, Gyeonggi-do 431-060; Choi, Yeong-Gon

Highlights: • Mfn1 and Fis1 are significantly increased in the hippocampal region of the ME7 prion-infected brain, whereas Dlp1 is significantly decreased in the infected brain. • Dlp1 is significantly decreased in the cytosolic fraction of the hippocampus in the infected brain. • Neuronal mitochondria in the prion-infected brains are enlarged and swollen compared to those of control brains. • There are significantly fewer mitochondria in the ME7-infected brain compared to the number in control brain. - Abstract: Mitochondrial dysfunction is a common and prominent feature of many neurodegenerative diseases, including prion diseases; it is induced by oxidative stress inmore » scrapie-infected animal models. In previous studies, we found swelling and dysfunction of mitochondria in the brains of scrapie-infected mice compared to brains of controls, but the mechanisms underlying mitochondrial dysfunction remain unclear. To examine whether the dysregulation of mitochondrial proteins is related to the mitochondrial dysfunction associated with prion disease, we investigated the expression patterns of mitochondrial fusion and fission proteins in the brains of ME7 prion-infected mice. Immunoblot analysis revealed that Mfn1 was up-regulated in both whole brain and specific brain regions, including the cerebral cortex and hippocampus, of ME7-infected mice compared to controls. Additionally, expression levels of Fis1 and Mfn2 were elevated in the hippocampus and the striatum, respectively, of the ME7-infected brain. In contrast, Dlp1 expression was significantly reduced in the hippocampus in the ME7-infected brain, particularly in the cytosolic fraction. Finally, we observed abnormal mitochondrial enlargement and histopathological change in the hippocampus of the ME7-infected brain. These observations suggest that the mitochondrial dysfunction, which is presumably caused by the dysregulation of mitochondrial fusion and fission proteins, may contribute to the neuropathological changes associated with prion disease.« less

Proteomics Analysis Reveals Abnormal Electron Transport and Excessive Oxidative Stress Cause Mitochondrial Dysfunction in Placental Tissues of Early-Onset Preeclampsia.

PubMed

Xu, Zhongwei; Jin, Xiaohan; Cai, Wei; Zhou, Maobin; Shao, Ping; Yang, Zhen; Fu, Rong; Cao, Jin; Liu, Yan; Yu, Fang; Fan, Rong; Zhang, Yan; Zou, Shuang; Zhou, Xin; Yang, Ning; Chen, Xu; Li, Yuming

2018-04-20

Early-onset preeclampsia (EOS-PE) refers to preeclampsia that occurred before 34 gestation weeks. This study is conducted to explore the relationship between mitochondrial dysfunction and the pathogenesis of EOS-PE using proteomic strategy. To identify altering expressed mitochondrial proteins between severe EOS-PE and healthy pregnancies, enrichment of mitochondria coupled with iTRAQ-based quantitative proteomic method is performed. Immunohistochemistry (IHC) and western blot are performed to detect the alteration of changing expression proteins, and confirmed the accuracy of proteomic results. A total of 1372 proteins were quantified and 132 altering expressed proteins were screened, including 86 downregulated expression proteins and 46 upregulated expression proteins (p < 0.05). Bioinformatics analysis showed that differentially expressed proteins participated in numerous biological processes, including oxidation-reduction process, respiratory electron transport chain, and oxidative phosphorylation. Especially, mitochondria-related molecules, PRDX2, PARK7, BNIP3, BCL2, PDHA1, SUCLG1, ACADM, and NDUFV1, are involved in energy-production process in the matrix and membrane of mitochondria. Results of the experiment show that abnormal electron transport, excessive oxidative stress, and mitochondrion disassembly might be the main cause of mitochondrial dysfunction, and is related to the pathogenesis of EOS-PE. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin.

PubMed

Waseem, Mohammad; Parvez, Suhel

2016-03-01

Peripheral neurotoxicity is one of the serious dose-limiting side effects of oxaliplatin (Oxa) when used in the treatment of malignant conditions. It is documented that it elicits major side effects specifically neurotoxicity due to oxidative stress forcing the patients to limit its clinical use in long-term treatment. Oxidative stress has been proven to be involved in Oxa-induced toxicity including neurotoxicity. The mitochondria have recently emerged as targets for anticancer drugs in various kinds of toxicity including neurotoxicity that can lead to neoplastic disease. However, there is paucity of literature involving the role of the mitochondria in mediating Oxa-induced neurotoxicity and its underlying mechanism is still debatable. The purpose of this study was to investigate the dose-dependent damage caused by Oxa on isolated brain mitochondria under in vitro conditions. The study was also designed to investigate the neuroprotective effects of nutraceuticals, curcumin (CMN), and quercetin (QR) on Oxa-induced mitochondrial oxidative stress and respiratory chain complexes in the brain of rats. Oxidative stress biomarkers, levels of nonenzymatic antioxidants, activities of enzymatic antioxidants, and mitochondrial complexes were evaluated against the neurotoxicity induced by Oxa. Pretreatment with CMN and QR significantly replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. CMN and QR ameliorated altered nonenzymatic and enzymatic antioxidants and complex enzymes of mitochondria. We conclude that CMN and QR, by attenuating oxidative stress as evident by mitochondrial dysfunction, hold promise as agents that can potentially reduce Oxa-induced adverse effects in the brain.

The Succinated Proteome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Merkley, Eric D.; Metz, Thomas O.; Smith, Richard D.

Succination is a chemical modification of cysteine in protein by the Krebs cycle intermediate, fumarate, yielding S-(2-succino)cysteine (2SC). Intracellular fumarate concentration and succination of proteins are increased by hyperpolarization of the inner mitochondrial membrane, in concert with mitochondrial, endoplasmic reticulum (ER) and oxidative stress in adipocytes grown in high glucose medium and in adipose tissue in obesity and diabetes. Increased succination of proteins is also detected in the kidney of a fumarase conditional knock-out mouse which develops renal tumors. Keap1, the gatekeeper of the antioxidant response, was identified as a major succinated protein in renal cancer cells, suggesting that succinationmore » may play a role in activation of the antioxidant response. A wide range of proteins is subject to succination, including enzymes, adipokines, cytoskeletal proteins and ER chaperones with functional cysteine residues. There is also significant overlap between succinated and glutathionylated proteins, and with proteins containing cysteine residues that are readily oxidized to the sulfenic (cysteic) acid. Succination of adipocyte proteins is inhibited by uncouplers, which discharge the mitochondrial membrane potential (Δψm) and by ER stress inhibitors. 2SC serves as a biomarker of mitochondrial stress or dysfunction in chronic diseases, such as obesity, diabetes and cancer, and recent studies suggest that succination is a mechanistic link between mitochondrial dysfunction, oxidative and ER stress, and cellular progression toward apoptosis. In this article, we review the history of the succinated proteome and the challenges associated with measuring this non-enzymatic post-translational modification of proteins by proteomics approaches.« less

Protein kinase C-ε activation induces mitochondrial dysfunction and fragmentation in renal proximal tubules

PubMed Central

Bakajsova, Diana; Samarel, Allen M.

2011-01-01

PKC-ε activation mediates protection from ischemia-reperfusion injury in the myocardium. Mitochondria are a subcellular target of these protective mechanisms of PKC-ε. Previously, we have shown that PKC-ε activation is involved in mitochondrial dysfunction in oxidant-injured renal proximal tubular cells (RPTC; Nowak G, Bakajsova D, Clifton GL Am J Physiol Renal Physiol 286: F307–F316, 2004). The goal of this study was to examine the role of PKC-ε activation in mitochondrial dysfunction and to identify mitochondrial targets of PKC-ε in RPTC. The constitutively active and inactive mutants of PKC-ε were overexpressed in primary cultures of RPTC using the adenoviral technique. Increases in active PKC-ε levels were accompanied by PKC-ε translocation to mitochondria. Sustained PKC-ε activation resulted in decreases in state 3 respiration, electron transport rate, ATP production, ATP content, and activities of complexes I and IV and F0F1-ATPase. Furthermore, PKC-ε activation increased mitochondrial membrane potential and oxidant production and induced mitochondrial fragmentation and RPTC death. Accumulation of the dynamin-related protein in mitochondria preceded mitochondrial fragmentation. Antioxidants blocked PKC-ε-induced increases in the oxidant production but did not prevent mitochondrial fragmentation and cell death. The inactive PKC-ε mutant had no effect on mitochondrial functions, morphology, oxidant production, and RPTC viability. We conclude that active PKC-ε targets complexes I and IV and F0F1-ATPase in RPTC. PKC-ε activation mediates mitochondrial dysfunction, hyperpolarization, and fragmentation. It also induces oxidant generation and cell death, but oxidative stress is not the mechanism of RPTC death. These results show that in contrast to protective effects of PKC-ε activation in cardiomyocytes, sustained PKC-ε activation is detrimental to mitochondrial function and viability in RPTC. PMID:21289057

A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

PubMed Central

Rossignol, D A; Frye, R E

2012-01-01

Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders. PMID:22143005

(p-ClPhSe)2 Reduces Hepatotoxicity Induced by Monosodium Glutamate by Improving Mitochondrial Function in Rats.

PubMed

Quines, Caroline B; Chagas, Pietro M; Hartmann, Diane; Carvalho, Nélson R; Soares, Félix A; Nogueira, Cristina W

2017-09-01

It is has been demonstrated that mitochondrial dysfunction, oxidative stress, and chronic inflammatory process are associated with progress of morbid obesity in human patients. For this reason, the searching for safe and effective antiobesity drugs has been the subject of intense research. In this context, the organic selenium compounds have attracted much attention due to their pharmacological properties, such as antihyperglycemic, antioxidant, and anti-inflammatory. The aim of this study was to evaluate the hepatoprotective action of p-chloro-diphenyl diselenide (p-ClPhSe) 2 , an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. Wistar rats were treated during the first ten postnatal days with MSG (4 g/kg by subcutaneous injections) and received (p-ClPhSe) 2 (10 mg/kg, intragastrically) from 90th to 97th postnatal day. Mitochondrial function, purine content and the levels of proteins involved in apoptotic (poly [ADP-ribose] polymerase [PARP]) and inflammatory processes (inducible nitric oxide synthases [iNOS] and p38) were determined in the liver of rats. The present study, demonstrated that postnatal administration of MSG to male rats induced a mitochondrial dysfunction, accompanied by oxidative stress and an increase in the ADP levels, without altering the efficiency of phosphorylation in the liver of adult rats. Furthermore, the MSG administration also induces hepatotoxicity, through an increase in PARP, iNOS, and p38 levels. (p-ClPhSe) 2 treatment had beneficial effects against mitochondrial dysfunction, oxidative stress, and modulated protein markers of apoptosis and inflammation in the liver of MSG-treated rats. J. Cell. Biochem. 118: 2877-2886, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Mitochondrial Function in Allergic Disease.

PubMed

Iyer, Divyaanka; Mishra, Navya; Agrawal, Anurag

2017-05-01

The connections between allergy, asthma and metabolic syndrome are becoming increasingly clear. Recent research suggests a unifying mitochondrial link between the diverse phenotypes of these interlinked morbidities. The scope of this review is to highlight cellular mechanisms, epidemiology and environmental allergens influencing mitochondrial function and its importance in allergy and asthma. We briefly also consider the potential of mitochondria-targeted therapies in prevention and cure. Recent research has shown allergy, asthma and metabolic syndrome to be linked to mitochondrial dysfunction. Environmental pollutants and allergens are observed to cause mitochondrial dysfunction, primarily by inducing oxidative stress and ROS production. Malfunctioning mitochondria change the bioenergetics of the cell and its metabolic profile to favour systemic inflammation, which drives all three types of morbidities. Given the existing experimental evidence, approaches targeting mitochondria (e.g. antioxidant therapy and mitochondrial replacement) are being conducted in relevant disease models-with some progressing towards clinical trials, making mitochondrial function the focus of translational therapy research in asthma, allergy and linked metabolic syndrome.

Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials

PubMed Central

Marzetti, Emanuele; Calvani, Riccardo; Cesari, Matteo; Buford, Thomas W.; Lorenzi, Maria; Behnke, Bradley J.; Leeuwenburgh, Christiaan

2013-01-01

Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes – including oxidative stress, quality control mechanisms and apoptotic signaling – on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial. PMID:23845738

Melatonin protects against uric acid-induced mitochondrial dysfunction, oxidative stress, and triglyceride accumulation in C2C12 myotubes.

PubMed

Maarman, Gerald J; Andrew, Brittany M; Blackhurst, Dee M; Ojuka, Edward O

2017-04-01

Excess uric acid has been shown to induce oxidative stress, triglyceride accumulation, and mitochondrial dysfunction in the liver and is an independent predictor of type-2 diabetes. Skeletal muscle plays a dominant role in type 2 diabetes and presents a large surface area to plasma uric acid. However, the effects of uric acid on skeletal muscle are underinvestigated. Our aim was therefore to characterize the effects of excessive uric acid on oxidative stress, triglyceride content, and mitochondrial function in skeletal muscle C 2 C 12 myotubes and assess how these are modulated by the antioxidant molecule melatonin. Differentiated C 2 C 12 myotubes were exposed to 750 µM uric acid or uric acid + 10 nM melatonin for 72 h. Compared with control, uric acid increased triglyceride content by ~237%, oxidative stress by 32%, and antioxidant capacity by 135%. Uric acid also reduced endogenous ROUTINE respiration, complex II-linked oxidative phosphorylation, and electron transfer system capacities. Melatonin counteracted the effects of uric acid without further altering antioxidant capacity. Our data demonstrate that excess uric acid has adverse effects on skeletal muscle similar to those previously reported in hepatocytes and suggest that melatonin at a low physiological concentration of 10 nM may be a possible therapy against some adverse effects of excess uric acid. NEW & NOTEWORTHY Few studies have investigated the effects of uric acid on skeletal muscle. This study shows that hyperuricemia induces mitochondrial dysfunction and triglyceride accumulation in skeletal muscle. The findings may explain why hyperuricemia is an independent predictor of diabetes. Copyright © 2017 the American Physiological Society.

Inhibition of neuroinflammation and mitochondrial dysfunctions by carbenoxolone in the rotenone model of Parkinson's disease.

PubMed

Thakur, Poonam; Nehru, Bimla

2015-02-01

α-Synuclein aggregation contributes to the Parkinson's disease (PD) pathology in multiple ways-the two most important being the activation of neuroinflammation and mitochondrial dysfunction. Our recent studies have shown the beneficial effects of a heat shock protein (HSP) inducer, carbenoxolone (Cbx), in reducing the aggregation of α-synuclein in a rotenone-based rat model of PD. The present study was designed to explore its ability to attenuate the α-synuclein-mediated alterations in neuroinflammation and mitochondrial functions. The PD model was generated by the rotenone administration (2 mg/kg b.wt.) to the male SD rats for a period of 5 weeks. Cbx (20 mg/kg b.wt.) co-administration was seen to reduce the activation of astrocytes incited by rotenone. Subsequently, the release of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β was inhibited. Further, the expression level of various inflammatory mediators such as COX-2, iNOS, and NF-κB was also reduced following Cbx co-treatment. Cbx was also shown to reduce the rotenone-induced decline in activity of mitochondrial complexes-I, -II, and -IV. Protection of mitochondrial functions and reduction in neuroinflammation lead to the lesser production of ROS and subsequently reduced oxidative stress. This was reflected by the increase in both the cytosolic and mitochondrial GSH levels as well as SOD activity during Cbx co-treatment. Thus, Cbx reduces the inflammatory response and improves the mitochondrial dysfunctions by reducing α-synuclein aggregation. In addition, it also reduces the associated oxidative stress. Due to its ability to target the multiple pathways implicated in the PD, Cbx can serve as a highly beneficial prophylactic agent.

Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids

PubMed Central

Song, Byoung-Joon; Moon, Kwan-Hoon; Olsson, Nils U.; Salem, Norman

2008-01-01

Background/Aims We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6, omega-6) and docosahexaenoic (DHA,22:6n3, omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet prevents alcohol-induced fatty liver. Methods Male Long-Evans rats were fed an ethanol or control liquid-diet with or without DHA/AA for 9 weeks. Plasma transaminase levels, liver histology, oxidative/nitrosative stress markers, and activities of oxidatively-modified mitochondrial proteins were evaluated. Results Chronic alcohol administration increased the degree of fatty liver but fatty liver decreased significantly in rats fed the alcohol-DHA/AA-supplemented diet. Alcohol exposure increased oxidative/nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. However, these increments were normalized in rats fed the alcohol-DHA/AA-supplemented diet. The number of oxidatively-modified mitochondrial proteins was markedly increased following alcohol exposure but significantly reduced in rats fed the alcohol-DHA/AA-supplemented diet. The suppressed activities of mitochondrial aldehyde dehydrogenase, ATP synthase, and 3-ketoacyl-CoA thiolase in ethanol-exposed rats were also recovered in animals fed the ethanol-DHA/AA-supplemented diet. Conclusions Addition of DHA/AA prevents alcohol-induced fatty liver and mitochondrial dysfunction in an animal model by protecting various mitochondrial enzymes most likely through reducing oxidative/nitrosative stress. PMID:18571270

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats.

PubMed

Cioffi, Federica; Senese, Rosalba; Lasala, Pasquale; Ziello, Angela; Mazzoli, Arianna; Crescenzo, Raffaella; Liverini, Giovanna; Lanni, Antonia; Goglia, Fernando; Iossa, Susanna

2017-03-24

Evidence indicates that many forms of fructose-induced metabolic disturbance are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage; however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are events involved in metabolic disease resulting from a fructose-rich diet. In the present study, we evaluated the degree of oxidative damage to liver mtDNA and its repair, in addition to the state of oxidative stress and antioxidant defense in the liver of rats fed a high-fructose diet. We used male rats feeding on a high-fructose or control diet for eight weeks. Our results showed an increase in mtDNA damage in the liver of rats fed a high-fructose diet and this damage, as evaluated by the expression of DNA polymerase γ, was not repaired; in addition, the mtDNA copy number was found to be significantly reduced. A reduction in the mtDNA copy number is indicative of impaired mitochondrial biogenesis, as is the finding of a reduction in the expression of genes involved in mitochondrial biogenesis. In conclusion, a fructose-rich diet leads to mitochondrial and mtDNA damage, which consequently may have a role in liver dysfunction and metabolic diseases.

Mitochondrial Dysfunction in Schizophrenia: Determination of Mitochondrial Respiratory Activity in a Two-Hit Mouse Model.

PubMed

Monpays, Cécile; Deslauriers, Jessica; Sarret, Philippe; Grignon, Sylvain

2016-08-01

Schizophrenia is a chronic mental illness in which mitochondrial dysfunction has been suggested. Our laboratory recently developed a juvenile murine two-hit model (THM) of schizophrenia based on the combination of gestational inflammation, followed by juvenile restraint stress. We previously reported that relevant behaviors and neurochemical disturbances, including oxidative stress, were reversed by the antioxidant lipoic acid (LA), thereby pointing to the central role played by oxidative abnormalities and prompting us to investigate mitochondrial function. Mitochondrial activity was determined with the MitoXpress® commercial kit in two schizophrenia-relevant regions (prefrontal cortex (PFC) and striatum). Measurements were performed in state 3, with substrates for complex I- and complex II-induced respiratory activity (IRA). We observed an increase in complex I IRA in the PFC and striatum in both sexes but an increase in complex II activity only in males. LA treatment prevented this increase only in complex II IRA in males. Expression levels of the different respiratory chain complexes, as well as fission/fusion proteins and protein carbonylation, were unchanged. In conclusion, our juvenile schizophrenia THM shows an increase in mitochondrial activity reversed by LA, specifically in complex II IRA in males. Further investigations are required to determine the mechanisms of these modifications.

Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.

PubMed

Fetterman, Jessica L; Zelickson, Blake R; Johnson, Larry W; Moellering, Douglas R; Westbrook, David G; Pompilius, Melissa; Sammy, Melissa J; Johnson, Michelle; Dunham-Snary, Kimberly J; Cao, Xuemei; Bradley, Wayne E; Zhang, Jinju; Wei, Chih-Chang; Chacko, Balu; Schurr, Theodore G; Kesterson, Robert A; Dell'italia, Louis J; Darley-Usmar, Victor M; Welch, Danny R; Ballinger, Scott W

2013-10-15

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.

Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes

USDA-ARS?s Scientific Manuscript database

Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However, cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin and causing inefficient electro...

In vitro mechanistic study of endosulfan-induced spermatogenic cell apoptosis in the mouse.

PubMed

Xu, Ying; Wang, Na; Shi, Zhi-Xiong; Li, Yan-Bo; Zhou, Xian-Qing; Sun, Zhi-Wei

2016-09-01

To investigate the mechanisms of endosulfan-induced reproductive toxicity, the spermatogenic cell lines (GC-1 spg) of mice were treated with 0, 6, 12, and 24 μg/ml endosulfan for 24 h in vitro The results showed that endosulfan induced apoptosis as well as oxidative stress and mitochondrial dysfunction. Reactive oxygen species and damage of mitochondrial structure were considered as major factors to GC-1 spg cells apoptosis. We further examined the expression of apoptosis-related proteins in mitochondria pathway by Western blot and immunohistochemistry analysis as well as activities. The results showed that endosulfan significantly improved the expressions of cytochrome c and B-cell lymphoma 2 (Bcl-2)-associated X protein and increased the activities of caspases 9 and 3 as well as the downregulation of the expression of Bcl-2 in GC-1 spg cells. The results suggested that exposure to endosulfan might induce the apoptosis of spermatogenic cells via mitochondria-dependent pathway mediated by oxidative stress resulting in the damage of mitochondrial structure and mitochondrial dysfunction. © The Author(s) 2015.

Vildagliptin and caloric restriction for cardioprotection in pre-diabetic rats.

PubMed

Tanajak, Pongpan; Pintana, Hiranya; Siri-Angkul, Natthaphat; Khamseekaew, Juthamas; Apaijai, Nattayaporn; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2017-02-01

Long-term high-fat diet (HFD) consumption causes cardiac dysfunction. Although calorie restriction (CR) has been shown to be useful in obesity, we hypothesized that combined CR with dipeptidyl peptidase-4 (DPP-4) inhibitor provides greater efficacy than monotherapy in attenuating cardiac dysfunction and metabolic impairment in HFD-induced obese-insulin resistant rats. Thirty male Wistar rats were divided into 2 groups to be fed on either a normal diet (ND, n = 6) or a HFD (n = 24) for 12 weeks. Then, HFD rats were divided into 4 subgroups (n = 6/subgroup) to receive just the vehicle, CR diet (60% of mean energy intake and changed to ND), vildagliptin (3 mg/kg/day) or combined CR and vildagliptin for 4 weeks. Metabolic parameters, heart rate variability (HRV), cardiac mitochondrial function, left ventricular (LV) and fibroblast growth factor (FGF) 21 signaling pathway were determined. Rats on a HFD developed insulin and FGF21 resistance, oxidative stress, cardiac mitochondrial dysfunction and impaired LV function. Rats on CR alone showed both decreased body weight and visceral fat accumulation, whereas vildagliptin did not alter these parameters. Rats in CR, vildagliptin and CR plus vildagliptin subgroups had improved insulin sensitivity and oxidative stress. However, vildagliptin improved heart rate variability (HRV), cardiac mitochondrial function and LV function better than the CR. Chronic HFD consumption leads to obese-insulin resistance and FGF21 resistance. Although CR is effective in improving metabolic regulation, vildagliptin provides greater efficacy in preventing cardiac dysfunction by improving anti-apoptosis and FGF21 signaling pathways and attenuating cardiac mitochondrial dysfunction in obese-insulin-resistant rats. © 2017 Society for Endocrinology.

Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases

PubMed Central

de Pablo-Latorre, Raquel; Saide, Assunta; Polishhuck, Elena V.; Nusco, Edoardo; Fraldi, Alessandro; Ballabio, Andrea

2012-01-01

Dysfunctional mitochondria are a well-known disease hallmark. The accumulation of aberrant mitochondria can alter cell homeostasis, thus resulting in tissue degeneration. Lysosomal storage disorders (LSDs) are a group of inherited diseases characterized by the buildup of undegraded material inside the lysosomes that leads to autophagic-lysosomal dysfunction. In LSDs, autophagic stress has been associated to mitochondrial accumulation and dysfunction. However, the mechanisms underlying mitochondrial aberrations and how these are involved in tissue pathogenesis remain largely unexplored. In normal conditions, mitochondrial clearance occurs by mitophagy, a selective form of autophagy, which relies on a parkin-mediated mitochondrial priming and subsequent sequestration by autophagosomes. Here, we performed a detailed analysis of key steps of mitophagy in a mouse model of multiple sulfatase deficiency (MSD), a severe type of LSD characterized by both neurological and systemic involvement. We demonstrated that in MSD liver reduced parkin levels resulted in inefficient mitochondrial priming, thus contributing to the accumulation of giant mitochondria that are located outside autophagic vesicles ultimately leading to cytochrome c release and apoptotic cell death. Morphological and functional changes were also observed in mitochondria from MSD brain but these were not directly associated with neuronal cell loss, suggesting a secondary contribution of mitochondria to neurodegeneration. Together, these data shed new light on the mechanisms underlying mitochondrial dysfunction in LSDs and on their tissue-specific differential contribution to the pathogenesis of this group of metabolic disorders. PMID:22215441

Lycopene protects human SH-SY5Y neuroblastoma cells against hydrogen peroxide-induced death via inhibition of oxidative stress and mitochondria-associated apoptotic pathways

PubMed Central

FENG, CHUNSHENG; LUO, TIANFEI; ZHANG, SHUYAN; LIU, KAI; ZHANG, YANHONG; LUO, YINAN; GE, PENGFEI

2016-01-01

Oxidative stress, which is characterized by excessive production of reactive oxygen species (ROS), is a common pathway that results in neuronal injury or death due to various types of pathological stress. Although lycopene has been identified as a potent antioxidant, its effect on hydrogen peroxide (H2O2)-induced neuronal damage remains unclear. In the present study, pretreatment with lycopene was observed to protect SH-SY5Y neuroblastoma cells against H2O2-induced death via inhibition of apoptosis resulting from activation of caspase-3 and translocation of apoptosis inducing factor (AIF) to the nucleus. Furthermore, the over-produced ROS, as well as the reduced activities of anti-oxidative enzymes, superoxide dismutase and catalase, were demonstrated to be alleviated by lycopene. Additionally, lycopene counteracted H2O2-induced mitochondrial dysfunction, which was evidenced by suppression of mitochondrial permeability transition pore opening, attenuation of the decline of the mitochondrial membrane potential, and inhibition of the increase of Bax and decrease of Bcl-2 levels within the mitochondria. The release of cytochrome c and AIF from the mitochondria was also reduced. These results indicate that lycopene is a potent neuroprotectant against apoptosis, oxidative stress and mitochondrial dysfunction, and could be administered to prevent neuronal injury or death. PMID:27035331

Endothelial AMPK Activation Induces Mitochondrial Biogenesis and Stress Adaptation via eNOS-Dependent mTORC1 Signaling

PubMed Central

Li, Chunying; Reif, Michaella M; Craige, Siobhan; Kant, Shashi; Keaney, John F.

2016-01-01

Metabolic stress sensors like AMP-activated protein kinase (AMPK) are known to confer stress adaptation and promote longevity in lower organisms. This study demonstrates that activating the metabolic stress sensor AMP-activated protein kinase (AMPK) in endothelial cells helps maintain normal cellular function by promoting mitochondrial biogenesis and stress adaptation. To better define the mechanisms whereby AMPK promotes endothelial stress resistance, we used 5-aminoimidazole-4-carboxamide riboside (AICAR) to chronically activate AMPK and observed stimulation of mitochondrial biogenesis in wild type mouse endothelium, but not in endothelium from endothelial nitric oxide synthase knockout (eNOS-null) mice. Interestingly, AICAR-enhanced mitochondrial biogenesis was blocked by pretreatment with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin. Further, AICAR stimulated mTORC1 as determined by phosphorylation of its known downstream effectors in wild type, but not eNOS-null, endothelial cells. Together these data indicate that eNOS is needed to couple AMPK activation to mTORC1 and thus promote mitochondrial biogenesis and stress adaptation in the endothelium. These data suggest a novel mechanism for mTORC1 activation that is significant for investigations in vascular dysfunction. PMID:26989010

Lipid-induced metabolic dysfunction in skeletal muscle.

PubMed

Muoio, Deborah M; Koves, Timothy R

2007-01-01

Insulin resistance is a hallmark of type 2 diabetes and commonly observed in other energy-stressed settings such as obesity, starvation, inactivity and ageing. Dyslipidaemia and 'lipotoxicity'--tissue accumulation of lipid metabolites-are increasingly recognized as important drivers of insulin resistant states. Mounting evidence suggests that lipid-induced metabolic dysfunction in skeletal muscle is mediated in large part by stress-activated serine kinases that interfere with insulin signal transduction. However, the metabolic and molecular events that connect lipid oversupply to stress kinase activation and glucose intolerance are as yet unclear. Application of transcriptomics and targeted mass spectrometry-based metabolomics tools has led to our finding that insulin resistance is a condition in which muscle mitochondria are persistently burdened with a heavy lipid load. As a result, high rates of beta-oxidation outpace metabolic flux through the TCA cycle, leading to accumulation of incompletely oxidized acyl-carnitine intermediates. In contrast, exercise training enhances mitochondrial performance, favouring tighter coupling between beta-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high fat diet. The exercise-activated transcriptional co-activator, PGC1alpha, plays a key role in co-ordinating metabolic flux through these two intersecting metabolic pathways, and its suppression by overfeeding may contribute to obesity-associated mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from mitochondrial lipid stress and a resultant disconnect between beta-oxidation and TCA cycle activity. Understanding this 'disconnect' and its molecular basis may lead to new therapeutic targets for combating metabolic disease.

Attenuation of Ca2+ homeostasis, oxidative stress, and mitochondrial dysfunctions in diabetic rat heart: insulin therapy or aerobic exercise?

PubMed

da Silva, Márcia F; Natali, Antônio J; da Silva, Edson; Gomes, Gilton J; Teodoro, Bruno G; Cunha, Daise N Q; Drummond, Lucas R; Drummond, Filipe R; Moura, Anselmo G; Belfort, Felipe G; de Oliveira, Alessandro; Maldonado, Izabel R S C; Alberici, Luciane C

2015-07-15

We tested the effects of swimming training and insulin therapy, either alone or in combination, on the intracellular calcium ([Ca(2+)]i) homeostasis, oxidative stress, and mitochondrial functions in diabetic rat hearts. Male Wistar rats were separated into control, diabetic, or diabetic plus insulin groups. Type 1 diabetes mellitus was induced by streptozotocin (STZ). Insulin-treated groups received 1 to 4 UI of insulin daily for 8 wk. Each group was divided into sedentary or exercised rats. Trained groups were submitted to swimming (90 min/day, 5 days/wk, 8 wk). [Ca(2+)]i transient in left ventricular myocytes (LVM), oxidative stress in LV tissue, and mitochondrial functions in the heart were assessed. Diabetes reduced the amplitude and prolonged the times to peak and to half decay of the [Ca(2+)]i transient in LVM, increased NADPH oxidase-4 (Nox-4) expression, decreased superoxide dismutase (SOD), and increased carbonyl protein contents in LV tissue. In isolated mitochondria, diabetes increased Ca(2+) uptake, susceptibility to permeability transition pore (MPTP) opening, uncoupling protein-2 (UCP-2) expression, and oxygen consumption but reduced H2O2 release. Swimming training corrected the time course of the [Ca(2+)]i transient, UCP-2 expression, and mitochondrial Ca(2+) uptake. Insulin replacement further normalized [Ca(2+)]i transient amplitude, Nox-4 expression, and carbonyl content. Alongside these benefits, the combination of both therapies restored the LV tissue SOD and mitochondrial O2 consumption, H2O2 release, and MPTP opening. In conclusion, the combination of swimming training with insulin replacement was more effective in attenuating intracellular Ca(2+) disruptions, oxidative stress, and mitochondrial dysfunctions in STZ-induced diabetic rat hearts. Copyright © 2015 the American Physiological Society.

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

PubMed Central

Ten, Vadim S.

2017-01-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units—alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise. PMID:27901512

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants.

PubMed

Ten, Vadim S

2017-02-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units-alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise.

Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes.

PubMed

Abu Bakar, Mohamad Hafizi; Sarmidi, Mohamad Roji; Tan, Joo Shun; Mohamad Rosdi, Mohamad Norisham

2017-03-15

Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resistance and inflammation in animal disease models. Nevertheless, the specific mechanistic actions of celastrol in modulating such improvements at the cellular level remain obscure. The present study sought to explore the mechanistic roles of celastrol upon insulin resistance induced by palmitate in C3A human hepatocytes. The hepatocytes exposed to palmitate (0.75mM) for 48h exhibited reduced both basal and insulin-stimulated glucose uptake, mitochondrial dysfunction, leading to increased mitochondrial oxidative stress with diminished fatty acid oxidation. Elevated expressions of nuclear factor-kappa B p65 (NF-κB p65), c-Jun NH(2)-terminal kinase (JNK) signaling pathways and the amplified release of pro-inflammatory cytokines including IL-8, IL-6, TNF-α and CRP were observed following palmitate treatment. Consistently, palmitate reduced and augmented phosphorylated Tyrosine-612 and Serine-307 of insulin receptor substrate-1 (IRS-1) proteins, respectively in hepatocytes. However, celastrol at the optimum concentration of 30nM was able to reverse these deleterious occasions and protected the cells from mitochondrial dysfunction and insulin resistance. Importantly, we presented evidence for the first time that celastrol efficiently prevented palmitate-induced insulin resistance in hepatocytes at least, via improved mitochondrial functions and insulin signaling pathways. In summary, the present investigation underlines a conceivable mechanism to elucidate the cytoprotective potential of celastrol in attenuating mitochondrial dysfunction and inflammation against the development of hepatic insulin resistance. Copyright © 2017 Elsevier B.V. All rights reserved.

GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation

PubMed Central

Chanana, Priyanka; Kumar, Anil

2016-01-01

Rationale: Panax quinquefolius (American Ginseng) is known for its therapeutic potential against various neurological disorders, but its plausible mechanism of action still remains undeciphered. GABA (Gamma Amino Butyric Acid) plays an important role in sleep wake cycle homeostasis. Thus, there exists rationale in exploring the GABA-ergic potential of Panax quinquefolius as neuroprotective strategy in sleep deprivation induced secondary neurological problems. Objective: The present study was designed to explore the possible GABA-ergic mechanism in the neuro-protective effect of Panax quinquefolius against 72-h sleep deprivation induced anxiety like behavior, oxidative stress, mitochondrial dysfunction, HPA-axis activation and neuroinflammation. Materials and Methods: Male laca mice were sleep deprived for 72-h by using Grid suspended over water method. Panax quinquefolius (American Ginseng 50, 100, and 200 mg/kg) was administered alone and in combination with GABA modulators (GABA Cl− channel inhibitor, GABA-benzodiazepine receptor inhibitor and GABAA agonist) for 8 days, starting 5 days prior to 72-h sleep deprivation period. Various behavioral (locomotor activity, mirror chamber test), biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels), mitochondrial complexes, neuroinflammation marker (Tumor Necrosis Factor, TNF-alpha), serum corticosterone, and histopathological sections of brains were assessed. Results: Seventy two hours sleep deprivation significantly impaired locomotor activity, caused anxiety-like behavior, conditions of oxidative stress, alterations in mitochondrial enzyme complex activities, raised serum corticosterone levels, brain TNFα levels and led to neuroinflammation like signs in discrete brain areas as compared to naive group. Panax quinquefolius (100 and 200 mg/kg) treatment restored the behavioral, biochemical, mitochondrial, molecular and histopathological alterations. Pre-treatment of GABA Cl− channel inhibitor as well as GABA-benzodiazepine receptor inhibitor, significantly reversed the protective effect of P. quinquefolius (100 mg/kg) in 72-h sleep deprived animals (P < 0.05). However, pretreatment with GABAA agonist, potentiated Panax quinquefolius's protective effect which was significant as compared to their effect per se (p < 0.05). Conclusion: GABA-ergic mechanism could be involved in the neuroprotective effect of P.quinquefolius against sleep deprivation induced anxiety-like behavior, oxidative stress, mitochondrial dysfunction, HPA axis activation and neuroinflammation. PMID:27013946

Mitochondrial Dynamics in Diabetic Cardiomyopathy

PubMed Central

Galloway, Chad A.

2015-01-01

Abstract Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545–1562. PMID:25738230

Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.

PubMed

Rocha, Nuno; Bulger, David A; Frontini, Andrea; Titheradge, Hannah; Gribsholt, Sigrid Bjerge; Knox, Rachel; Page, Matthew; Harris, Julie; Payne, Felicity; Adams, Claire; Sleigh, Alison; Crawford, John; Gjesing, Anette Prior; Bork-Jensen, Jette; Pedersen, Oluf; Barroso, Inês; Hansen, Torben; Cox, Helen; Reilly, Mary; Rossor, Alex; Brown, Rebecca J; Taylor, Simeon I; McHale, Duncan; Armstrong, Martin; Oral, Elif A; Saudek, Vladimir; O'Rahilly, Stephen; Maher, Eamonn R; Richelsen, Bjørn; Savage, David B; Semple, Robert K

2017-04-19

MFN2 encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication. MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth. We describe similar massive adipose overgrowth with suppressed leptin expression in four further patients with biallelic MFN2 mutations and at least one p.Arg707Trp allele. Overgrown tissue was composed of normal-sized, UCP1-negative unilocular adipocytes, with mitochondrial network fragmentation, disorganised cristae, and increased autophagosomes. There was strong transcriptional evidence of mitochondrial stress signalling, increased protein synthesis, and suppression of signatures of cell death in affected tissue, whereas mitochondrial morphology and gene expression were normal in skin fibroblasts. These findings suggest that specific MFN2 mutations cause tissue-selective mitochondrial dysfunction with increased adipocyte proliferation and survival, confirm a novel form of excess adiposity with paradoxical suppression of leptin expression, and suggest potential targeted therapies.

Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: Possible mechanism of nephroprotection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahu, Bidya Dhar; Tatireddy, Srujana; Koneru, Meghana

Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrialmore » NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100 mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney. - Highlights: • Naringin ameliorated gentamicin-induced nephrotoxicity in rats. • Naringin treatment attenuated gentamicin-induced renal apoptosis in rats. • Naringin ameliorated gentamicin-induced renal mitochondrial dysfunction in rats. • Naringin decreased NF-κB activation and pro-inflammatory cytokine release. • U-HPLC-MS data revealed that naringin did not alter the renal uptake of gentamicin.« less

Diabetic Retinal Neurodegeneration Is Associated With Mitochondrial Oxidative Stress and Is Improved by an Angiotensin Receptor Blocker in a Model Combining Hypertension and Diabetes

PubMed Central

Silva, Kamila C.; Rosales, Mariana A.B.; Biswas, Subrata K.; Lopes de Faria, Jose B.; Lopes de Faria, Jacqueline M.

2009-01-01

OBJECTIVE Diabetic retinopathy displays the features of a neurodegenerative disease. Oxidative stress is involved in the pathogenesis of diabetic retinopathy. This investigation sought to determine whether hypertension exacerbates the oxidative stress, neurodegeneration, and mitochondrial dysfunction that exists in diabetic retinopathy and whether these changes could be minimized by the angiotensin II type 1 (AT1) receptor blocker (ARB) losartan. RESEARCH DESIGN AND METHODS Diabetes was induced in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. The diabetic SHRs were assigned to receive or not receive losartan. RESULTS The level of apoptosis in the retina was higher in diabetic WKY rats than in the control group, and higher levels were found in diabetic SHRs. The apoptotic cells expressed neural and glial markers. The retinal glial reaction was more evident in diabetic WKY rats and was markedly accentuated in diabetic SHRs. Superoxide production in retinal tissue increased in diabetic WKY rats, and a greater increase occurred in diabetic SHRs. Glutathione levels decreased only in diabetic SHRs. As a consequence, the levels of nitrotyrosine and 8-hydroxy 2′-deoxyguanosine, markers of oxidative stress, were elevated in diabetic groups, mainly in diabetic SHRs. Mitochondrial integrity was dramatically affected in the diabetic groups. The ARB treatment reestablished all of the above-mentioned parameters. CONCLUSIONS These findings suggest that concomitance of hypertension and diabetes exacerbates oxidative stress, neurodegeneration, and mitochondrial dysfunction in the retinal cells. These data provide the first evidence of AT1blockage as a neuroprotective treatment of diabetic retinopathy by reestablishing oxidative redox and the mitochondrial function. PMID:19289456

Targeting Mitochondria and Reactive Oxygen Species-Driven Pathogenesis in Diabetic Nephropathy

PubMed Central

Lindblom, Runa; Higgins, Gavin; Coughlan, Melinda; de Haan, Judy B.

2015-01-01

Diabetic kidney disease is one of the major microvascular complications of both type 1 and type 2 diabetes mellitus. Approximately 30% of patients with diabetes experience renal complications. Current clinical therapies can only mitigate the symptoms and delay the progression to end-stage renal disease, but not prevent or reverse it. Oxidative stress is an important player in the pathogenesis of diabetic nephropathy. The activity of reactive oxygen and nitrogen species (ROS/NS), which are by-products of the diabetic milieu, has been found to correlate with pathological changes observed in the diabetic kidney. However, many clinical studies have failed to establish that antioxidant therapy is renoprotective. The discovery that increased ROS/NS activity is linked to mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, cellular senescence, and cell death calls for a refined approach to antioxidant therapy. It is becoming clear that mitochondria play a key role in the generation of ROS/NS and their consequences on the cellular pathways involved in apoptotic cell death in the diabetic kidney. Oxidative stress has also been associated with necrosis via induction of mitochondrial permeability transition. This review highlights the importance of mitochondria in regulating redox balance, modulating cellular responses to oxidative stress, and influencing cell death pathways in diabetic kidney disease. ROS/NS-mediated cellular dysfunction corresponds with progressive disease in the diabetic kidney, and consequently represents an important clinical target. Based on this consideration, this review also examines current therapeutic interventions to prevent ROS/NS-derived injury in the diabetic kidney. These interventions, mainly aimed at reducing or preventing mitochondrial-generated oxidative stress, improving mitochondrial antioxidant defense, and maintaining mitochondrial integrity, may deliver alternative approaches to halt or prevent diabetic kidney disease. PMID:26676666

Glutamate Signaling and Mitochnodrial Dysfunction in Models of Parkinson’s Disease

DTIC Science & Technology

2012-12-01

synaptic response; 3) antagonism of ionotropic glutamate receptors essentially eliminates the response to PPN stimulation, suggesting that nicotinic...systemic administration of drug, significantly lowers mitochondrial oxidant stress. Third, antagonizing glutamatergic NMDA receptors , but not...metabotropic glutamate receptors , diminishes oxidant stress in dopaminergic neurons; stimulating NMDA receptors raises stress levels. Fourth, blocking

Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Cong; Sekine, Shuichi, E-mail: ssekine@facult

Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and inmore » hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.« less

Mitochondrial bioenergetics decay in aging: beneficial effect of melatonin.

PubMed

Paradies, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M; Petrosillo, Giuseppe

2017-11-01

Aging is a biological process characterized by progressive decline in physiological functions, increased oxidative stress, reduced capacity to respond to stresses, and increased risk of contracting age-associated disorders. Mitochondria are referred to as the powerhouse of the cell through their role in the oxidative phosphorylation to generate ATP. These organelles contribute to the aging process, mainly through impairment of electron transport chain activity, opening of the mitochondrial permeability transition pore and increased oxidative stress. These events lead to damage to proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid of the inner mitochondrial membrane, plays a pivotal role in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis and in mitochondrial membrane stability and dynamics. Cardiolipin alterations are associated with mitochondrial bienergetics decline in multiple tissues in a variety of physiopathological conditions, as well as in the aging process. Melatonin, the major product of the pineal gland, is considered an effective protector of mitochondrial bioenergetic function. Melatonin preserves mitochondrial function by preventing cardiolipin oxidation and this may explain, at least in part, the protective role of this compound in mitochondrial physiopathology and aging. Here, mechanisms through which melatonin exerts its protective role against mitochondrial dysfunction associated with aging and age-associated disorders are discussed.

Neuroprotective Effect of Ginkgolide B on Bupivacaine-Induced Apoptosis in SH-SY5Y Cells

PubMed Central

Li, Le; Zhang, Qing-guo; Lai, Lu-ying; Wen, Xian-jie; Zheng, Ting; Cheung, Chi-wai; Zhou, Shu-qin; Xu, Shi-yuan

2013-01-01

Local anesthetics are used routinely and effectively. However, many are also known to activate neurotoxic pathways. We tested the neuroprotective efficacy of ginkgolide B (GB), an active component of Ginkgo biloba, against ROS-mediated neurotoxicity caused by the local anesthetic bupivacaine. SH-SY5Y cells were treated with different concentrations of bupivacaine alone or following preincubation with GB. Pretreatment with GB increased SH-SY5Y cell viability and attenuated intracellular ROS accumulation, apoptosis, mitochondrial dysfunction, and ER stress. GB suppressed bupivacaine-induced mitochondrial depolarization and mitochondria complex I and III inhibition and increased cleaved caspase-3 and Htra2 expression, which was strongly indicative of activation of mitochondria-dependent apoptosis with concomitantly enhanced expressions of Grp78, caspase-12 mRNA, protein, and ER stress. GB also improved ultrastructural changes indicative of mitochondrial and ER damage induced by bupivacaine. These results implicate bupivacaine-induced ROS-dependent mitochondria, ER dysfunction, and apoptosis, which can be attenuated by GB through its antioxidant property. PMID:24228138

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by ß-amyloid peptide

PubMed Central

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, WE

2010-01-01

Background and purpose: β-Amyloid peptide (Aβ) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. Experimental approach: We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Aβ-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Aβ and on neurite outgrowth in PC12 cells were investigated. Key results: Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Aβ1-42. Similar protective effects against Aβ1-42 were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Aβ load was markedly diminished in the brain of those animals after treatment with piracetam. Aβ production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Aβ-induced mitochondrial dysfunction and Aβ-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Conclusion and implications: Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Aβ on brain function. This article is commented on by Moncada, pp. 217–219 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00706.x and to view related papers by Pravdic et al. and Puerta et al. visit http://dx.doi.org/10.1111/j.1476-5381.2010.00698.x and http://dx.doi.org/10.1111/j.1476-5381.2010.00663.x PMID:20218980

Mitochondrial Approaches to Protect Against Cardiac Ischemia and Reperfusion Injury

PubMed Central

Camara, Amadou K. S.; Bienengraeber, Martin; Stowe, David F.

2011-01-01

The mitochondrion is a vital component in cellular energy metabolism and intracellular signaling processes. Mitochondria are involved in a myriad of complex signaling cascades regulating cell death vs. survival. Importantly, mitochondrial dysfunction and the resulting oxidative and nitrosative stress are central in the pathogenesis of numerous human maladies including cardiovascular diseases, neurodegenerative diseases, diabetes, and retinal diseases, many of which are related. This review will examine the emerging understanding of the role of mitochondria in the etiology and progression of cardiovascular diseases and will explore potential therapeutic benefits of targeting the organelle in attenuating the disease process. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate or manipulate mitochondrial function, to the use of light therapy directed to the mitochondrial function, and to modification of the mitochondrial genome for potential therapeutic benefit. The approach to rationally treat mitochondrial dysfunction could lead to more effective interventions in cardiovascular diseases that to date have remained elusive. The central premise of this review is that if mitochondrial abnormalities contribute to the etiology of cardiovascular diseases (e.g., ischemic heart disease), alleviating the mitochondrial dysfunction will contribute to mitigating the severity or progression of the disease. To this end, this review will provide an overview of our current understanding of mitochondria function in cardiovascular diseases as well as the potential role for targeting mitochondria with potential drugs or other interventions that lead to protection against cell injury. PMID:21559063

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.

PubMed

Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

2015-01-06

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

PubMed Central

Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

2015-01-01

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX’s cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury. PMID:25569804

Modeling cardiac action potential shortening driven by oxidative stress-induced mitochondrial oscillations in guinea pig cardiomyocytes.

PubMed

Zhou, Lufang; Cortassa, Sonia; Wei, An-Chi; Aon, Miguel A; Winslow, Raimond L; O'Rourke, Brian

2009-10-07

Ischemia-induced shortening of the cardiac action potential and its heterogeneous recovery upon reperfusion are thought to set the stage for reentrant arrhythmias and sudden cardiac death. We have recently reported that the collapse of mitochondrial membrane potential (DeltaPsi(m)) through a mechanism triggered by reactive oxygen species (ROS), coupled to the opening of sarcolemmal ATP-sensitive potassium (K(ATP)) channels, contributes to electrical dysfunction during ischemia-reperfusion. Here we present a computational model of excitation-contraction coupling linked to mitochondrial bioenergetics that incorporates mitochondrial ROS-induced ROS release with coupling between the mitochondrial energy state and electrical excitability mediated by the sarcolemmal K(ATP) current (I(K,ATP)). Whole-cell model simulations demonstrate that increasing the fraction of oxygen diverted from the respiratory chain to ROS production triggers limit-cycle oscillations of DeltaPsi(m), redox potential, and mitochondrial respiration through the activation of a ROS-sensitive inner membrane anion channel. The periods of transient mitochondrial uncoupling decrease the cytosolic ATP/ADP ratio and activate I(K,ATP), consequently shortening the cellular action potential duration and ultimately suppressing electrical excitability. The model simulates emergent behavior observed in cardiomyocytes subjected to metabolic stress and provides a new tool for examining how alterations in mitochondrial oxidative phosphorylation will impact the electrophysiological, contractile, and Ca(2+) handling properties of the cardiac cell. Moreover, the model is an important step toward building multiscale models that will permit investigation of the role of spatiotemporal heterogeneity of mitochondrial metabolism in the mechanisms of arrhythmogenesis and contractile dysfunction in cardiac muscle.

Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload.

PubMed

Yancey, Danielle M; Guichard, Jason L; Ahmed, Mustafa I; Zhou, Lufang; Murphy, Michael P; Johnson, Michelle S; Benavides, Gloria A; Collawn, James; Darley-Usmar, Victor; Dell'Italia, Louis J

2015-03-15

Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and β₂-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF.

Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload

PubMed Central

Yancey, Danielle M.; Guichard, Jason L.; Ahmed, Mustafa I.; Zhou, Lufang; Murphy, Michael P.; Johnson, Michelle S.; Benavides, Gloria A.; Collawn, James; Darley-Usmar, Victor

2015-01-01

Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and β2-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF. PMID:25599572

Adipocyte Fatty Acid-Binding Protein Promotes Palmitate-Induced Mitochondrial Dysfunction and Apoptosis in Macrophages

PubMed Central

Li, Hui; Xiao, Yang; Tang, Lin; Zhong, Feng; Huang, Gan; Xu, Jun-Mei; Xu, Ai-Min; Dai, Ru-Ping; Zhou, Zhi-Guang

2018-01-01

A high level of circulating free fatty acids (FFAs) is known to be an important trigger for macrophage apoptosis during the development of atherosclerosis. However, the underlying mechanism by which FFAs result in macrophage apoptosis is not well understood. In cultured human macrophage Thp-1 cells, we showed that palmitate (PA), the most abundant FFA in circulation, induced excessive reactive oxidative substance production, increased malondialdehyde concentration, and decreased adenosine triphosphate levels. Furthermore, PA treatment also led to mitochondrial dysfunction, including the decrease of mitochondrial number, the impairment of respiratory complex IV and succinate dehydrogenase activity, and the reduction of mitochondrial membrane potential. Mitochondrial apoptosis was also detected after PA treatment, indicated by a decrease in cytochrome c release, downregulation of Bcl-2, upregulation of Bax, and increased caspase-3 activity. PA treatment upregulated the expression of adipocyte fatty acid-binding protein (A-FABP), a critical regulator of fatty acid trafficking and lipid metabolism. Inhibition of A-FABP with BMS309403, a small-molecule A-FABP inhibitor, almost reversed all of these indexes. Thus, this study suggested that PA-mediated macrophage apoptosis through A-FABP upregulation, which subsequently resulted in mitochondrial dysfunction and reactive oxidative stress. Inhibition of A-FABP may be a potential therapeutic target for macrophage apoptosis and to delay the progress of atherosclerosis. PMID:29441065

Mitochondrial Dysfunction in Parkinson's Disease.

PubMed

Moon, Hyo Eun; Paek, Sun Ha

2015-06-01

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) with motor and nonmotor symptoms. Defective mitochondrial function and increased oxidative stress (OS) have been demonstrated as having an important role in PD pathogenesis, although the underlying mechanism is not clear. The etiopathogenesis of sporadic PD is complex with variable contributions of environmental factors and genetic susceptibility. Both these factors influence various mitochondrial aspects, including their life cycle, bioenergetic capacity, quality control, dynamic changes of morphology and connectivity (fusion, fission), subcellular distribution (transport), and the regulation of cell death pathways. Mitochondrial dysfunction has mainly been reported in various non-dopaminergic cells and tissue samples from human patients as well as transgenic mouse and fruit fly models of PD. Thus, the mitochondria represent a highly promising target for the development of PD biomarkers. However, the limited amount of dopaminergic neurons prevented investigation of their detailed study. For the first time, we established human telomerase reverse transcriptase (hTERT)-immortalized wild type, idiopathic and Parkin deficient mesenchymal stromal cells (MSCs) isolated from the adipose tissues of PD patients, which could be used as a good cellular model to evaluate mitochondrial dysfunction for the better understanding of PD pathology and for the development of early diagnostic markers and effective therapy targets of PD. In this review, we examine evidence for the roles of mitochondrial dysfunction and increased OS in the neuronal loss that leads to PD and discuss how this knowledge further improve the treatment for patients with PD.

Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction.

PubMed

Lee, Hyo Jung; Choi, Joo Sun; Lee, Hye Ja; Kim, Won-Ho; Park, Sang Ick; Song, Jihyun

2015-12-01

Excessive tissue iron levels are a risk factor for insulin resistance and type 2 diabetes, which are associated with alterations in iron metabolism. However, the mechanisms underlying this association are not well understood. This study used human liver SK-HEP-1 cells to examine how excess iron induces mitochondrial dysfunction and how hepcidin controls gluconeogenesis. Excess levels of reactive oxygen species (ROS) and accumulated iron due to iron overload induced mitochondrial dysfunction, leading to a decrease in cellular adenosine triphosphate content and cytochrome c oxidase III expression, with an associated increase in gluconeogenesis. Disturbances in mitochondrial function caused excess iron deposition and unbalanced expression of iron metabolism-related proteins such as hepcidin, ferritin H and ferroportin during the activation of p38 mitogen-activated protein kinase (MAPK) and CCAAT/enhancer-binding protein alpha (C/EBPα), which are responsible for increased phosphoenolpyruvate carboxykinase expression. Desferoxamine and n-acetylcysteine ameliorated these deteriorations by inhibiting p38 MAPK and C/EBPα activity through iron chelation and ROS scavenging activity. Based on experiments using hepcidin shRNA and hepcidin overexpression, the activation of hepcidin affects ROS generation and iron deposition, which disturbs mitochondrial function and causes an imbalance in iron metabolism and increased gluconeogenesis. Repression of hepcidin activity can reverse these changes. Our results demonstrate that iron overload is associated with mitochondrial dysfunction and that together they can cause abnormal hepatic gluconeogenesis. Hepcidin expression may modulate this disorder by regulating ROS generation and iron deposition. Copyright © 2015 Elsevier Inc. All rights reserved.

Mitochondrial Transfer from Wharton's Jelly Mesenchymal Stem Cell to MERRF Cybrid Reduces Oxidative Stress and Improves Mitochondrial Bioenergetics

PubMed Central

Liou, Chia-Wei; Chen, Shang-Der; Wang, Pei-Wen; Chuang, Jiin-Haur; Tiao, Mao-Meng; Hsu, Te-Yao

2017-01-01

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a maternally inherited mitochondrial disease affecting neuromuscular functions. Mt.8344A>G mutation in mitochondrial DNA (mtDNA) is the most common cause of MERRF syndrome and has been linked to an increase in reactive oxygen species (ROS) level and oxidative stress, as well as impaired mitochondrial bioenergetics. Here, we tested whether WJMSC has therapeutic potential for the treatment of MERRF syndrome through the transfer of mitochondria. The MERRF cybrid cells exhibited a high mt.8344A>G mutation ratio, enhanced ROS level and oxidative damage, impaired mitochondrial bioenergetics, defected mitochondria-dependent viability, exhibited an imbalance of mitochondrial dynamics, and are susceptible to apoptotic stress. Coculture experiments revealed that mitochondria were intercellularly conducted from the WJMSC to the MERRF cybrid. Furthermore, WJMSC transferred mitochondria exclusively to cells with defective mitochondria but not to cells with normal mitochondria. MERRF cybrid following WJMSC coculture (MF+WJ) demonstrated improvement of mt.8344A>G mutation ratio, ROS level, oxidative damage, mitochondrial bioenergetics, mitochondria-dependent viability, balance of mitochondrial dynamics, and resistance against apoptotic stress. WJMSC-derived mitochondrial transfer and its therapeutic effect were noted to be blocked by F-actin depolymerizing agent cytochalasin B. Collectively, the WJMSC ability to rescue cells with defective mitochondrial function through donating healthy mitochondria may lead to new insights into the development of more efficient strategies to treat diseases related to mitochondrial dysfunction. PMID:28607632

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target

PubMed Central

Scholpa, Natalie E.

2017-01-01

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI. PMID:28935700

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target.

PubMed

Scholpa, Natalie E; Schnellmann, Rick G

2017-12-01

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI. U.S. Government work not protected by U.S. copyright.

Mitochondrial plasticity in cancer-related muscle wasting: potential approaches for its management.

PubMed

Vitorino, Rui; Moreira-Gonçalves, Daniel; Ferreira, Rita

2015-05-01

Cancer cachexia represents a critical problem in clinical oncology due to its negative impact on patients' quality of life, therapeutic tolerance and survival. This paraneoplasic condition is characterized by significant weight loss mainly from skeletal muscle wasting. Understanding the molecular mechanisms underlying cancer cachexia is urgent in order to develop and apply efficient therapeutic strategies. Mitochondrial dysfunction is an early event in cancer-induced muscle wasting. Decreased ability for ATP synthesis, impaired mitochondrial biogenesis, increased oxidative stress, impairment of protein quality control systems, increased susceptibility to mitophagy and to apoptosis were all shown to mediate contractile dysfunction and wasting in cancer cachexia. Anti-inflammatory therapies as well as exercise training seem to counteract muscle mass loss in part by improving mitochondrial functionality. Given its central role in muscle wasting, mitochondrial plasticity should be viewed as a key therapeutic target for the preservation of muscle mass in cancer cachexia. Few studies have addressed the mitochondrial events modulated by cancer cachexia and contradictory data were reported. Scarcer studies have focused on the mitochondrial adaptation to anticancer cachexia strategies.

Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson's disease: Involvement of mitochondrial dysfunctions and oxidative stress.

PubMed

Paul, Rajib; Choudhury, Amarendranath; Kumar, Sanjeev; Giri, Anirudha; Sandhir, Rajat; Borah, Anupom

2017-01-01

Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer's disease while its role in the occurrence of Parkinson's disease (PD) is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.

Dynamic survey of mitochondria by ubiquitin

PubMed Central

Escobar-Henriques, Mafalda; Langer, Thomas

2014-01-01

Ubiquitin is a post-translational modifier with proteolytic and non-proteolytic roles in many biological processes. At mitochondria, it performs regulatory homeostatic functions and contributes to mitochondrial quality control. Ubiquitin is essential for mitochondrial fusion, regulates mitochondria-ER contacts, and participates in maternal mtDNA inheritance. Under stress, mitochondrial dysfunction induces ubiquitin-dependent responses that involve mitochondrial proteome remodeling and culminate in organelle removal by mitophagy. In addition, many ubiquitin-dependent mechanisms have been shown to regulate innate immune responses and xenophagy. Here, we review the emerging roles of ubiquitin at mitochondria. PMID:24569520

Inhibition of Drp1 attenuates mitochondrial damage and myocardial injury in Coxsackievirus B3 induced myocarditis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Lin; Zhang, Ming; Yan, Rui

Viral myocarditis (VMC) is closely related to apoptosis, oxidative stress, innate immunity, and energy metabolism, which are all linked to mitochondrial dysfunction. A close nexus between mitochondrial dynamics and cardiovascular disease with mitochondrial dysfunction has been deeply researched, but there is still no relevant report in viral myocarditis. In this study, we aimed to explore the role of Dynamin-related protein 1 (Drp1)-linked mitochondrial fission in VMC. Mice were inoculated with the Coxsackievirus B3 (CVB3) and treated with mdivi1 (a Drp1 inhibitor). Protein expression of Drp1 was increased in mitochondria while decreased in cytoplasm and accompanied by excessive mitochondrial fission inmore » VMC mice. In addition, midivi1 treatment attenuate inflammatory cells infiltration in myocardium of the mice, serum Cardiac troponin I (CTnI) and Creatine kinase-MB (CK-MB) level. Mdivi1 also could improved the survival rate of mice and mitochondrial dysfunction reflected as the up-regulated mitochondrial marker enzymatic activities of succinate dehydrogenase (SDH), cytochrome c oxidase (COX) and mitochondrial membrane potential (MMP). At the same time, mdivi1 rescued the body weight loss, myocardial injury and apoptosis of cardiomyocyte. Furthermore, decease in LVEDs and increase in EF and FS were detected by echocardiogram, which indicated the improved myocardial function. Thus, Drp1-linked excessive mitochondrial fission contributed to VMC and midivi1 may be a potential therapeutic approach. - Highlights: • The expression of Drp1 is significantly increased in mitochondria while decreased in cytoplasm in VMC mice. • Drp1-linked excessive mitochondrial fission is involved in VMC. • Midivi1 treatment mitigate the mitochondrial damage, inflammation, apoptosis in VMC mice. • The disturbance of mitochondrial dynamics may be a new therapeutic target for VMC.« less

Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein.

PubMed

Yang, Rui-Xin; Lei, Jie; Wang, Bo-Dong; Feng, Da-Yun; Huang, Lu; Li, Yu-Qian; Li, Tao; Zhu, Gang; Li, Chen; Lu, Fang-Fang; Nie, Tie-Jian; Gao, Guo-Dong; Gao, Li

2017-01-01

Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro . SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein

PubMed Central

Yang, Rui-Xin; Lei, Jie; Wang, Bo-Dong; Feng, Da-Yun; Huang, Lu; Li, Yu-Qian; Li, Tao; Zhu, Gang; Li, Chen; Lu, Fang-Fang; Nie, Tie-Jian; Gao, Guo-Dong; Gao, Li

2017-01-01

Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro. SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke. PMID:28649223

Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice.

PubMed

Paul, Rajib; Borah, Anupom

2017-12-20

There exists an intricate relationship between hypercholesterolemia (elevated plasma cholesterol) and brain functions. The present study aims to understand the impact of hypercholesterolemia on pathological consequences in mouse brain. A chronic mouse model of hypercholesterolemia was induced by giving high-cholesterol diet for 12 weeks. The hypercholesterolemic mice developed cognitive impairment as evident from object recognition memory test. Cholesterol accumulation was observed in four discrete brain regions, such as cortex, striatum, hippocampus and substantia nigra along with significantly damaged blood-brain barrier by hypercholesterolemia. The crucial finding is the loss of acetylcholinesterase activity with mitochondrial dysfunction globally in the brain of hypercholesterolemic mice, which is related to the levels of cholesterol. Moreover, the levels of hydroxyl radical were elevated in the regions of brain where the activity of mitochondrial complexes was found to be reduced. Intriguingly, elevations of inflammatory stress markers in the cholesterol-rich brain regions were observed. As cognitive impairment, diminished brain acetylcholinesterase activity, mitochondrial dysfunctions, and inflammation are the prima facie pathologies of neurodegenerative diseases, the findings impose hypercholesterolemia as potential risk factor towards brain dysfunction.

Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood–Brain Barrier Damage

PubMed Central

Qie, Xiaojuan; Wen, Di; Guo, Hongyan; Xu, Guanjie; Liu, Shuai; Shen, Qianchao; Liu, Yi; Zhang, Wenfang; Cong, Bin; Ma, Chunling

2017-01-01

Methamphetamine (METH) abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood–brain barrier (BBB). Herein, we explored the potential mechanism of endoplasmic reticulum (ER) stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3) cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS) and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo) and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption. PMID:28959203

Overexpression of DNA ligase III in mitochondria protects cells against oxidative stress and improves mitochondrial DNA base excision repair.

PubMed

Akbari, Mansour; Keijzers, Guido; Maynard, Scott; Scheibye-Knudsen, Morten; Desler, Claus; Hickson, Ian D; Bohr, Vilhelm A

2014-04-01

Base excision repair (BER) is the most prominent DNA repair pathway in human mitochondria. BER also results in a temporary generation of AP-sites, single-strand breaks and nucleotide gaps. Thus, incomplete BER can result in the generation of DNA repair intermediates that can disrupt mitochondrial DNA replication and transcription and generate mutations. We carried out BER analysis in highly purified mitochondrial extracts from human cell lines U2OS and HeLa, and mouse brain using a circular DNA substrate containing a lesion at a specific position. We found that DNA ligation is significantly slower than the preceding mitochondrial BER steps. Overexpression of DNA ligase III in mitochondria improved the rate of overall BER, increased cell survival after menadione induced oxidative stress and reduced autophagy following the inhibition of the mitochondrial electron transport chain complex I by rotenone. Our results suggest that the amount of DNA ligase III in mitochondria may be critical for cell survival following prolonged oxidative stress, and demonstrate a functional link between mitochondrial DNA damage and repair, cell survival upon oxidative stress, and removal of dysfunctional mitochondria by autophagy. Copyright © 2014. Published by Elsevier B.V.

Triterpenic acids-enriched fraction from Cyclocarya paliurus attenuates non-alcoholic fatty liver disease via improving oxidative stress and mitochondrial dysfunction.

PubMed

Zhao, Meng-Ge; Sheng, Xue-Ping; Huang, Ya-Ping; Wang, Yi-Ting; Jiang, Cui-Hua; Zhang, Jian; Yin, Zhi-Qi

2018-08-01

The effects of triterpenic acids-enriched fraction from Cyclocarya paliurus (CPT) on nonalcoholic fatty liver disease (NAFLD) were investigated using in vivo and in vitro models. In high fat diet-induced Wister rats, CPT significantly increased superoxide dismutase (SOD) activity and glutathione/oxidized glutathione (GSH/GSSG) ratio, reduced malondialdehyde (MDA) and protein carbonyl (PCO) levels. Moreover, CPT restored mitochondrial membrane potential dysfunction, decreased cytochrome P450 enzyme 2E1 (CYP2E1) activity, improved nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-mediated antioxidant enzyme heme oxygenase1 (HO-1) expression. In free fatty acids-induced HepG2 cells, CPT dramatically decreased ROS content, increased mitochondrial NADH dehydrogenase (Complex I) and mitochondrial cytochrome C oxidase (Complex IV) levels. Furthermore, CPT could upregulate HO-1, quinine oxidoreductase 1 (NQO1) expression, and increase Nrf2 translocation from cytoplasm-to-nucleus. The results indicated CPT could protect mitochondria function and improve oxidative stress by activating Nrf2. Therefore, it can be inferred that CPT may be a potential agent against NAFLD. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

PubMed Central

Moreno-Beltrán, Blas; Guerra-Castellano, Alejandra; Del Conte, Rebecca; García-Mauriño, Sofía M.; Díaz-Moreno, Sofía; González-Arzola, Katiuska; Santos-Ocaña, Carlos; Velázquez-Campoy, Adrián; De la Rosa, Miguel A.; Turano, Paola; Díaz-Moreno, Irene

2017-01-01

Regulation of mitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia-dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation—in particular, at tyrosine 48—is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-l-phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects. PMID:28348229

Mitochondria and Cardiovascular Aging

PubMed Central

Dai, Dao-Fu; Ungvari, Zoltan

2013-01-01

Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (e.g. renin-angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants, calorie restriction, calorie restriction mimetics and exercise training. PMID:22499901

Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control

PubMed Central

McLelland, Gian-Luca; Soubannier, Vincent; Chen, Carol X; McBride, Heidi M; Fon, Edward A

2014-01-01

Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD. PMID:24446486

Protective effects of phosphodiesterase-1 (PDE1) and ATP sensitive potassium (KATP) channel modulators against 3-nitropropionic acid induced behavioral and biochemical toxicities in experimental Huntington׳s disease.

PubMed

Gupta, Surbhi; Sharma, Bhupesh

2014-06-05

Huntington׳s disease (HD), a devastating neurodegenerative disorder, is characterized by weight loss, impairment of motor function, cognitive dysfunction, neuropsychiatric disturbances and striatal damage. Phosphodiesterase-1 (PDE1) has been implicated in various neurological diseases. Mitochondrial potassium channels in the brain take part in neuroprotection. This study has been structured to investigate the role of vinpocetine, a selective PDE1 inhibitor as well as nicorandil, selective ATP sensitive potassium (KATP) channel opener in 3-nitropropionic acid (3-NP) induced HD symptoms in rats. Systemic administration of 3-NP significantly, reduced body weight, impaired locomotion, grip strength and impaired cognition. 3-NP elicited marked oxidative stress in the brain (enhanced malondialdehyde-MDA, reduced glutathione-GSH content, superoxide dismutase-SOD and catalase-CAT), elevated brain acetylcholinesterase activity and inflammation (myeloperoxidase-MPO), with marked nitrosative stress (nitrite/nitrate) in the brain. 3-NP has also induced mitochondrial dysfunction (impaired mitochondrial NADH dehydrogenase-complex I, succinate dehydrogenase-complex II and cytochrome oxidase-complex IV) activities in the striatum of the rat. Tetrabenazine was used as a positive control. Treatment with vinpocetine, nicorandil and tetrabenazine ameliorated 3-NP induced reduction in body weight, impaired locomotion, grip strength and impaired cognition. Treatment with these drugs reduced brain striatum oxidative (MDA, GSH, SOD and CAT) and nitrosative (nitrite/nitrate) stress, acetylcholinesterase activity, inflammation and mitochondrial dysfunctions. These results indicate that vinpocetine, a selective PDE1 inhibitor and nicorandil, a KATP channel opener have attenuated 3-NP induced experimental HD. Hence, pharmacological modulation of PDE1 as well as KATP channels may be considered as potential research targets for mitigation of HD. Copyright © 2014 Elsevier B.V. All rights reserved.

The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis.

PubMed

Lowes, Damon A; Thottakam, Bensita M V; Webster, Nigel R; Murphy, Michael P; Galley, Helen F

2008-12-01

Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.

p53/CEP-1 Increases or Decreases Lifespan, Depending on Level of Mitochondrial Bioenergetic Stress

PubMed Central

Ventura, Natascia; Rea, Shane L.; Schiavi, Alfonso; Torgovnick, Alessandro; Testi, Roberto; Johnson, Thomas E.

2009-01-01

SUMMARY Mitochondrial pathologies underlie a number of life-shortening diseases in humans. In the nematode Caenorhabditis elegans, severely reduced expression of mitochondrial proteins involved in electron transport chain-mediated energy production also leads to pathological phenotypes, including arrested development and/or shorter life; in sharp contrast, mild suppression of these same proteins extends lifespan. Here we show that the C. elegans p53 ortholog cep-1 mediates these opposite effects. We find that cep-1 is required to extend longevity in response to mild suppression of several bioenergetically relevant mitochondrial proteins, including frataxin - the protein defective in patients with Friedreich’s Ataxia. Importantly we show that cep-1 also mediates both the developmental arrest and life shortening induced by severe mitochondrial stress. Our findings support an evolutionarily conserved function for p53 in modulating organismal responses to mitochondrial dysfunction and suggest that metabolic checkpoint responses may play a role in longevity control and in human mitochondrial-associated diseases. PMID:19416129

Rotenone, Paraquat, and Parkinson’s Disease

PubMed Central

Tanner, Caroline M.; Kamel, Freya; Ross, G. Webster; Hoppin, Jane A.; Goldman, Samuel M.; Korell, Monica; Marras, Connie; Bhudhikanok, Grace S.; Kasten, Meike; Chade, Anabel R.; Comyns, Kathleen; Richards, Marie Barber; Meng, Cheryl; Priestley, Benjamin; Fernandez, Hubert H.; Cambi, Franca; Umbach, David M.; Blair, Aaron; Sandler, Dale P.; Langston, J. William

2011-01-01

Background Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Objectives Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Methods We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case. Results In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7). Conclusions PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology. PMID:21269927

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

PubMed

Su, Chen-Ming; Chen, Chien-Yu; Lu, Tingting; Sun, Yi; Li, Weimin; Huang, Yuan-Li; Tsai, Chun-Hao; Chang, Chih-Shiang; Tang, Chih-Hsin

2016-12-13

Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo.

Lack of β, β-carotene -9’, 10’-oxygenase 2 leads to hepatic mitochondrial dysfunction and cellular oxidative stress in mice

PubMed Central

Wu, Lei; Guo, Xin; Hartson, Steven D.; Davis, Mary Abby; He, Hui; Medeiros, Denis M.; Wang, Weiqun; Clarke, Stephen L.; Lucas, Edralin; Smith, Brenda J.; von Lintig, Johannes; Lin, Dingbo

2017-01-01

Scope β,β-carotene-9’,10’-dioxygenase 2 (BCO2) is a carotenoid cleavage enzyme localized to the inner mitochondrial membrane in mammals. This study was aimed to assess the impact of genetic ablation of BCO2 on hepatic oxidative stress through mitochondrial function in mice. Methods and Results Liver samples from 6 week old male BCO2−/− knockout (KO) and isogenic wild-type (WT) mice were subjected to proteomics and functional activity assays. Compared to the WT, KO mice consumed more food (by 18 %) yet displayed significantly lower body weight (by 12 %). Mitochondrial proteomic results demonstrated that loss of BCO2 was associated with quantitative changes of the mitochondrial proteome mainly shown by suppressed expression of enzymes and/or proteins involved in fatty acid β–oxidation, the tricarboxylic acid cycle, and the electron transport chain (ETC). The mitochondrial basal respiratory rate, proton leak, and ETC complex II capacity were significantly elevated in the livers of KO compared to WT mice. Moreover, elevated reactive oxygen species and increased mitochondrial protein carbonylation were also demonstrated in liver of KO mice. Conclusions Loss of BCO2 induces mitochondrial hyperactivation, mitochondrial stress and changes of the mitochondrial proteome, leading to mitochondrial energy insufficiency. BCO2 appears to be critical for proper hepatic mitochondrial function. PMID:27991717

N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses.

PubMed

Small, David M; Sanchez, Washington Y; Roy, Sandrine F; Morais, Christudas; Brooks, Heddwen L; Coombes, Jeff S; Johnson, David W; Gobe, Glenda C

2018-05-01

Oxidative stress and mitochondrial dysfunction exacerbate acute kidney injury (AKI), but their role in any associated progress to chronic kidney disease (CKD) remains unclear. Antioxidant therapies often benefit AKI, but their benefits in CKD are controversial since clinical and preclinical investigations often conflict. Here we examined the influence of the antioxidant N-acetyl-cysteine (NAC) on oxidative stress and mitochondrial function during AKI (20-min bilateral renal ischemia plus reperfusion/IR) and progression to chronic kidney pathologies in mice. NAC (5% in diet) was given to mice 7 days prior and up to 21 days post-IR (21d-IR). NAC treatment resulted in the following: prevented proximal tubular epithelial cell apoptosis at early IR (40-min postischemia), yet enhanced interstitial cell proliferation at 21d-IR; increased transforming growth factor-β1 expression independent of IR time; and significantly dampened nuclear factor-like 2-initiated cytoprotective signaling at early IR. In the long term, NAC enhanced cellular metabolic impairment demonstrated by increased peroxisome proliferator activator-γ serine-112 phosphorylation at 21d-IR. Intravital multiphoton microscopy revealed increased endogenous fluorescence of nicotinamide adenine dinucleotide (NADH) in cortical tubular epithelial cells during ischemia, and at 21d-IR that was not attenuated with NAC. Fluorescence lifetime imaging microscopy demonstrated persistent metabolic impairment by increased free/bound NADH in the cortex at 21d-IR that was enhanced by NAC. Increased mitochondrial dysfunction in remnant tubular cells was demonstrated at 21d-IR by tetramethylrhodamine methyl ester fluorimetry. In summary, NAC enhanced progression to CKD following AKI not only by dampening endogenous cellular antioxidant responses at time of injury but also by enhancing persistent kidney mitochondrial and metabolic dysfunction.

A Functional Antagonistic Relationship between Auxin and Mitochondrial Retrograde Signaling Regulates Alternative Oxidase1a Expression in Arabidopsis1[W][OPEN

PubMed Central

Ivanova, Aneta; Law, Simon R.; Narsai, Reena; Duncan, Owen; Lee, Jae-Hoon; Zhang, Botao; Van Aken, Olivier; Radomiljac, Jordan D.; van der Merwe, Margaretha; Yi, KeKe; Whelan, James

2014-01-01

The perception and integration of stress stimuli with that of mitochondrion function are important during periods of perturbed cellular homeostasis. In a continuous effort to delineate these mitochondrial/stress-interacting networks, forward genetic screens using the mitochondrial stress response marker alternative oxidase 1a (AOX1a) provide a useful molecular tool to identify and characterize regulators of mitochondrial stress signaling (referred to as regulators of alternative oxidase 1a [RAOs] components). In this study, we reveal that mutations in genes coding for proteins associated with auxin transport and distribution resulted in a greater induction of AOX1a in terms of magnitude and longevity. Three independent mutants for polarized auxin transport, rao3/big, rao4/pin-formed1, and rao5/multidrug-resistance1/abcb19, as well as the Myb transcription factor rao6/asymmetric leaves1 (that displays altered auxin patterns) were identified and resulted in an acute sensitivity toward mitochondrial dysfunction. Induction of the AOX1a reporter system could be inhibited by the application of auxin analogs or reciprocally potentiated by blocking auxin transport. Promoter activation studies with AOX1a::GUS and DR5::GUS lines further confirmed a clear antagonistic relationship between the spatial distribution of mitochondrial stress and auxin response kinetics, respectively. Genome-wide transcriptome analyses revealed that mitochondrial stress stimuli, such as antimycin A, caused a transient suppression of auxin signaling and conversely, that auxin treatment repressed a part of the response to antimycin A treatment, including AOX1a induction. We conclude that mitochondrial stress signaling and auxin signaling are reciprocally regulated, balancing growth and stress response(s). PMID:24820025

Calcium and ER stress mediate hepatic apoptosis after burn injury

PubMed Central

Gauglitz, Gerd G.; Song, Juquan; Kulp, Gabriela A.; Finnerty, Celeste C.; Cox, Robert A.; Barral, José M.; Herndon, David N.; Boehning, Darren

2009-01-01

Abstract A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time‐points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn‐induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function – effects which may be mediated by increased calcium release by inositol 1,4,5‐trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury. PMID:20141609

Metabolic Stress and Disorders Related to Alterations in Mitochondrial Fission or Fusion

PubMed Central

Babbar, Mansi; Sheikh, M. Saeed

2014-01-01

Mitochondrial morphology and metabolism play an important role in cellular homeostasis. Recent studies have shown that the fidelity of mitochondrial morphology is important in maintaining mitochondrial shape, number, size, membrane potential, ATP synthesis, mtDNA, motility, signaling, quality control, response to cellular stress, mitophagy and apoptosis. This article provides an overview of the current state of knowledge of the fission and fusion machinery with a focus on the mechanisms underlying the regulation of the mitochondrial morphology and cellular energy state. Several lines of evidence indicate that dysregulation of mitochondrial fission or fusion is associated with mitochondrial dysfunction, which in turn impacts mitophagy and apoptosis. Metabolic disorders are also associated with dysregulation of fission or fusion and the available lines of evidence point to a bidirectional interplay between the mitochondrial fission or fusion reactions and bioenergetics. Clearly, more in-depth studies are needed to fully elucidate the mechanisms that control mitochondrial fission and fusion. It is envisioned that the outcome of such studies will improve the understanding of the molecular basis of related metabolic disorders and also facilitate the development of better therapeutics. PMID:24533171

The Cytomegalovirus protein pUL37×1 targets mitochondria to mediate neuroprotection

PubMed Central

Hong, Chien Tai; Chau, Kai-Yin; Schapira, Anthony H. V.

2016-01-01

There is substantial evidence that mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson disease (PD). This contribution probably encompasses defects of oxidative phosphorylation, mitochondrial turnover (mitophagy), mitochondrial derived oxidative stress, and apoptotic signalling. Human cytomegalovirus immediate-early protein pUL37 × 1 induces Bax mitochondrial translocation and inactivation to prevent apoptosis. Over-expressing pUL37 × 1 in neuronal cells protects against staurosporin and 6-hydroxydopamine induced apoptosis and cell death. Protection is not enhanced by bax silencing in pUL37 × 1 over-expressing cells, suggesting a bax-dependent mechanism of action. pUL37 × 1 increases glycolysis and induces mitochondrial hyperpolarization, a bax independent anti-apoptotic action. pUL37 × 1 increases glycolysis through activation of phosphofructokinase by a calcium-dependent pathway. The dual anti-apoptotic mechanism of pUL37 × 1 may be considered a novel neuroprotective strategy in diseases where mitochondrial dysfunction and apoptotic pathways are involved. PMID:27562039

Sulforaphane Inhibits Mitochondrial Permeability Transition and Oxidative Stress

PubMed Central

Greco, Tiffany; Shafer, Jonathan; Fiskum, Gary

2012-01-01

Exposure of mitochondria to oxidative stress and elevated Ca2+ promotes opening of the mitochondrial permeability transition pore (PTP), resulting in membrane depolarization, uncoupling of oxidative phosphorylation, and potentially cell death. This study tested the hypothesis that treatment of rats with sulforaphane (SFP), an activator of the Nrf2 pathway of antioxidant gene expression, increases the resistance of liver mitochondria to redox-regulated PTP opening and elevates mitochondrial levels of antioxidants. Rats were injected with SFP or drug vehicle and liver mitochondria were isolated 40 hr later. Respiring mitochondria actively accumulated added Ca2+, which was then released through PTP opening induced by agents that either cause an oxidized shift in the mitochondrial redox state or that directly oxidize protein thiol groups. SFP treatment of rats inhibited the rate of pro-oxidant-induced mitochondrial Ca2+ release and increased expression of the glutathione peroxidase/reductase system, thioredoxin, and malic enzyme. These results are the first to demonstrate that SFP treatment of animals increases liver mitochondrial antioxidant defenses and inhibits redox-sensitive PTP opening. This novel form of preconditioning could protect against a variety of pathologies that include oxidative stress and mitochondrial dysfunction in their etiologies. PMID:21986339

Spirulina platensis prevents high glucose-induced oxidative stress mitochondrial damage mediated apoptosis in cardiomyoblasts.

PubMed

Jadaun, Pratiksha; Yadav, Dhananjay; Bisen, Prakash Singh

2018-04-01

The current study was undertaken to study the effect of Spirulina platensis (Spirulina) extract on enhanced oxidative stress during high glucose induced cell death in H9c2 cells. H9c2 cultured under high glucose (33 mM) conditions resulted in a noteworthy increase in oxidative stress (free radical species) accompanied by loss of mitochondrial membrane potential, release of cytochrome c, increase in caspase activity and pro-apoptotic protein (Bax). Spirulina extract (1 μg/mL), considerably inhibited increased ROS and RNS levels, reduction in cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax and suppressed the Bax/Bcl2 ratio with induced apoptosis without affecting cell viability. Overall results suggest that Spirulina extract plays preventing role against enhanced oxidative stress during high glucose induced apoptosis in cardiomyoblasts as well as related dysfunction in H9c2 cells.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction.

PubMed

Lord, Kevin C; Shenouda, Sylvia K; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A; Varner, Kurt J

2010-07-01

Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Echocardiography and Millar pressure-volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased -dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction

PubMed Central

Lord, Kevin C.; Shenouda, Sylvia K.; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A.; Varner, Kurt J.

2010-01-01

Aims Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Methods and results Echocardiography and Millar pressure–volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased −dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. Conclusion This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction. PMID:20139112

Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants.

PubMed

Roubicek, Deborah A; Souza-Pinto, Nadja C de

2017-11-01

The mitochondrial DNA (mtDNA) is a closed circular molecule that encodes, in humans, 13 polypeptides components of the oxidative phosphorylation complexes. Integrity of the mitochondrial genome is essential for mitochondrial function and cellular homeostasis, and mutations and deletions in the mtDNA lead to oxidative stress, mitochondrial dysfunction and cell death. In vitro and in situ studies suggest that when exposed to certain genotoxins, mtDNA accumulates more damage than nuclear DNA, likely owing to its organization and localization in the mitochondrial matrix, which tends to accumulate lipophilic, positively charged molecules. In that regard, several relevant environmental and occupational contaminants have physical-chemical characteristics that indicate that they might accumulate in mitochondria and target mtDNA. Nonetheless, very little is known so far about mtDNA damage and mitochondrial dysfunction due to environmental exposure, either in model organisms or in humans. In this article, we discuss some of the characteristics of mtDNA which render it a potentially relevant target for damage by environmental contaminants, as well as possible functional consequences of damage/mutation accumulation. In addition, we review the data available in the literature focusing on mitochondrial effects of the most common classes of environmental pollutants. From that, we conclude that several lines of experimental evidence support the idea that mitochondria and mtDNA are susceptible and biologically relevant targets for pollutants, and more studies, including mechanistic ones, are needed to shed more light into the contribution of mitochondrial dysfunction to the environmental and human health effects of chemical exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Yingying; Fang, Shanshan; Sun, Qiushi

Glioblastoma is one of the most vascular brain tumour and highly resistant to current therapy. Targeting both glioblastoma cells and angiogenesis may present an effective therapeutic strategy for glioblastoma. In our work, we show that an anthelmintic drug, ivermectin, is active against glioblastoma cells in vitro and in vivo, and also targets angiogenesis. Ivermectin significantly inhibits growth and anchorage-independent colony formation in U87 and T98G glioblastoma cells. It induces apoptosis in these cells through a caspase-dependent manner. Ivermectin significantly suppresses the growth of two independent glioblastoma xenograft mouse models. In addition, ivermectin effectively targets angiogenesis through inhibiting capillary network formation, proliferation andmore » survival in human brain microvascular endothelial cell (HBMEC). Mechanistically, ivermectin decreases mitochondrial respiration, membrane potential, ATP levels and increases mitochondrial superoxide in U87, T98G and HBMEC cells exposed to ivermectin. The inhibitory effects of ivermectin are significantly reversed in mitochondria-deficient cells or cells treated with antioxidants, further confirming that ivermectin acts through mitochondrial respiration inhibition and induction of oxidative stress. Importantly, we show that ivermectin suppresses phosphorylation of Akt, mTOR and ribosomal S6 in glioblastoma and HBMEC cells, suggesting its inhibitory role in deactivating Akt/mTOR pathway. Altogether, our work demonstrates that ivermectin is a useful addition to the treatment armamentarium for glioblastoma. Our work also highlights the therapeutic value of targeting mitochondrial metabolism in glioblastoma. - Highlights: • Ivermectin is effective in glioblastoma cells in vitro and in vivo. • Ivermectin inhibits angiogenesis. • Ivermectin induces mitochondrial dysfunction and oxidative stress. • Ivermectin deactivates Akt/mTOR signaling pathway.« less

Tryptamine-gallic acid hybrid prevents non-steroidal anti-inflammatory drug-induced gastropathy: correction of mitochondrial dysfunction and inhibition of apoptosis in gastric mucosal cells.

PubMed

Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd Shameel; Sarkar, Souvik; Kumar, Rahul; Halder, Kamal Krishna; Debnath, Mita Chatterjee; Adhikari, Susanta; Bandyopadhyay, Uday

2012-01-27

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.

Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine.

PubMed

de Cavanagh, Elena M V; Toblli, Jorge E; Ferder, León; Piotrkowski, Bárbara; Stella, Inés; Inserra, Felipe

2006-06-01

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

PubMed Central

Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie; Hamill, Cecily; Chen, Yuming; Santos, Janine Hertzog

2016-01-01

Abstract Aims: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. Results: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in ΔΨm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. Innovation: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. Conclusion: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. Antioxid. Redox Signal. 24, 1072–1083. PMID:26935406

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy.

PubMed

Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie; Hamill, Cecily; Chen, Yuming; Santos, Janine Hertzog; Jurkunas, Ula V

2016-06-20

Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in ΔΨm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. Antioxid. Redox Signal. 24, 1072-1083.

IGF-1 Alleviates High Fat Diet-Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function

PubMed Central

Zhang, Yingmei; Yuan, Ming; Bradley, Katherine M.; Dong, Feng; Anversa, Piero; Ren, Jun

2012-01-01

Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling. PMID:22275536

Diabetes and Kidney Disease: Role of Oxidative Stress

PubMed Central

Jha, Jay C.; Banal, Claudine; Chow, Bryna S.M.; Cooper, Mark E.

2016-01-01

Abstract Significance: Intrarenal oxidative stress plays a critical role in the initiation and progression of diabetic kidney disease (DKD). Enhanced oxidative stress results from overproduction of reactive oxygen species (ROS) in the context of concomitant, insufficient antioxidant pathways. Renal ROS production in diabetes is predominantly mediated by various NADPH oxidases (NOXs), but a defective antioxidant system as well as mitochondrial dysfunction may also contribute. Recent Advances: Effective agents targeting the source of ROS generation hold the promise to rescue the kidney from oxidative damage and prevent subsequent progression of DKD. Critical Issues and Future Directions: In the present review, we summarize and critically analyze molecular and cellular mechanisms that have been demonstrated to be involved in NOX-induced renal injury in diabetes, with particular focus on the role of increased glomerular injury, the development of albuminuria, and tubulointerstitial fibrosis, as well as mitochondrial dysfunction. Furthermore, novel agents targeting NOX isoforms are discussed. Antioxid. Redox Signal. 25, 657–684. PMID:26906673

Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction

PubMed Central

Zhang, Yingmei; Li, Linlin; Hua, Yinan; Nunn, Jennifer M.; Dong, Feng; Yanagisawa, Masashi; Ren, Jun

2012-01-01

Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function. PMID:22442497

Adiponectin improves the osteointegration of titanium implant under diabetic conditions by reversing mitochondrial dysfunction via the AMPK pathway in vivo and in vitro.

PubMed

Hu, Xiao-Fan; Wang, Lin; Lu, Yi-Zhao; Xiang, Geng; Wu, Zi-Xiang; Yan, Ya-Bo; Zhang, Yang; Zhao, Xiong; Zang, Yuan; Shi, Lei; Lei, Wei; Feng, Ya-Fei

2017-10-01

Diabetes-induced reactive oxygen species (ROS) overproduction would result in compromised osteointegration of titanium implant (TI) and high rate of implant failure, yet the underlying mechanisms remain elusive. Adiponectin (APN) is a fat-derived adipocytokine with strong antioxidant, mitochondrial-protective and anti-diabetic efficacies. We hypothesized that mitochondrial dysfunction under diabetes may account for the oxidative stress in osteoblasts and titanium-bone interface (TBI) instability, which could be ameliorated by APN. To test this hypothesis, we incubated primary rat osteoblasts on TI and tested the cellular behaviors when subjected to normal milieu (NM), diabetic milieu (DM), DM+APN, DM+AICAR (AMPK activator) and DM+APN+Compound C (AMPK inhibitor). In vivo, APN or APN+Compound C were administered to diabetic db/db mice with TI implanted in their femurs. Results showed that diabetes induced structural damage, dysfunction and content decrease of mitochondria in osteoblasts, which led to ROS overproduction, dysfunction and apoptosis of osteoblasts accompanied by the inhibition of AMPK signaling. APN alleviated the mitochondrial damage by activating AMPK, thus reversing osteoblast impairment and improving the osteointegration of TI evidenced by Micro-CT and histological analysis. Furthermore, AICAR showed beneficial effects similar to APN treatment, while the protective effects of APN were abolished when AMPK activation was blocked by Compound C. This study clarifies mitochondrial dysfunction as a crucial mechanism in the impaired bone healing and implant loosening in diabetes, and provides APN as a novel promising active component for biomaterial-engineering to improve clinical performance of TI in diabetic patients. The loosening rate of titanium implants in diabetic patients is high. The underlying mechanisms remain elusive and, with the rapid increase of diabetic morbility, efficacious strategies to mitigate this problem have become increasingly important. Our study showed that the mitochondrial impairment and the consequent oxidative stress in osteoblasts at the titanium-bone interface (TBI) play a critical role in the diabetes-induced poor bone repair and implant destabilization, which could become therapeutic targets. Furthermore, adiponectin, a cytokine, promotes the bio-functional recovery of osteoblasts and bone regeneration at the TBI in diabetes. This provides APN as a novel bioactive component used in material-engineering to promote the osteointegration of implants, which could reduce implant failure, especially for diabetic patients. Copyright © 2017. Published by Elsevier Ltd.

Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

PubMed

Lu, Qing; Mundy, Miles; Chambers, Eboni; Lange, Thilo; Newton, Julie; Borgas, Diana; Yao, Hongwei; Choudhary, Gaurav; Basak, Rajshekhar; Oldham, Mahogany; Rounds, Sharon

2017-12-01

Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet–Fed Mice

PubMed Central

Ryan, Terence E.; Schmidt, Cameron A.; Green, Thomas D.; Spangenburg, Espen E.; Neufer, P. Darrell

2016-01-01

Patients with type 2 diabetes respond poorly to treatments for peripheral arterial disease (PAD) and are more likely to present with the most severe manifestation of the disease, critical limb ischemia. The underlying mechanisms linking type 2 diabetes and the severity of PAD manifestation are not well understood. We sought to test whether diet-induced mitochondrial dysfunction and oxidative stress would increase the susceptibility of the peripheral limb to hindlimb ischemia (HLI). Six weeks of high-fat diet (HFD) in C57BL/6 mice was insufficient to alter skeletal muscle mitochondrial content and respiratory function or the size of ischemic lesion after HLI, despite reducing blood flow. However, 16 weeks of HFD similarly decreased ischemic limb blood flow, but also exacerbated limb tissue necrosis, increased the myopathic lesion size, reduced muscle regeneration, attenuated muscle function, and exacerbated ischemic mitochondrial dysfunction. Mechanistically, mitochondrial-targeted overexpression of catalase prevented the HFD-induced ischemic limb necrosis, myopathy, and mitochondrial dysfunction, despite no improvement in limb blood flow. These findings demonstrate that skeletal muscle mitochondria are a critical pathological link between type 2 diabetes and PAD. Furthermore, therapeutically targeting mitochondria and oxidant burden is an effective strategy to alleviate tissue loss and ischemic myopathy during PAD. PMID:27284110

Cinnamon polyphenols attenuate cell swelling and mitochondrial dysfunction following oxygen-glucose deprivation in glial cells.

PubMed

Panickar, Kiran S; Polansky, Marilyn M; Anderson, Richard A

2009-04-01

Astrocyte swelling is an integral component of cytotoxic brain edema in ischemic injury. While mechanisms underlying astrocyte swelling are likely multifactorial, oxidative stress and mitochondrial dysfunction are hypothesized to contribute to such swelling. We investigated the protective effects of cinnamon polyphenol extract (CPE) that has anti-oxidant and insulin-potentiating effects on cell swelling and depolarization of the inner mitochondrial membrane potential (DeltaPsi(m)) in ischemic injury. C6 glial cells were subjected to oxygen-glucose deprivation (OGD) and cell volume determined using the 3-O-methyl-[3H]-glucose method at 90 min after the end of OGD. When compared with controls, OGD increased cell volume by 34%. This increase was blocked by CPE or insulin but not by blockers of oxidative/nitrosative stress including vitamin E, resveratrol, N-nitro-L-arginine methyl ester (L-NAME) or uric acid. Mitochondrial dysfunction, a key component of ischemic injury, contributes to cell swelling. Changes in DeltaPsi(m) were assessed at the end of OGD with tetramethylrhodamine ethyl ester (TMRE), a potentiometric dye. OGD induced a 39% decline in DeltaPsi(m) and this decline was blocked by CPE as well as insulin. To test the involvement of the mitochondrial permeability transition (mPT), we used Cyclosporin A (CsA), an immunosuppressant and a blocker of the mPT pore. CsA blocked cell swelling and the decline in DeltaPsi(m) but FK506, an immunosuppressant that does not block the mPT, did not. Our results show that CPE reduces OGD-induced cell swelling as well as the decline in DeltaPsi(m) in cultures and some of its protective effects may be through inhibiting the mPT.

Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson’s disease: Involvement of mitochondrial dysfunctions and oxidative stress

PubMed Central

Kumar, Sanjeev; Giri, Anirudha; Sandhir, Rajat

2017-01-01

Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer’s disease while its role in the occurrence of Parkinson’s disease (PD) is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia. PMID:28170429

Microvascular and mitochondrial dysfunction in the female F1 generation after gestational TiO2 nanoparticle exposure

PubMed Central

Stapleton, Phoebe A.; Nichols, Cody E.; Yi, Jinghai; McBride, Carroll R.; Minarchick, Valerie C.; Shepherd, Danielle L.; Hollander, John M.; Nurkiewicz, Timothy R.

2016-01-01

Due to the ongoing evolution of nanotechnology, there is a growing need to assess the toxicological outcomes in under-studied populations in order to properly consider the potential of engineered nanomaterials (ENM) and fully enhance their safety. Recently, we and others have explored the vascular consequences associated with gestational nanomaterial exposure, reporting microvascular dysfunction within the uterine circulation of pregnant dams and the tail artery of fetal pups. It has been proposed (via work derived by the Barker Hypothesis) that mitochondrial dysfunction and subsequent oxidative stress mechanisms as a possible link between a hostile gestational environment and adult disease. Therefore, in this study, we exposed pregnant Sprague-Dawley rats to nanosized titanium dioxide aerosols after implantation (gestational day 6). Pups were delivered, and the progeny grew into adulthood. Microvascular reactivity, mitochondrial respiration and hydrogen peroxide production of the coronary and uterine circulations of the female offspring were evaluated. While there were no significant differences within the maternal or litter characteristics, endothelium-dependent dilation and active mechanotransduction in both coronary and uterine arterioles were significantly impaired. In addition, there was a significant reduction in maximal mitochondrial respiration (state 3) in the left ventricle and uterus. These studies demonstrate microvascular dysfunction and coincide with mitochondrial inefficiencies in both the cardiac and uterine tissues, which may represent initial evidence that prenatal ENM exposure produces microvascular impairments that persist throughout multiple developmental stages. PMID:25475392

Metabolism alteration in follicular niche: The nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome.

PubMed

Zhao, Hongcui; Zhao, Yue; Li, Tianjie; Li, Min; Li, Junsheng; Li, Rong; Liu, Ping; Yu, Yang; Qiao, Jie

2015-09-01

Classic polycystic ovary syndrome (PCOS) is a high-risk phenotype accompanied by increased risks of reproductive and metabolic abnormalities; however, the local metabolism characteristics of the ovaries and their effects on germ cell development are unclear. The present study used targeted metabolomics to detect alterations in the intermediate metabolites of follicular fluid from classic PCOS patients, and the results indicated that hyperandrogenism but not obesity induced the changed intermediate metabolites in classic PCOS patients. Regarding the direct contact, we identified mitochondrial function, redox potential, and oxidative stress in cumulus cells which were necessary to support oocyte growth before fertilization, and suggested dysfunction of mitochondria, imbalanced redox potential, and increased oxidative stress in cumulus cells of classic PCOS patients. Follicular fluid intermediary metabolic profiles provide signatures of classic PCOS ovary local metabolism and establish a close link with mitochondria dysfunction of cumulus cells, highlighting the role of metabolic signal and mitochondrial cross talk involved in the pathogenesis of classic PCOS. Copyright © 2015 Elsevier Inc. All rights reserved.

Reactive oxygen species mediates homocysteine-induced mitochondrial biogenesis in human endothelial cells: Modulation by antioxidants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez-de-Arce, Karen; Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago; Foncea, Rocio

2005-12-16

It has been proposed that homocysteine (Hcy)-induces endothelial dysfunction and atherosclerosis by generation of reactive oxygen species (ROS). A previous report has shown that Hcy promotes mitochondrial damage. Considering that oxidative stress can affect mitochondrial biogenesis, we hypothesized that Hcy-induced ROS in endothelial cells may lead to increased mitochondrial biogenesis. We found that Hcy-induced ROS (1.85-fold), leading to a NF-{kappa}B activation and increase the formation of 3-nitrotyrosine. Furthermore, expression of the mitochondrial biogenesis factors, nuclear respiratory factor-1 and mitochondrial transcription factor A, was significantly elevated in Hcy-treated cells. These changes were accompanied by increase in mitochondrial mass and higher mRNAmore » and protein expression of the subunit III of cytochrome c oxidase. These effects were significantly prevented by pretreatment with the antioxidants, catechin and trolox. Taken together, our results suggest that ROS is an important mediator of mitochondrial biogenesis induced by Hcy, and that modulation of oxidative stress by antioxidants may protect against the adverse vascular effects of Hcy.« less

Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis.

PubMed

Karnewar, Santosh; Vasamsetti, Sathish Babu; Gopoju, Raja; Kanugula, Anantha Koteswararao; Ganji, Sai Krishna; Prabhakar, Sripadi; Rangaraj, Nandini; Tupperwar, Nitin; Kumar, Jerald Mahesh; Kotamraju, Srigiridhar

2016-04-11

Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE(-/-) mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3 treatment not only completely reversed Mito-Esc-mediated mitochondrial biogenetic marker expressions but also caused endothelial cell death. Furthermore, Mito-Esc administration to ApoE(-/-) mice greatly alleviated Ang-II-induced atheromatous plaque formation, monocyte infiltration and serum pro-inflammatory cytokines levels. We conclude that Mito-Esc is preferentially taken up by the mitochondria and preserves endothelial cell survival during oxidative stress by modulating NO generation via AMPK. Also, Mito-Esc-induced SIRT3 plays a pivotal role in mediating mitochondrial biogenesis and perhaps contributes to its anti-atherogenic effects.

Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells.

PubMed

Vacek, Jonathan C; Behera, Jyotirmaya; George, Akash K; Kamat, Pradip K; Kalani, Anuradha; Tyagi, Neetu

2018-04-01

Homocysteine (Hcy) causes endothelial dysfunction by inducing oxidative stress in most neurodegenerative disorders. This dysfunction is highly correlated with mitochondrial dynamics such as fusion and fission. However, there are no strategies to prevent Hcy-induced mitochondrial remodeling. Tetrahydrocurcumin (THC) is an anti-inflammatory and anti-oxidant compound. We hypothesized that THC may ameliorates Hcy-induced mitochondria remodeling in mouse brain endothelial cells (bEnd3) cells. bEnd3 cells were exposed to Hcy treatment in the presence or absence of THC. Cell viability and autophagic cell death were measured with MTT and MDC staining assay. Reactive oxygen species (ROS) production was determined using DCFH-DA staining by confocal microscopy. Autophagy flux was assessed using a conventional GFP-microtubule-associated protein 1 light chain 3 (LC3) dot assay. Interaction of phagophore marker LC-3 with mitochondrial receptor NIX was observed by confocal imaging. Mitochondrial fusion and fission were evaluated by western blot and RT-PCR. Our results demonstrated that Hcy resulted in cell toxicity in a dose-dependent manner and supplementation of THC prevented the detrimental effects of Hcy on cell survival. Furthermore, Hcy also upregulated fission marker (DRP-1), fusion marker (Mfn2), and autophagy marker (LC-3). Finally, we observed that Hcy activated mitochondrial specific phagophore marker (LC-3) and co-localized with the mitochondrial receptor NIX, as viewed by confocal microscopy. Pretreatment of bEnd3 with THC (15 μM) ameliorated Hcy-induced oxidative damage, mitochondrial fission/fusion, and mitophagy. Our studies strongly suggest that THC has beneficial effects on mitochondrial remodeling and could be developed as a potential therapeutic agent against hyperhomocysteinemia (HHcy) induced mitochondrial dysfunction. © 2017 Wiley Periodicals, Inc.

Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

PubMed Central

Pagano, Giovanni; Aiello Talamanca, Annarita; Castello, Giuseppe; Cordero, Mario D.; d’Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V.; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

2014-01-01

An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed “mitochondrial nutrients” (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with “classical” antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed. PMID:25380523

Nigrostriatal neuronal death following chronic dichlorvos exposure: crosstalk between mitochondrial impairments, α synuclein aggregation, oxidative damage and behavioral changes

PubMed Central

2010-01-01

Background In recent years, several lines of evidence have shown an increase in Parkinson's disease prevalence in rural environments where pesticides are heavily used. Although, the underlying mechanism for neuronal degeneration in sporadic PD remains unknown, mitochondrial dysfunction, oxidative stress and proteasomal dysfunction are proposed as contributing factors. In this study rats were chronically and continuously exposed to the pesticide, dichlorvos to identify the molecular mechanism of nigrostaital neuronal degeneration. Result Chronic dichlorvos exposure (2.50 mg/kg b.wt.s.c/daily for 12 weeks) caused nigrostriatal dopaminergic degeneration. The degenerative changes were accompanied by a loss of 60-80% of the nigral dopamine neurons and 60-70% reduction in striatal dopamine and tyrosine hydroxylase levels. Dichlorvos exposed animals also showed α -synuclein and ubiquitin positive inclusions along with swollen, dystrophic neurites and mitochondrial abnormalities like decreased complex I&IV activities, increased mitochondrial size, axonal degeneration and presence of electron dense perinuclear cytoplasmic inclusions in the substantia nigra of rats. These animals also showed evidence of oxidative stress, including increased mitochondrial ROS levels, decreased MnSOD activity and increased lipid peroxidation. Measurable impairments in neurobehavioral indices were also observed. Notable exacerbations in motor impairments, open field and catalepsy were also evident in dichlorvos exposed animals. Conclusion All these findings taken together indicate that chronic dichlorvos exposure may cause nigrostaital neurodegenaration and significant behavioral impairments. PMID:21073741

Detection of Redox Imbalance in Normal Lymphocytes with Induced Mitochondrial Dysfunction - EPR Study.

PubMed

Georgieva, Ekaterina; Zhelev, Zhivko; Aoki, Ichio; Bakalova, Rumiana; Higashi, Tatsuya

2016-10-01

The present study describes a new approach for direct imaging of redox status in live cells using paramagnetic spin-probes, which allows evaluation of the level of oxidative stress due to overproduction of superoxide. The method is based on redox cycling of cell/mitochondria-penetrating nitroxide radicals (e.g. mito-TEMPO) and their electron-paramagnetic resonance (EPR) contrast, which makes them useful molecular sensors for analysis of redox status and oxidative stress in cells and tissues. Oxidative stress was induced in normal human lymphocytes by treatment with 2-methoxyestradiol and rotenone (ME/Rot) at different concentrations. This combination provokes mitochondrial dysfunction, which is accompanied by overproduction of superoxide. The EPR measurements were performed in dynamics on X-Band spectrometer after addition of mito-TEMPO to cell suspensions. The intensity of the EPR signal in untreated cells decreased significantly, which indicates a conversion of paramagnetic mito-TEMPO to its non-contrast diamagnetic form (hydroxylamine - mito-TEMPOH) due to reduction. In ME/Rot-treated cells, the signal decreased more slowly and to a lower level with increasing the concentration of ME/Rot. These data indicate an induction of oxidative stress in the cells in a concentration-dependent manner. A very good positive correlation between the intensity of EPR signal of mito-TEMPO and the intracellular level of superoxide was found, analyzed by conventional dihydroethidium test (R=0.9143, p<0.001). In conclusion, our study demonstrated that cell-penetrating paramagnetic spin-probes, such as mito-TEMPO, are valuable tools for EPR imaging of the superoxide level in live cells, as well as for EPR imaging of mitochondrial dysfunction and metabolic activity, accompanied by superoxide imbalance. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Gallic acid prevents nonsteroidal anti-inflammatory drug-induced gastropathy in rat by blocking oxidative stress and apoptosis.

PubMed

Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd Shameel; Maity, Pallab; Adhikari, Susanta S; Bandyopadhyay, Uday

2010-07-15

Nonsteroidal anti-inflammatory drug (NSAID)-induced oxidative stress plays a critical role in gastric mucosal cell apoptosis and gastropathy. NSAIDs induce the generation of hydroxyl radical ((*)OH) through the release of free iron, which plays an important role in developing gastropathy. Thus, molecules having both iron-chelating and antiapoptotic properties will be beneficial in preventing NSAID-induced gastropathy. Gallic acid (GA), a polyphenolic natural product, has the capacity to chelate free iron. Here, we report that GA significantly prevents, as well as heals, NSAID-induced gastropathy. In vivo, GA blocks NSAID-mediated mitochondrial oxidative stress by preventing mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. In vitro, GA scavenges free radicals and blocks (*)OH-mediated oxidative damage. GA also attenuates gastric mucosal cell apoptosis in vivo as well as in vitro in cultured gastric mucosal cells as evident from the TUNEL assay. GA prevents NSAID-induced activation of caspase-9, a marker for the mitochondrial pathway of apoptosis, and restores NSAID-mediated collapse of the mitochondrial transmembrane potential and dehydrogenase activity. Thus, the inhibition of mitochondrial oxidative stress by GA is associated with the inhibition of NSAID-induced mitochondrial dysfunction and activation of apoptosis in gastric mucosal cells, which are responsible for gastric injury or gastropathy. Copyright 2010 Elsevier Inc. All rights reserved.

Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes.

PubMed

Valvassori, Samira S; Bavaresco, Daniela V; Feier, Gustavo; Cechinel-Recco, Kelen; Steckert, Amanda V; Varela, Roger B; Borges, Cenita; Carvalho-Silva, Milena; Gomes, Lara M; Streck, Emílio L; Quevedo, João

2018-06-01

The present study aims to investigate the oxidative stress parameters in isolated mitochondria, as well as looking at mitochondrial complex activity in patients with Bipolar Disorder (BD) during depressive or euthymic episodes. This study evaluated the levels of mitochondrial complex (I, II, II-III and IV) activity in lymphocytes from BD patients. We evaluated the following oxidative stress parameters: superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl levels in submitochondrial particles of lymphocytes from bipolar patients. 51 bipolar patients were recruited into this study: 34 in the euthymic phase, and 17 in the depressive phase. Our results indicated that the depressive phase could increase the levels of mitochondrial superoxide, carbonyl and TBARS, and superoxide dismutase, and could decrease the levels of mitochondrial complex II activity in the lymphocytes of bipolar patients. It was also observed that there was a negative correlation between the Hamilton Depression Rating Scale (HDRS) and complex II activity in the lymphocytes of depressive bipolar patients. In addition, there was a positive correlation between HDRS and superoxide, superoxide dismutase, TBARS and carbonyl. Additionally, there was a negative correlation between complex II activity and oxidative stress parameters. In conclusion, our results suggest that mitochondrial oxidative stress and mitochondrial complex II dysfunction play important roles in the depressive phase of BD. Copyright © 2018. Published by Elsevier B.V.

Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility.

PubMed

Qi, Haiying; Casalena, Gabriella; Shi, Shaolin; Yu, Liping; Ebefors, Kerstin; Sun, Yezhou; Zhang, Weijia; D'Agati, Vivette; Schlondorff, Detlef; Haraldsson, Börje; Böttinger, Erwin; Daehn, Ilse

2017-03-01

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1-Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis. © 2017 by the American Diabetes Association.

Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells.

PubMed

Kim, Ji-Seok; Kim, Boa; Lee, Hojun; Thakkar, Sunny; Babbitt, Dianne M; Eguchi, Satoru; Brown, Michael D; Park, Joon-Young

2015-08-01

The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise, which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in prehypertensive individuals and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31(+)/CD42a(-)) and activated (CD62E(+)) microparticles released by endothelial cells were significantly decreased (∼40% for both) after a 6-mo supervised aerobic exercise training program in individuals with prehypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a sirtuin 1 (SIRT1)-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using small-interfering RNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or peroxisome proliferator-activated receptor-γ coactivator-1α small-interfering RNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial biogenesis. Copyright © 2015 the American Physiological Society.

Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

PubMed Central

Xie, Yufen; Zhou, Sichang; Jiang, Zhongliang; Dai, Jing; Puscheck, Elizabeth E; Lee, Icksoo; Parker, Graham; Hüttemann, Maik; Rappolee, Daniel A

2014-01-01

Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal-placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. Implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor (FGF)4 enabled highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24 hr despite FGF4. However, hypoxic stress supported differentiation poorly after 4–7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential, maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited differentiation at the differentiation optimum at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2>0.5–2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation. PMID:25239494

Naringin Improves Diet-Induced Cardiovascular Dysfunction and Obesity in High Carbohydrate, High Fat Diet-Fed Rats

PubMed Central

Alam, Md. Ashraful; Kauter, Kathleen; Brown, Lindsay

2013-01-01

Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats. PMID:23446977

Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage.

PubMed

Jiang, Dan; Gao, Fei; Zhang, Yuelin; Wong, David Sai Hung; Li, Qing; Tse, Hung-Fat; Xu, Goufeng; Yu, Zhendong; Lian, Qizhou

2016-11-10

Recent studies have demonstrated that mesenchymal stem cells (MSCs) can donate mitochondria to airway epithelial cells and rescue mitochondrial damage in lung injury. We sought to determine whether MSCs could donate mitochondria and protect against oxidative stress-induced mitochondrial dysfunction in the cornea. Co-culturing of MSCs and corneal epithelial cells (CECs) indicated that the efficiency of mitochondrial transfer from MSCs to CECs was enhanced by Rotenone (Rot)-induced oxidative stress. The efficient mitochondrial transfer was associated with increased formation of tunneling nanotubes (TNTs) between MSCs and CECs, tubular connections that allowed direct intercellular communication. Separation of MSCs and CECs by a transwell culture system revealed no mitochiondrial transfer from MSCs to CECs and mitochondrial function was impaired when CECs were exposed to Rot challenge. CECs with or without mitochondrial transfer from MSCs displayed a distinct survival capacity and mitochondrial oxygen consumption rate. Mechanistically, increased filopodia outgrowth in CECs for TNT formation was associated with oxidative inflammation-activated NFκB/TNFαip2 signaling pathways that could be attenuated by reactive oxygen species scavenger N-acetylcysteine (NAC) treatment. Furthermore, MSCs grown on a decellularized porcine corneal scaffold were transplanted onto an alkali-injured eye in a rabbit model. Enhanced corneal wound healing was evident following healthy MSC scaffold transplantation. And transferred mitochondria was detected in corneal epithelium. In conclusion, mitochondrial transfer from MSCs provides novel protection for the cornea against oxidative stress-induced mitochondrial damage. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.

CaMKII determines mitochondrial stress responses in heart

PubMed Central

Joiner, Mei-ling A.; Koval, Olha M.; Jingdong, Li; He, B. Julie; Allamargot, Chantal; Gao, Zhan; Luczak, Elizabeth D.; Hall, Duane D.; Fink, Brian D.; Chen, Biyi; Yang, Jinying; Moore, Steven A.; Scholz, Thomas D.; Strack, Stefan; Mohler, Peter J.; Sivitz, William I.; Song, Long-Sheng; Anderson, Mark E.

2012-01-01

Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry, causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm)1,2. However, the signaling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3–5 are not known. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion (I/R), myocardial infarction (MI) and neurohumoral injury, common causes of myocardial death and heart failure, suggesting CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A (CsA), an mPTP antagonist with clinical efficacy in I/R injury6, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to I/R injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition are resistant to I/R injury, MI and neurohumoral injury, suggesting pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress. PMID:23051746

Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse.

PubMed

Liu, Qianying; Lei, Zhixin; Guo, Jingchao; Liu, Aimei; Lu, Qirong; Fatima, Zainab; Khaliq, Haseeb; Shabbir, Muhammad A B; Maan, Muhammad Kashif; Wu, Qinghua; Dai, Menghong; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

2018-01-01

Mequindox (MEQ), belonging to quinoxaline-di- N -oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo .

Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse

PubMed Central

Liu, Qianying; Lei, Zhixin; Guo, Jingchao; Liu, Aimei; Lu, Qirong; Fatima, Zainab; Khaliq, Haseeb; Shabbir, Muhammad A. B.; Maan, Muhammad Kashif; Wu, Qinghua; Dai, Menghong; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

2018-01-01

Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo. PMID:29765325

Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.

PubMed

Santos, N A G; Catão, C S; Martins, N M; Curti, C; Bianchi, M L P; Santos, A C

2007-07-01

The clinical use of cisplatin (cis-diamminedichloroplatinum II) is highly limited by its nephrotoxicity. The precise mechanisms involved in cisplatin-induced mitochondrial dysfunction in kidney have not been completely clarified. Therefore, we investigated in vivo the effects of cisplatin on mitochondrial bioenergetics, redox state, and oxidative stress as well as the occurrence of cell death by apoptosis in cisplatin-treated rat kidney. Adult male Wistar rats weighing 200-220 g were divided into two groups. The control group (n = 8) was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml per 100 g body weight), and the cisplatin group (n = 8) was given a single injection of cisplatin (10 mg/kg body weight, i.p.). Animals were sacrificed 72 h after the treatment. The cisplatin group presented acute renal failure characterized by increased plasmatic creatinine and urea levels. Mitochondrial dysfunction was evidenced by the decline in membrane electrochemical potential and the substantial decrease in mitochondrial calcium uptake. The mitochondrial antioxidant defense system was depleted, as shown by decreased GSH and NADPH levels, GSH/GSSG ratio, and increased GSSG level. Moreover, cisplatin induced oxidative damage to mitochondrial lipids, including cardiolipin, and oxidation of mitochondrial proteins, as demonstrated by the significant decrease of sulfhydryl protein concentrations and increased levels of carbonylated proteins. Additionally, aconitase activity, which is essential for mitochondrial function, was also found to be lower in the cisplatin group. Renal cell death via apoptosis was evidenced by the increased caspase-3 activity. Results show the central role of mitochondria and the intensification of apoptosis in cisplatin-induced acute renal failure, highlighting a number of steps that might be targeted to minimize cisplatin-induced nephrotoxicity.

Calcium Homeostatasis and Mitochondrial Dysfunction in Dopaminergic Neurons of the Substantia Nigra

DTIC Science & Technology

2010-03-01

discovery that calcium entry through L-type channels during normal pacemaking elevates the sensitivity of SNc dopaminergic neurons to toxins; • the...discovery that L-type calcium channels participate in but are not necessary for pacemaking; • the discovery that serum concentration of the...FDA approved doses; • the discovery that calcium entry through L-type channels during pacemaking elevates mitochondrial oxidant stress and leads

The Role of PGC-1α in Vascular Regulation: Implications for Atherosclerosis

PubMed Central

Kadlec, Andrew O.; Chabowski, Dawid S.; Ait-Aissa, Karima; Gutterman, David D.

2016-01-01

Mitochondrial dysfunction results in high levels of oxidative stress and mitochondrial damage, leading to disruption of endothelial homeostasis. Recent discoveries have clarified several pathways whereby mitochondrial dysregulation contributes to endothelial dysfunction and vascular disease burden. One such pathway centers around PGC-1α, a transcriptional coactivator linked to mitochondrial biogenesis and antioxidant defense, among other functions. Although primarily investigated for its therapeutic potential in obesity and skeletal muscle differentiation, the ability of PGC-1α to alter a multitude of cellular functions has sparked interest in its role in the vasculature. Within this context, recent studies demonstrate that PGC-1α plays a key role in endothelial cell and smooth muscle cell regulation through effects on oxidative stress, apoptosis, inflammation, and cell proliferation. The ability of PGC-1α to impact these parameters is relevant to vascular disease progression, particularly in relation to atherosclerosis. Upregulation of PGC-1α can prevent the development of, and even encourage regression of, atherosclerotic lesions. Therefore, PGC-1α is poised to serve as a promising target in vascular disease. This review details recent findings related to PGC-1α in vascular regulation, regulation of PGC-1α itself, the role of PGC-1α in atherosclerosis, and therapies that target this key protein. PMID:27312223

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sekine, Shuichi; Ito, Konomi; Watanabe, Haruna

Patients with long-lasting hepatitis C virus (HCV) infection are at major risk of hepatocellular carcinoma (HCC). Iron accumulation in the livers of these patients is thought to exacerbate conditions of oxidative stress. Transgenic mice that express the HCV core protein develop HCC after the steatosis stage and produce an excess of hepatic reactive oxygen species (ROS). The overproduction of ROS in the liver is the net result of HCV core protein-induced dysfunction of the mitochondrial respiratory chain. This study examined the impact of ferric nitrilacetic acid (Fe-NTA)-mediated iron overload on mitochondrial damage and ROS production in HCV core protein-expressing HepG2more » (human HCC) cells (Hep39b cells). A decrease in mitochondrial membrane potential and ROS production were observed following Fe-NTA treatment. After continuous exposure to Fe-NTA for six days, cell toxicity was observed in Hep39b cells, but not in mock (vector-transfected) HepG2 cells. Moreover, mitochondrial iron ({sup 59}Fe) uptake was increased in the livers of HCV core protein-expressing transgenic mice. This increase in mitochondrial iron uptake was inhibited by Ru360, a mitochondrial Ca{sup 2+} uniporter inhibitor. Furthermore, the Fe-NTA-induced augmentation of mitochondrial dysfunction, ROS production, and cell toxicity were also inhibited by Ru360 in Hep39b cells. Taken together, these results indicate that Ca{sup 2+} uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein. - Highlights: • Iron accumulation in the livers of patients with hepatitis C virus (HCV) infection is thought to exacerbate oxidative stress. • The impact of iron overload on mitochondrial damage and ROS production in HCV core protein-expressing cells were examined. • Mitochondrial iron uptake was increased in the livers of HCV core protein-expressing transgenic mice. • Ca{sup 2+} uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein.« less

Uncoupling Protein 2 and Metabolic Diseases

PubMed Central

Sreedhar, Annapoorna; Zhao, Yunfeng

2017-01-01

Mitochondria are fascinating organelles involved in various cellular-metabolic activities that are integral for mammalian development. Although they perform diverse, yet interconnected functions, mitochondria are remarkably regulated by complex signaling networks. Therefore, it is not surprising that mitochondrial dysfunction is involved in plethora of diseases, including neurodegenerative and metabolic disorders. One of the many factors that lead to mitochondrial-associated metabolic diseases is the uncoupling protein-2, a family of mitochondrial anion proteins present in the inner mitochondrial membrane. Since their discovery, uncoupling proteins have attracted considerable attention due to their involvement in mitochondrial-mediated oxidative stress and energy metabolism. This review attempts to provide a summary of recent developments in the field of uncoupling protein 2 relating to mitochondrial associated metabolic diseases. PMID:28351676

Is antioxidant potential of the mitochondrial targeted ubiquinone derivative MitoQ conserved in cells lacking mtDNA?

PubMed

Lu, Chao; Zhang, Dawei; Whiteman, Matthew; Armstrong, Jeffrey S

2008-03-01

MitoQ has been developed as a mitochondrial targeted antioxidant for diseases associated with oxidative stress. Here we show that MitoQ blocks the generation of reactive oxygen species (ROS) and mitochondrial protein thiol oxidation, and preserves mitochondrial function and ultrastructure after glutathione (GSH) depletion. Furthermore, the antioxidant effect of MitoQ is conserved in cells lacking mitochondrial DNA, indicating that its antioxidant properties do not depend on a functional electron transport chain (ETC). Our results elucidate the antioxidant mechanism of MitoQ and suggest that it may be a useful therapeutic for disorders associated with a dysfunctional ETC and increased ROS production.

Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer.

PubMed

Xue, Jing; Li, Rui; Zhao, Xinrui; Ma, Congcong; Lv, Xin; Liu, Lidong; Liu, Peishu

2018-03-01

Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological cancers. Morusin, a prenylated flavonoid extracted from the root bark of Morus australis, has been reported to exhibit anti-tumor activity against various human cancers except EOC. In the present study, we explored the potential anti-cancer activity of morusin against EOC in vitro and in vivo and possible underlying mechanisms for the first time. We first found that morusin effectively inhibited EOC cell proliferation and survival in vitro and suppressed tumor growth in vivo. Then we observed that treatment of EOC cells with morusin resulted in paraptosis-like cell death, a novel mode of non-apoptotic programmed cell death that is characterized by extensive cytoplasmic vacuolation due to dilation of the endoplasmic reticulum (ER) and mitochondria and lack of apoptotic hallmarks. In addition, we discovered that morusin induced obvious increase in mitochondrial Ca 2+ levels, accumulation of ER stress markers, generation of reactive oxygen species (ROS), and loss of mitochondrial membrane potential (Δψm) in EOC cells. Furthermore, pretreatment with 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS), a chemical inhibitor of voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane, effectively inhibited mitochondrial Ca 2+ influx, cytoplasmic vacuolation and cell death induced by morusin in EOC cells. Moreover, DIDS pretreatment also suppressed morusin-induced accumulation of ER stress markers, ROS production and depletion of Δψm. Consistently, tumor xenograft assays showed that co-treatment with DIDS partially reversed the inhibitory effects of morusin on tumor growth in vivo and inhibited the increased levels of ER stress markers induced by morusin in tumor tissues. Collectively, our results suggest that VDAC-mediated Ca 2+ influx into mitochondria and subsequent mitochondrial Ca 2+ overload contribute to mitochondrial swelling and dysfunction, leading to morusin-induced paraptosis-like cell death in EOC. This study may provide alternative therapeutic strategies for EOC exhibiting resistance to apoptosis. Copyright © 2018 Elsevier B.V. All rights reserved.

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress

PubMed Central

Su, Chen-Ming; Chen, Chien-Yu; Lu, Tingting; Sun, Yi; Li, Weimin; Huang, Yuan-Li; Tsai, Chun-Hao; Chang, Chih-Shiang; Tang, Chih-Hsin

2016-01-01

Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo. PMID:27835579

Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress.

PubMed

Mohammad, Mohammad K; Avila, Diana; Zhang, Jingwen; Barve, Shirish; Arteel, Gavin; McClain, Craig; Joshi-Barve, Swati

2012-11-15

Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentrations, caused a dose-dependent loss of viability of hepatocytes. The death was apoptotic at moderate and necrotic at high concentrations of acrolein. Acrolein exposure rapidly and dramatically decreased intracellular glutathione and overall antioxidant capacity, and activated the stress-signaling MAP-kinases JNK, p42/44 and p38. Our data demonstrate for the first time in human hepatocytes, that acrolein triggered endoplasmic reticulum (ER) stress and activated eIF2α, ATF-3 and -4, and Gadd153/CHOP, resulting in cell death. Notably, the protective/adaptive component of ER stress was not activated, and acrolein failed to up-regulate the protective ER-chaperones, GRP78 and GRP94. Additionally, exposure to acrolein disrupted mitochondrial integrity/function, and led to the release of pro-apoptotic proteins and ATP depletion. Acrolein-induced cell death was attenuated by N-acetyl cysteine, phenyl-butyric acid, and caspase and JNK inhibitors. Our data demonstrate that exposure to acrolein induces a variety of stress responses in hepatocytes, including GSH depletion, oxidative stress, mitochondrial dysfunction and ER stress (without ER-protective responses) which together contribute to acrolein toxicity. Our study defines basic mechanisms underlying liver injury caused by reactive aldehyde pollutants such as acrolein. Copyright © 2012 Elsevier Inc. All rights reserved.

Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome.

PubMed

Valenti, Daniela; de Bari, Lidia; De Filippis, Bianca; Henrion-Caude, Alexandra; Vacca, Rosa Anna

2014-10-01

Clinical manifestations typical of mitochondrial diseases are often present in various genetic syndromes associated with intellectual disability, a condition leading to deficit in cognitive functions and adaptive behaviors. Until now, the causative mechanism leading to intellectual disability is unknown and the progression of the condition is poorly understood. We first report latest advances on genetic and environmental regulation of mitochondrial function and its role in brain development. Starting from the structure, function and regulation of the oxidative phosphorylation apparatus, we review how mitochondrial biogenesis and dynamics play a central role in neurogenesis and neuroplasticity. We then discuss how dysfunctional mitochondria and alterations in reactive oxygen species homeostasis are potentially involved in the pathogenesis of various neurodevelopmental syndromes with a special focus on Down, Rett, Fragile X syndromes and autism spectrum disorders. Finally, we review and suggest novel therapeutic approaches aimed at improving intellectual disability by activating mitochondrial function and reducing oxidative stress to amiliorate the quality of life in the subjects affected. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neuroprotective effects of ginsenoside Rb1 on high glucose-induced neurotoxicity in primary cultured rat hippocampal neurons.

PubMed

Liu, Di; Zhang, Hong; Gu, Wenjuan; Liu, Yuqin; Zhang, Mengren

2013-01-01

Ginsenoside Rb1 is one of the main active principles in traditional herb ginseng and has been reported to have a wide variety of neuroprotective effects. Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, so the present study aimed to observe the effects of ginsenoside Rb1 on ER stress signaling pathways in high glucose-treated hippocampal neurons. The results from MTT, TUNEL labeling and Annexin V-FITC/PI/Hoechst assays showed that incubating neurons with 50 mM high glucose for 72 h decreased cell viability and increased the number of apoptotic cells whereas treating neurons with 1 μM Rb1 for 72 h protected the neurons against high glucose-induced cell damage. Further molecular mechanism study demonstrated that Rb1 suppressed the activation of ER stress-associated proteins including protein kinase RNA (PKR)-like ER kinase (PERK) and C/EBP homology protein (CHOP) and downregulation of Bcl-2 induced by high glucose. Moreover, Rb1 inhibited both the elevation of intracellular reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential induced by high glucose. In addition, the high glucose-induced cell apoptosis, activation of ER stress, ROS accumulation and mitochondrial dysfunction can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA) and anti-oxidant N-acetylcysteine(NAC). In conclusion, these results suggest that Rb1 may protect neurons against high glucose-induced cell injury through inhibiting CHOP signaling pathway as well as oxidative stress and mitochondrial dysfunction.

Renal Tubular Cell Mitochondrial Dysfunction Occurs Despite Preserved Renal Oxygen Delivery in Experimental Septic Acute Kidney Injury

PubMed Central

Pollen, Sean; Greco, Elisabetta; Courtneidge, Holly; Hall, Andrew M.; Duchen, Michael R.; Tam, Frederick W. K.; Unwin, Robert J.; Singer, Mervyn

2018-01-01

Objective: To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Intervention: Using a fluid-resuscitated sublethal rat model of fecal peritonitis, changes in renal function were characterized in relation to global and renal hemodynamics, and histology at 6 and 24 hours (n = 6–10). Sham-operated animals were used as comparison (n = 8). Tubular cell mitochondrial function was assessed using multiphoton confocal imaging of live kidney slices incubated in septic serum. Measurements and Main Results: By 24 hours, serum creatinine was significantly elevated with a concurrent decrease in renal lactate clearance in septic animals compared with sham-operated and 6-hour septic animals. Renal uncoupling protein-2 was elevated in septic animals at 24 hours although tubular cell injury was minimal and mitochondrial ultrastructure in renal proximal tubular cells preserved. There was no significant change in global or renal hemodynamics and oxygen delivery/consumption between sham-operated and septic animals at both 6- and 24-hour timepoints. In the live kidney slice model, mitochondrial dysfunction was seen in proximal tubular epithelial cells incubated with septic serum with increased production of reactive oxygen species, and decreases in nicotinamide adenine dinucleotide and mitochondrial membrane potential. These effects were prevented by coincubation with the reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independently of hemodynamic instability or structural damage. Mitochondrial dysfunction mediated by circulating mediators that induce local oxidative stress may represent an important pathophysiologic mechanism. PMID:29293148

Cytosolic Proteostasis via Importing of Misfolded Proteins into Mitochondria

PubMed Central

Ruan, Linhao; Zhou, Chuankai; Jin, Erli; Kucharavy, Andrei; Zhang, Ying; Wen, Zhihui; Florens, Laurence; Li, Rong

2017-01-01

Loss of proteostasis underlies aging and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction1–5. Although many neurodegenerative-disease proteins can be found in mitochondria4,6, it remains unclear how these disease manifestations may be related. In yeast, protein aggregates formed under stress or during aging are preferentially retained by the mother cell in part through tethering to mitochondria, while the disaggregase Hsp104 helps dissociate aggregates to enable refolding or degradation of misfolded proteins7–10. Here we show that in yeast cytosolic proteins prone to aggregation are imported into mitochondria for degradation. Protein aggregates formed under heat shock (HS) contain both cytosolic and mitochondrial proteins and interact with mitochondrial import complex. Many aggregation-prone proteins enter mitochondrial intermembrane space and matrix after HS, while some do so even without stress. Timely dissolution of cytosolic aggregates requires mitochondrial import machinery and proteases. Blocking mitochondrial import but not the proteasome activity causes a marked delay in the degradation of aggregated proteins. Defects in cytosolic Hsp70s leads to enhanced entry of misfolded proteins into mitochondria and elevated mitochondrial stress. We term this mitochondria-mediated proteostasis mechanism MAGIC (mitochondria as guardian in cytosol) and provide evidence that it may exist in human cells. PMID:28241148

Mitochondrial alterations in Parkinson's disease: new clues.

PubMed

Vila, Miquel; Ramonet, David; Perier, Celine

2008-10-01

Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). In particular, complex I impairment and subsequent oxidative stress have been widely demonstrated in experimental models of PD and in post-mortem PD samples. A recent wave of new studies is providing novel clues to the potential involvement of mitochondria in PD. In particular, (i) mitochondria-dependent programmed cell death pathways have been shown to be critical to PD-related dopaminergic neurodegeneration, (ii) many disease-causing proteins associated with familial forms of PD have been demonstrated to interact either directly or indirectly with mitochondria, (iii) aging-related mitochondrial changes, such as alterations in mitochondrial DNA, are increasingly being associated with PD, and (iv) anomalies in mitochondrial dynamics and intra-neuronal distribution are emerging as critical participants in the pathogenesis of PD. These new findings are revitalizing the field and reinforcing the potential role of mitochondria in the pathogenesis of PD. Whether a primary or secondary event, or part of a multi-factorial pathogenic process, mitochondrial dysfunction remains at the forefront of PD research and holds the promise as a potential molecular target for the development of new therapeutic strategies for this devastating, currently incurable, disease.

Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction

PubMed Central

Scioli, Maria Giovanna; Lo Giudice, Pietro; Bielli, Alessandra; Tarallo, Valeria; De Rosa, Alfonso; De Falco, Sandro; Orlandi, Augusto

2015-01-01

Background Impaired wound healing represents a high cost for health care systems. Endothelial dysfunction characterizes dermal microangiopathy and contributes to delayed wound healing and chronic ulcers. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and the increase of oxidative stress and inflammation. Propionyl-L-carnitine (PLC) is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery. Methods and Results We investigated the effects of PLC in rat skin flap and cutaneous wound healing. A daily oral PLC treatment improved skin flap viability and associated with reactive oxygen species (ROS) reduction, inducible nitric oxide synthase (iNOS) and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation for iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and reduction of NADPH-oxidase 4 (Nox4) expression. In serum-deprived human dermal microvascular endothelial cell cultures, PLC ameliorated endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO level. In addition, PLC counteracted serum deprivation-induced impairment of mitochondrial β-oxidation, Nox4 and cellular adhesion molecule (CAM) expression, ROS generation and leukocyte adhesion. Moreover, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction. Conclusion PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis. The beneficial effects of PLC likely derived from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction. Antioxidant therapy and pharmacological targeting of endothelial dysfunction may represent a promising tool for the treatment of delayed wound healing or chronic ulcers. PMID:26473356

Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice.

PubMed

Langley, Monica; Ghosh, Anamitra; Charli, Adhithiya; Sarkar, Souvarish; Ay, Muhammet; Luo, Jie; Zielonka, Jacek; Brenza, Timothy; Bennett, Brian; Jin, Huajun; Ghaisas, Shivani; Schlichtmann, Benjamin; Kim, Dongsuk; Anantharam, Vellareddy; Kanthasamy, Arthi; Narasimhan, Balaji; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G

2017-11-10

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction. Oral administration of Mito-apocynin (10 mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation. The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches. Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD. Antioxid. Redox Signal. 27, 1048-1066.

Insulin protects against hepatic damage postburn.

PubMed

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.

Insulin Protects against Hepatic Damage Postburn

PubMed Central

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

4-Phenylbutyrate Benefits Traumatic Hemorrhagic Shock in Rats by Attenuating Oxidative Stress, Not by Attenuating Endoplasmic Reticulum Stress.

PubMed

Yang, Guangming; Peng, Xiaoyong; Hu, Yi; Lan, Dan; Wu, Yue; Li, Tao; Liu, Liangming

2016-07-01

Vascular dysfunction such as vascular hyporeactivity following severe trauma and shock is a major cause of death in injured patients. Oxidative stress and endoplasmic reticulum stress play an important role in vascular dysfunction. The objective of the present study was to determine whether or not 4-phenylbutyrate can improve vascular dysfunction and elicit antishock effects by inhibiting oxidative and endoplasmic reticulum stress. Prospective, randomized, controlled laboratory experiment. State key laboratory of trauma, burns, and combined injury. Five hundred and fifty-two Sprague-Dawley rats. Rats were anesthetized, and a model of traumatic hemorrhagic shock was established by left femur fracture and hemorrhage. The effects of 4-phenylbutyrate (5, 20, 50, 100, 200, and 300 mg/kg) on vascular reactivity, animal survival, hemodynamics, and vital organ function in traumatic hemorrhagic shock rats and cultured vascular smooth muscle cells, and the relationship to oxidative stress and endoplasmic reticulum stress was observed. Lower doses of 4-phenylbutyrate significantly improved the vascular function, stabilized the hemodynamics, and increased the tissue blood flow and vital organ function in traumatic hemorrhagic shock rats, and markedly improved the survival outcomes. Among all dosages observed in the present study, 20 mg/kg of 4-phenylbutyrate had the best effect. Further results indicated that 4-phenylbutyrate significantly inhibited the oxidative stress, decreased shock-induced oxidative stress index such as the production of reactive oxygen species, increased the antioxidant enzyme levels such as superoxide dismutase, catalase, and glutathione, and improved the mitochondrial function by inhibiting the opening of the mitochondrial permeability transition pore in rat artery and vascular smooth muscle cells. In contrast, 4-phenylbutyrate did not affect the changes of endoplasmic reticulum stress markers following traumatic hemorrhagic shock. Furthermore, 4-phenylbutyrate increased the nuclear levels of nuclear factor-E2-related factor 2, and decreased the nuclear levels of nuclear factor κB in hypoxic vascular smooth muscle cells. 4-phenylbutyrate has beneficial effects for traumatic hemorrhagic shock including improving animal survival and protecting organ function. These beneficial effects of 4-phenylbutyrate in traumatic hemorrhagic shock result from its vascular function protection via attenuation of the oxidative stress and mitochondrial permeability transition pore opening. Nuclear factor-E2-related factor 2 and nuclear factor-κB may be involved in 4-phenylbutyrate-mediated inhibition of oxidative stress.

Ptpmt1 induced by HIF-2α regulates the proliferation and glucose metabolism in erythroleukemia cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Qin-Qin; Qinghai Provincial People's Hospital, Xining; Xiao, Feng-Jun

Hypoxia provokes metabolism misbalance, mitochondrial dysfunction and oxidative stress in both human and animal cells. However, the mechanisms which hypoxia causes mitochondrial dysfunction and energy metabolism misbalance still remain unclear. In this study, we presented evidence that mitochondrial phosphatase Ptpmt1 is a hypoxia response molecule that regulates cell proliferation, survival and glucose metabolism in human erythroleukemia TF-1 cells. Exposure to hypoxia or DFO treatment results in upregulation of HIF1-α, HIF-2α and Ptpmt1. Only inhibition of HIF-2α by shRNA transduction reduces Ptpmt1 expression in TF-1 cells under hypoxia. Ptpmt1 inhibitor suppresses the growth and induces apoptosis of TF-1 cells. Furthermore, we demonstrated that Ptpmt1more » inhibition reduces the Glut1 and Glut3 expression and decreases the glucose consumption in TF-1 cells. In additional, Ptpmt1 knockdown also results in the mitochondrial dysfunction determined by JC1 staining. These results delineate a key role for HIF-2α-induced Ptpmt1 upregulation in proliferation, survival and glucose metabolism of erythroleukemia cells. It is indicated that Ptpmt1 plays important roles in hypoxia-induced cell metabolism and mitochondrial dysfunction. - Highlights: • Hypoxia induces upregulation of HIF-1α, HIF-2α and Ptpmt1; HIF-2a induces Ptpmt1 upregulation in TF-1 cells. • PTPMT-1 inhibition reduces growth and induces apoptosis of TF-1 cells. • PTPMT1 inhibition downregulates Glut-1, Glut-3 expression and reduces glucose consumption.« less

Nitrate tolerance, oxidative stress, and mitochondrial function: another worrisome chapter on the effects of organic nitrates

PubMed Central

Parker, John D.

2004-01-01

A shortcoming in the clinical use of organic nitrates is the development of tolerance. Recent data have suggested that the denitrification of organic nitrates is mediated by mitochondrial aldehyde dehydrogenase and that dysfunction of this enzyme is an important cause of tolerance. In this issue of the JCI, evidence in support of this hypothesis is presented in an in vivo model of nitrate tolerance. PMID:14755331

The Unfolded Protein Response Plays a Predominant Homeostatic Role in Response to Mitochondrial Stress in Pancreatic Stellate Cells

PubMed Central

Su, Hsin-Yuan; Waldron, Richard T.; Gong, Raymond; Ramanujan, V. Krishnan; Pandol, Stephen J.; Lugea, Aurelia

2016-01-01

Activated pancreatic stellate cells (PaSC) are key participants in the stroma of pancreatic cancer, secreting extracellular matrix proteins and inflammatory mediators. Tumors are poorly vascularized, creating metabolic stress conditions in cancer and stromal cells that necessitate adaptive homeostatic cellular programs. Activation of autophagy and the endoplasmic reticulum unfolded protein response (UPR) have been described in hepatic stellate cells, but the role of these processes in PaSC responses to metabolic stress is unknown. We reported that the PI3K/mTOR pathway, which AMPK can regulate through multiple inputs, modulates PaSC activation and fibrogenic potential. Here, using primary and immortalized mouse PaSC, we assess the relative contributions of AMPK/mTOR signaling, autophagy and the UPR to cell fate responses during metabolic stress induced by mitochondrial dysfunction. The mitochondrial uncoupler rottlerin at low doses (0.5–2.5 μM) was added to cells cultured in 10% FBS complete media. Mitochondria rapidly depolarized, followed by altered mitochondrial dynamics and decreased cellular ATP levels. This mitochondrial dysfunction elicited rapid, sustained AMPK activation, mTOR pathway inhibition, and blockade of autophagic flux. Rottlerin treatment also induced rapid, sustained PERK/CHOP UPR signaling. Subsequently, high doses (>5 μM) induced loss of cell viability and cell death. Interestingly, AMPK knock-down using siRNA did not prevent rottlerin-induced mTOR inhibition, autophagy, or CHOP upregulation, suggesting that AMPK is dispensable for these responses. Moreover, CHOP genetic deletion, but not AMPK knock-down, prevented rottlerin-induced apoptosis and supported cell survival, suggesting that UPR signaling is a major modulator of cell fate in PaSC during metabolic stress. Further, short-term rottlerin treatment reduced both PaSC fibrogenic potential and IL-6 mRNA expression. In contrast, expression levels of the angiogenic factors HGF and VEGFα were unaffected, and the immune modulator IL-4 was markedly upregulated. These data imply that metabolic stress-induced PaSC reprogramming differentially modulates neighboring cells in the tumor microenvironment. PMID:26849807

Butyric acid induces apoptosis via oxidative stress in Jurkat T-cells.

PubMed

Kurita-Ochiai, T; Ochiai, K

2010-07-01

Reactive oxygen species (ROS) are essential for the induction of T-cell apoptosis by butyric acid, an extracellular metabolite of periodontopathic bacteria. To determine the involvement of oxidative stress in apoptosis pathways, we investigated the contribution of ROS in mitochondrial signaling pathways, death-receptor-initiated signaling pathway, and endoplasmic reticulum stress in butyric-acid-induced T-cell apoptosis. N-acetyl-L-Cysteine (NAC) abrogated mitochondrial injury, cytochrome c, AIF, and Smac release, and Bcl-2 and Bcl-xL suppression and Bax and Bad activation induced by butyric acid. However, the decrease in cFLIP expression by butyric acid was not restored by treatment with NAC; increases in caspase-4 and -10 activities by butyric acid were completely abrogated by NAC. NAC also affected the elevation of GRP78 and CHOP/GADD153 expression by butyric acid. These results suggest that butyric acid is involved in mitochondrial-dysfunction- and endoplasmic reticulum stress-mediated apoptosis in human Jurkat T-cells via a ROS-dependent mechanism.

Preventive effects of fructose and N-acetyl-L-cysteine against cytotoxicity induced by the psychoactive compounds N-methyl-5-(2-aminopropyl)benzofuran and 3,4-methylenedioxy-N-methamphetamine in isolated rat hepatocytes.

PubMed

Nakagawa, Yoshio; Suzuki, Toshinari; Inomata, Akiko

2018-02-01

Psychoactive compounds, N-methyl-5-(2-aminopropyl)benzofuran (5-MAPB) and 3,4-methylenedioxy-N-methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N-acetyl-l-cysteine (NAC) on 5-MAPB- and MDMA-induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration-dependent (0-4 mm) and time-dependent (0-3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH. The toxic effects of 5-MAPB were greater than those of MDMA. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or NAC at a concentration of 2.5 mm prevented 5-MAPB-/MDMA-induced cytotoxicity. In addition, the exposure of hepatocytes to 5-MAPB/MDMA caused the loss of mitochondrial membrane potential, although the preventive effect of fructose was weaker than that of NAC. These results suggest that: (1) 5-MAPB-/MDMA-induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were ameliorated, at least in part, by the addition of fructose; and (3) GSH loss via oxidative stress was prevented by NAC. Taken collectively, these results indicate that the onset of toxic effects caused by 5-MAPB/MDMA may be partially attributable to cellular energy stress as well as oxidative stress. Copyright © 2017 John Wiley & Sons, Ltd.

Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension.

PubMed

Afolayan, Adeleye J; Eis, Annie; Alexander, Maxwell; Michalkiewicz, Teresa; Teng, Ru-Jeng; Lakshminrusimha, Satyan; Konduri, Girija G

2016-01-01

Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O2 alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O2 was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of FiO2 , partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN-PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O2 amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen. Copyright © 2016 the American Physiological Society.

Resveratrol attenuates methylglyoxal-induced mitochondrial dysfunction and apoptosis by Sestrin2 induction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seo, Kyuhwa; Seo, Suho; Han, Jae Yun

2014-10-15

Methylglyoxal is found in high levels in the blood and other tissues of diabetic patients and exerts deleterious effects on cells and tissues. Previously, we reported that resveratrol, a polyphenol in grapes, induced the expression of Sestrin2 (SESN2), a novel antioxidant protein, and inhibited hepatic lipogenesis. This study investigated whether resveratrol protects cells from the methylglyoxal-induced toxicity via SESN2 induction. Methylglyoxal significantly induced cell death in HepG2 cells. However, cells pretreated with resveratrol were rescued from methylglyoxal-induced apoptosis. Resveratrol attenuated glutathione (GSH) depletion and ROS production promoted by methylglyoxal. Moreover, mitochondrial damage was observed by methylglyoxal treatment, but resveratrol restoredmore » mitochondrial function, as evidenced by the observed lack of mitochondrial permeability transition and increased ADP/ATP ratio. Resveratrol treatment inhibited SESN2 depletion elicited by methylglyoxal. SESN2 overexpression repressed methylglyoxal-induced mitochondrial dysfunction and apoptosis. Likewise, rotenone-induced cytotoxicity was not observed in SESN2 overexpressed cells. Furthermore, siRNA knockdown of SESN2 reduced the ability of resveratrol to prevent methylglyoxal-induced mitochondrial permeability transition. In addition, when mice were exposed to methylglyoxal after infection of Ad-SESN2, the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and GSH depletion by methylglyoxal in liver was reduced in Ad-SESN2 infected mice. Our results demonstrated that resveratrol is capable of protecting cells from methylglyoxal-induced mitochondrial dysfunction and oxidative stress via SESN2 induction. - Highlights: • Resveratrol decreased methylglyoxal-induced apoptosis. • Resveratrol attenuated GSH depletion and ROS production promoted by methylglyoxal. • Resveratrol restored the mitochondrial function by Sestrin2 induction. • Induction of Sestrin2 prevented methylglyoxal-induced GSH depletion in liver.« less

Targeted overexpression of mitochondrial catalase prevents radiation-induced cognitive dysfunction.

PubMed

Parihar, Vipan K; Allen, Barrett D; Tran, Katherine K; Chmielewski, Nicole N; Craver, Brianna M; Martirosian, Vahan; Morganti, Josh M; Rosi, Susanna; Vlkolinsky, Roman; Acharya, Munjal M; Nelson, Gregory A; Allen, Antiño R; Limoli, Charles L

2015-01-01

Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain.

Endoplasmic reticulum and mitochondria interplay mediates apoptotic cell death: relevance to Parkinson's disease.

PubMed

Arduíno, Daniela Moniz; Esteves, A Raquel; Cardoso, Sandra M; Oliveira, Catarina R

2009-09-01

Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Many cellular mechanisms are thought to be involved in the death of these specific neurons in PD, including oxidative stress, changes of intracellular calcium homeostasis, and mitochondrial dysfunction. Since recent studies have revealed that also endoplasmic reticulum (ER) stress in conjunction with abnormal protein degradation can contribute to the PD pathophysiology, we investigated here the molecular mechanisms underlying the interplay between ER and mitochondria and its relevance in the control of neuronal cell death in PD. We observed that MPP+ induced changes in the mitochondrial function, affecting mitochondrial membrane potential and electron transport chain function. Likewise, it was also evident the unfolded protein response activation by an overexpression of GRP78 protein. Moreover, stress stimuli caused the release of Ca2+ from the ER that consistently induced mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free Ca2+. Besides, Ca2+ release inhibition prevented MPP+ mediated mitochondria-dependent caspases activation. Our findings show that ER and mitochondria are in a close communication, establishing a dynamic ER-Ca2+-mitochondria interconnection that can play a prominent role in the neuronal cell death induction under particular stressful circumstances of PD pathology.

Idh2 deficiency accelerates renal dysfunction in aged mice.

PubMed

Lee, Su Jeong; Cha, Hanvit; Lee, Seoyoon; Kim, Hyunjin; Ku, Hyeong Jun; Kim, Sung Hwan; Park, Jung Hyun; Lee, Jin Hyup; Park, Kwon Moo; Park, Jeen-Woo

2017-11-04

The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP + -dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2 -/- ) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2 -/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2 -/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging. Copyright © 2017 Elsevier Inc. All rights reserved.

SIRT3 aggravates metformin-induced energy stress and apoptosis in ovarian cancer cells.

PubMed

Wu, Yao; Gao, Wei-Nan; Xue, Ya-Nan; Zhang, Li-Chao; Zhang, Juan-Juan; Lu, Sheng-Yao; Yan, Xiao-Yu; Yu, Hui-Mei; Su, Jing; Sun, Lian-Kun

2018-06-15

Increasing evidence suggests that mitochondrial respiratory chain complex I participates in carcinogenesis and cancer progression by providing energy and maintaining mitochondrial function. However, the role of complex I in ovarian cancer is largely unknown. In this study we showed that metformin, considered to be an inhibitor of complex I, simultaneously inhibited cell growth and induced mitochondrial-related apoptosis in human ovarian cancer cells. Metformin interrupted cellular energy metabolism mainly by causing damage to complex I that impacted mitochondrial function. Additionally, treatment with metformin increased the activation of sirtuin 3 (SIRT3), a mitochondrial deacetylase. We demonstrated that SIRT3 overexpression aggravated metformin-induced apoptosis, energy stress and mitochondrial dysfunction. Moreover, treatment with metformin or SIRT3 overexpression increased activation of AMP-activated protein kinase (AMPK), a major sensor of cellular energy status. AMPK compensated for energy loss by increasing glycolysis. The impact of this was assessed by reducing glucose levels in the media or by using inhibitors (2-deoxyglucose, Compound C) of glycolysis and AMPK. The combination of these factors with metformin intensified cytotoxicity through further downregulation of ATP. Our study outlines an important role for SIRT3 in the antitumor effect of mitochondrial complex I inhibitors in human ovarian cancer cells. This effect appears to be mediated by induction of energy stress and apoptosis. Strategies that target the mitochondria could be enhanced by modulating glycolysis to further aggravate energy stress that may increase the antitumor effect. Copyright © 2018 Elsevier Inc. All rights reserved.

Mitochondrial oxidative stress in aging and healthspan

PubMed Central

2014-01-01

The free radical theory of aging proposes that reactive oxygen species (ROS)-induced accumulation of damage to cellular macromolecules is a primary driving force of aging and a major determinant of lifespan. Although this theory is one of the most popular explanations for the cause of aging, several experimental rodent models of antioxidant manipulation have failed to affect lifespan. Moreover, antioxidant supplementation clinical trials have been largely disappointing. The mitochondrial theory of aging specifies more particularly that mitochondria are both the primary sources of ROS and the primary targets of ROS damage. In addition to effects on lifespan and aging, mitochondrial ROS have been shown to play a central role in healthspan of many vital organ systems. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and dysfunction in aging and healthspan, including cardiac aging, age-dependent cardiovascular diseases, skeletal muscle aging, neurodegenerative diseases, insulin resistance and diabetes as well as age-related cancers. The crosstalk of mitochondrial ROS, redox, and other cellular signaling is briefly presented. Potential therapeutic strategies to improve mitochondrial function in aging and healthspan are reviewed, with a focus on mitochondrial protective drugs, such as the mitochondrial antioxidants MitoQ, SkQ1, and the mitochondrial protective peptide SS-31. PMID:24860647

Mitochondrial Stress Tests Using Seahorse Respirometry on Intact Dictyostelium discoideum Cells.

PubMed

Lay, Sui; Sanislav, Oana; Annesley, Sarah J; Fisher, Paul R

2016-01-01

Mitochondria not only play a critical and central role in providing metabolic energy to the cell but are also integral to the other cellular processes such as modulation of various signaling pathways. These pathways affect many aspects of cell physiology, including cell movement, growth, division, differentiation, and death. Mitochondrial dysfunction which affects mitochondrial bioenergetics and causes oxidative phosphorylation defects can thus lead to altered cellular physiology and manifest in disease. The assessment of the mitochondrial bioenergetics can thus provide valuable insights into the physiological state, and the alterations to the state of the cells. Here, we describe a method to successfully use the Seahorse XF(e)24 Extracellular Flux Analyzer to assess the mitochondrial respirometry of the cellular slime mold Dictyostelium discoideum.

F1F0 ATP Synthase-Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline.

PubMed

Yan, Shijun; Du, Fang; Wu, Long; Zhang, Zhihua; Zhong, Changjia; Yu, Qing; Wang, Yongfu; Lue, Lih-Fen; Walker, Douglas G; Douglas, Justin T; Yan, Shirley ShiDu

2016-11-01

Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif -/- ) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca 2+ -induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca 2+ overload. Diabetes-induced elevation of CypD triggers enhancement of F 1 F 0 ATP synthase-CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F 1 F 0 ATP synthase-CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy. © 2016 by the American Diabetes Association.

Sulforaphane Protects against High Cholesterol-Induced Mitochondrial Bioenergetics Impairments, Inflammation, and Oxidative Stress and Preserves Pancreatic β-Cells Function.

PubMed

Carrasco-Pozo, Catalina; Tan, Kah Ni; Gotteland, Martin; Borges, Karin

2017-01-01

Cholesterol plays an important role in inducing pancreatic β -cell dysfunction, leading to an impaired insulin secretory response to glucose. This study aimed to determine the protective effects of sulforaphane, a natural isothiocyanate Nrf2-inducer, against cholesterol-induced pancreatic β -cells dysfunction, through molecular and cellular mechanisms involving mitochondrial bioenergetics. Sulforaphane prevented cholesterol-induced alterations in the coupling efficiency of mitochondrial respiration, improving ATP turnover and spare capacity, and averted the impairment of the electron flow at complexes I, II, and IV. Sulforaphane also attenuated the cholesterol-induced activation of the NF κ B pathway, normalizing the expression of pro- and anti-inflammatory cytokines. In addition, it also inhibited the decrease in sirtuin 1 expression and greatly increased Pgc-1α expression in Min6 cells. Sulforaphane increased the expression of antioxidant enzymes downstream of the Nrf2 pathway and prevented lipid peroxidation induced by cholesterol. The antioxidant and anti-inflammatory properties of sulforaphane and its ability to protect and improve mitochondrial bioenergetic function contribute to its protective action against cholesterol-induced pancreatic β -cell dysfunction. Our data provide a scientifically tested foundation upon which sulforaphane can be developed as nutraceutical to preserve β -cell function and eventually control hyperglycemia.

Sulforaphane Protects against High Cholesterol-Induced Mitochondrial Bioenergetics Impairments, Inflammation, and Oxidative Stress and Preserves Pancreatic β-Cells Function

PubMed Central

Tan, Kah Ni; Gotteland, Martin

2017-01-01

Cholesterol plays an important role in inducing pancreatic β-cell dysfunction, leading to an impaired insulin secretory response to glucose. This study aimed to determine the protective effects of sulforaphane, a natural isothiocyanate Nrf2-inducer, against cholesterol-induced pancreatic β-cells dysfunction, through molecular and cellular mechanisms involving mitochondrial bioenergetics. Sulforaphane prevented cholesterol-induced alterations in the coupling efficiency of mitochondrial respiration, improving ATP turnover and spare capacity, and averted the impairment of the electron flow at complexes I, II, and IV. Sulforaphane also attenuated the cholesterol-induced activation of the NFκB pathway, normalizing the expression of pro- and anti-inflammatory cytokines. In addition, it also inhibited the decrease in sirtuin 1 expression and greatly increased Pgc-1α expression in Min6 cells. Sulforaphane increased the expression of antioxidant enzymes downstream of the Nrf2 pathway and prevented lipid peroxidation induced by cholesterol. The antioxidant and anti-inflammatory properties of sulforaphane and its ability to protect and improve mitochondrial bioenergetic function contribute to its protective action against cholesterol-induced pancreatic β-cell dysfunction. Our data provide a scientifically tested foundation upon which sulforaphane can be developed as nutraceutical to preserve β-cell function and eventually control hyperglycemia. PMID:28386307

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes*

PubMed Central

Collins, John A.; Wood, Scott T.; Nelson, Kimberly J.; Rowe, Meredith A.; Carlson, Cathy S.; Chubinskaya, Susan; Poole, Leslie B.; Furdui, Cristina M.; Loeser, Richard F.

2016-01-01

Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1–3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism. PMID:26797130

Taurine and its neuroprotective role.

PubMed

Kumari, Neeta; Prentice, Howard; Wu, Jang-Yen

2013-01-01

Taurine plays multiple roles in the CNS including acting as a -neuro-modulator, an osmoregulator, a regulator of cytoplasmic calcium levels, a trophic factor in development, and a neuroprotectant. In neurons taurine has been shown to prevent mitochondrial dysfunction and to protect against endoplasmic reticulum (ER) stress associated with neurological disorders. In cortical neurons in culture taurine protects against excitotoxicity through reversing an increase in levels of key ER signaling components including eIF-2-alpha and cleaved ATF6. The role of communication between the ER and mitochondrion is also important and examples are presented of protection by taurine against ER stress together with prevention of subsequent mitochondrial initiated apoptosis.

Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications

PubMed Central

Song, Byoung-Joon; Akbar, Mohammed; Abdelmegeed, Mohamed A.; Byun, Kyunghee; Lee, Bonghee; Yoon, Seung Kew; Hardwick, James P.

2014-01-01

Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondrial dysfunction, fat accumulation and tissue injury. PMID:25465468

Inhibitory Effect of Lycopene on Amyloid-β-Induced Apoptosis in Neuronal Cells.

PubMed

Hwang, Sinwoo; Lim, Joo Weon; Kim, Hyeyoung

2017-08-16

Alzheimer's disease (AD) is a fatal neurodegenerative disease. Brain amyloid-β deposition is a crucial feature of AD, causing neuronal cell death by inducing oxidative damage. Reactive oxygen species (ROS) activate NF-κB, which induces expression of Nucling. Nucling is a pro-apoptotic factor recruiting the apoptosome complex. Lycopene is an antioxidant protecting from oxidative stress-induced cell damage. We investigated whether lycopene inhibits amyloid-β-stimulated apoptosis through reducing ROS and inhibiting mitochondrial dysfunction and NF-κB-mediated Nucling expression in neuronal SH-SY5Y cells. We prepared cells transfected with siRNA for Nucling or nontargeting control siRNA to determine the role of Nucling in amyloid-β-induced apoptosis. The amyloid-β increased intracellular and mitochondrial ROS levels, apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), NF-kB activation and Nucling expression, while cell viability, mitochondrial membrane potential, and oxygen consumption rate decreased in SH-SY5Y cells. Lycopene inhibited these amyloid-β-induced alterations. However, amyloid-β did not induce apoptosis, determined by cell viability and apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), in the cells transfected with siRNA for Nucling. Lycopene inhibited apoptosis by reducing ROS, and by inhibiting mitochondrial dysfunction and NF-κB-target gene Nucling expression in neuronal cells. Lycopene may be beneficial for preventing oxidative stress-mediated neuronal death in patients with neurodegeneration.

Curcuminoid EF24 enhances the anti-tumour activity of Akt inhibitor MK-2206 through ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction in gastric cancer.

PubMed

Chen, Xi; Dai, Xuanxuan; Zou, Peng; Chen, Weiqian; Rajamanickam, Vinothkumar; Feng, Chen; Zhuge, Weishan; Qiu, Chenyu; Ye, Qingqing; Zhang, Xiaohua; Liang, Guang

2017-05-01

Gastric cancer is one of the leading causes of morbidity and mortality worldwide. Akt is an anti-apoptotic kinase that plays a dynamic role in cell survival and is implicated in the pathogenesis of gastric cancer. MK-2206, the first allosteric inhibitor of Akt, is in clinical trials for a number of cancers. Although preclinical studies showed promise, clinical trials reported it had no effect when given alone at tolerated doses. The aim of our study was to delineate the effects of MK-2206 on gastric cancer cells and explore the ability of combination treatments to enhance the anti-tumour activity of MK-2206. SGC-7901, BGC-823 cells and immunodeficient mice were chosen as a model to study the treatment effects. Changes in cell viability, apoptosis and ROS, endoplasmic reticulum stress and mitochondrial dysfunction in the cells were analysed by MTT assays, ROS imaging and FACSCalibur, electron microscopy, JC-1 staining and western blotting. MK-2206 induced apoptotic cell death through the generation of ROS. We utilized ROS production to target gastric cancer cells by combining MK-2206 and an ROS inducer EF24. Our in vitro and in vivo xenograft studies showed that combined treatment with MK-2206 and EF24 synergistically induced apoptosis in gastric cancer cells and caused cell cycle arrest. These activities were mediated through ROS generation and the induction of endoplasmic reticulum stress and mitochondrial dysfunction. Targeting ROS generation by using a combination of an Akt inhibitor and EF24 could have potential as a therapy for gastric cancer. © 2017 The British Pharmacological Society.

Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders.

PubMed

Bhandari, Ranjana; Kuhad, Anurag

2017-02-01

Neuronal dysfunction caused by neuroinflammation triggered by the stimulation of matrix metalloproteinases and the subsequent release of pro-inflammatory cytokines, as a result of oxidative stress and mitochondrial dysfunction, is one of the probable mechanisms involved in the pathogenesis of autism spectrum disorders (ASD). The aim of the present study was to explore the ameliorative potential of resveratrol on neuroinflammation in the experimental paradigm of neuroinflammatory model of ASD in rats. 1M Propanoic acid (PPA) (4 μl) was infused over 10 min into the anterior portion of the lateral ventricle to induce ASD like symptoms in rats. Resveratrol (5, 10 and 15 mg/kg) was administered starting from the 2nd day of the surgery and continued upto 28th day. Rats were tested for various behavioural paradigms such as social interaction, stereotypy, locomotor activity, anxiety, novelty, depression, spatial learning, memory, repetitive and pervasive behaviour between the 7th day and 28th day. In addition, biochemical tests for oxidative stress, mitochondrial complexes, TNF-α and MMP-9 were also assessed. Treatment with resveratrol for four weeks restored, significantly and dose dependently, all the neurological, sensory, behavioural, biochemical and molecular deficits in PPA induced autistic phenotype in rats. The major finding of the study is that resveratrol restored the core and associated symptoms of autistic phenotype by suppressing oxidative-nitrosative stress, mitochondrial dysfunction, TNF-α and MMP-9 expression in PPA induced ASD in rats. Therefore, resveratrol might serve as an adjunct potential therapeutic agent for amelioration of neurobehavioural and biochemical deficits associated with autism spectrum disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Curcuminoid EF24 enhances the anti‐tumour activity of Akt inhibitor MK‐2206 through ROS‐mediated endoplasmic reticulum stress and mitochondrial dysfunction in gastric cancer

PubMed Central

Chen, Xi; Dai, Xuanxuan; Zou, Peng; Chen, Weiqian; Rajamanickam, Vinothkumar; Feng, Chen; Zhuge, Weishan; Qiu, Chenyu; Ye, Qingqing

2017-01-01

Background and Purpose Gastric cancer is one of the leading causes of morbidity and mortality worldwide. Akt is an anti‐apoptotic kinase that plays a dynamic role in cell survival and is implicated in the pathogenesis of gastric cancer. MK‐2206, the first allosteric inhibitor of Akt, is in clinical trials for a number of cancers. Although preclinical studies showed promise, clinical trials reported it had no effect when given alone at tolerated doses. The aim of our study was to delineate the effects of MK‐2206 on gastric cancer cells and explore the ability of combination treatments to enhance the anti‐tumour activity of MK‐2206. Experimental Approach SGC‐7901, BGC‐823 cells and immunodeficient mice were chosen as a model to study the treatment effects. Changes in cell viability, apoptosis and ROS, endoplasmic reticulum stress and mitochondrial dysfunction in the cells were analysed by MTT assays, ROS imaging and FACSCalibur, electron microscopy, JC‐1 staining and western blotting. Key Results MK‐2206 induced apoptotic cell death through the generation of ROS. We utilized ROS production to target gastric cancer cells by combining MK‐2206 and an ROS inducer EF24. Our in vitro and in vivo xenograft studies showed that combined treatment with MK‐2206 and EF24 synergistically induced apoptosis in gastric cancer cells and caused cell cycle arrest. These activities were mediated through ROS generation and the induction of endoplasmic reticulum stress and mitochondrial dysfunction. Conclusion and Implications Targeting ROS generation by using a combination of an Akt inhibitor and EF24 could have potential as a therapy for gastric cancer. PMID:28255993

Anthelminthic drug niclosamide sensitizes the responsiveness of cervical cancer cells to paclitaxel via oxidative stress-mediated mTOR inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Liping; Wang, Li; Shen, Haibin

Drug repurposing represents an alternative therapeutic strategy to cancer treatment. The potent anti-cancer activities of a FDA-approved anthelminthic drug niclosamide have been demonstrated in various cancers. However, whether niclosamide is active against cervical cancer is unknown. In this study, we investigated the effects of niclosamide alone and its combination with paclitaxel in cervical cancer in vitro and in vivo. We found that niclosamide significantly inhibited proliferation and induced apoptosis of a panel of cervical cancer cell lines, regardless of their cellular origin and genetic pattern. Niclosamide also inhibited tumor growth in cervical cancer xenograft mouse model. Importantly, niclosamide significantly enhanced the responsivenessmore » of cervical cancer cell to paclitaxel. We further found that niclosamide induced mitochondrial dysfunctions via inhibiting mitochondrial respiration, complex I activity and ATP generation, which led to oxidative stress. ROS scavenge agent N-acetyl-L-cysteine (NAC) completely reversed the effects of niclosamide in increasing cellular ROS, inhibiting proliferation and inducing apoptosis, suggesting that oxidative stress induction is the mechanism of action of niclosamide in cervical cancer cells. In addition, niclosamide significantly inhibited mammalian target of rapamycin (mTOR) signaling pathway in cervical cancer cells and its inhibitory effect on mTOR is modulated by oxidative stress. Our work suggests that niclosamide is a useful addition to the treatment armamentarium for cervical cancer and induction of oxidative stress may be a potential therapeutic strategy in cervical cancer. - Highlights: • Niclosamide is active against cervical cancer cells in vitro and in vivo. • Niclosamide sensitizes cervical cancer cell response to paclitaxel. • Niclosamide induces mitochondrial dysfunction and oxidative damage. • Niclosamide inhibits mTOR signaling in an oxidative stress-dependent manner.« less

Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGill, Mitchell R.; Williams, C. David; Xie, Yuchao

2012-11-01

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites amore » reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The limited mitochondrial adducts in rats are insufficient to trigger cell necrosis.« less

Trichodermin induces cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress in human chondrosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Chen-Ming; Wang, Shih-Wei; Lee, Tzong-Huei

2013-10-15

Chondrosarcoma is the second most common primary bone tumor, and it responds poorly to both chemotherapy and radiation treatment. Nalanthamala psidii was described originally as Myxosporium in 1926. This is the first study to investigate the anti-tumor activity of trichodermin (trichothec-9-en-4-ol, 12,13-epoxy-, acetate), an endophytic fungal metabolite from N. psidii against human chondrosarcoma cells. We demonstrated that trichodermin induced cell apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 cells) instead of primary chondrocytes. In addition, trichodermin triggered endoplasmic reticulum (ER) stress protein levels of IRE1, p-PERK, GRP78, and GRP94, which were characterized by changes in cytosolic calcium levels. Furthermore,more » trichodermin induced the upregulation of Bax and Bid, the downregulation of Bcl-2, and the dysfunction of mitochondria, which released cytochrome c and activated caspase-3 in human chondrosarcoma. In addition, animal experiments illustrated reduced tumor volume, which led to an increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and an increased level of cleaved PARP protein following trichodermin treatment. Together, this study demonstrates that trichodermin is a novel anti-tumor agent against human chondrosarcoma cells both in vitro and in vivo via mitochondrial dysfunction and ER stress. - Highlights: • Trichodermin induces chondrosarcoma apoptosis. • ER stress is involved in trichodermin-induced cell death. • Trichodermin induces chondrosarcoma death in vivo.« less

Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohammad, Mohammad K.; Alcohol Research Center, University of Louisville; Avila, Diana

2012-11-15

Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentrations, caused a dose-dependent loss of viability of hepatocytes. The death was apoptotic at moderate and necrotic at high concentrations of acrolein. Acrolein exposure rapidly and dramatically decreased intracellular glutathione and overall antioxidantmore » capacity, and activated the stress-signaling MAP-kinases JNK, p42/44 and p38. Our data demonstrate for the first time in human hepatocytes, that acrolein triggered endoplasmic reticulum (ER) stress and activated eIF2α, ATF-3 and -4, and Gadd153/CHOP, resulting in cell death. Notably, the protective/adaptive component of ER stress was not activated, and acrolein failed to up-regulate the protective ER-chaperones, GRP78 and GRP94. Additionally, exposure to acrolein disrupted mitochondrial integrity/function, and led to the release of pro-apoptotic proteins and ATP depletion. Acrolein-induced cell death was attenuated by N-acetyl cysteine, phenyl-butyric acid, and caspase and JNK inhibitors. Our data demonstrate that exposure to acrolein induces a variety of stress responses in hepatocytes, including GSH depletion, oxidative stress, mitochondrial dysfunction and ER stress (without ER-protective responses) which together contribute to acrolein toxicity. Our study defines basic mechanisms underlying liver injury caused by reactive aldehyde pollutants such as acrolein. -- Highlights: ► Human primary hepatocytes and cultured cell lines are used. ► Multiple cell death signaling pathways are activated by acrolein. ► Novel finding of acrolein-induced ER stress ► Acrolein fails to activate ER stress-induced protective responses. ► Combinatorial therapies may be needed for preventing acrolein hepatotoxicity.« less

A Time to Reap, a Time to Sow: Mitophagy and Biogenesis in Cardiac Pathophysiology

PubMed Central

Andres, Allen M.; Stotland, Aleksandr; Queliconi, Bruno B.; Gottlieb, Roberta A.

2014-01-01

Balancing mitophagy and mitochondrial biogenesis is essential for maintaining a healthy population of mitochondria and cellular homeostasis. Coordinated interplay between these two forces that govern mitochondrial turnover plays an important role as an adaptive response against various cellular stresses that can compromise cell survival. Failure to maintain the critical balance between mitophagy and mitochondrial biogenesis or homeostatic turnover of mitochondria results in a population of dysfunctional mitochondria that contribute to various disease processes. In this review we outline the mechanics and relationships between mitophagy and mitochondrial biogenesis, and discuss the implications of a disrupted balance between these two forces, with an emphasis on cardiac physiology. PMID:25444712

Regulation of mitochondrial biogenesis and its intersection with inflammatory responses.

PubMed

Cherry, Anne D; Piantadosi, Claude A

2015-04-20

Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.

Fisetin Confers Cardioprotection against Myocardial Ischemia Reperfusion Injury by Suppressing Mitochondrial Oxidative Stress and Mitochondrial Dysfunction and Inhibiting Glycogen Synthase Kinase 3β Activity.

PubMed

Shanmugam, Karthi; Ravindran, Sriram; Kurian, Gino A; Rajesh, Mohanraj

2018-01-01

Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. Timely reperfusion is considered an optimal treatment for AMI. Paradoxically, the procedure of reperfusion can itself cause myocardial tissue injury. Therefore, a strategy to minimize the reperfusion-induced myocardial tissue injury is vital for salvaging the healthy myocardium. Herein, we investigated the cardioprotective effects of fisetin, a natural flavonoid, against ischemia/reperfusion (I/R) injury (IRI) using a Langendorff isolated heart perfusion system. I/R produced significant myocardial tissue injury, which was characterized by elevated levels of lactate dehydrogenase and creatine kinase in the perfusate and decreased indices of hemodynamic parameters. Furthermore, I/R resulted in elevated oxidative stress, uncoupling of the mitochondrial electron transport chain, increased mitochondrial swelling, a decrease of the mitochondrial membrane potential, and induction of apoptosis. Moreover, IRI was associated with a loss of the mitochondrial structure and decreased mitochondrial biogenesis. However, when the animals were pretreated with fisetin, it significantly attenuated the I/R-induced myocardial tissue injury, blunted the oxidative stress, and restored the structure and function of mitochondria. Mechanistically, the fisetin effects were found to be mediated via inhibition of glycogen synthase kinase 3 β (GSK3 β ), which was confirmed by a biochemical assay and molecular docking studies.

Unraveling Biochemical Pathways Affected by Mitochondrial Dysfunctions Using Metabolomic Approaches

PubMed Central

Demine, Stéphane; Reddy, Nagabushana; Renard, Patricia; Raes, Martine; Arnould, Thierry

2014-01-01

Mitochondrial dysfunction(s) (MDs) can be defined as alterations in the mitochondria, including mitochondrial uncoupling, mitochondrial depolarization, inhibition of the mitochondrial respiratory chain, mitochondrial network fragmentation, mitochondrial or nuclear DNA mutations and the mitochondrial accumulation of protein aggregates. All these MDs are known to alter the capacity of ATP production and are observed in several pathological states/diseases, including cancer, obesity, muscle and neurological disorders. The induction of MDs can also alter the secretion of several metabolites, reactive oxygen species production and modify several cell-signalling pathways to resolve the mitochondrial dysfunction or ultimately trigger cell death. Many metabolites, such as fatty acids and derived compounds, could be secreted into the blood stream by cells suffering from mitochondrial alterations. In this review, we summarize how a mitochondrial uncoupling can modify metabolites, the signalling pathways and transcription factors involved in this process. We describe how to identify the causes or consequences of mitochondrial dysfunction using metabolomics (liquid and gas chromatography associated with mass spectrometry analysis, NMR spectroscopy) in the obesity and insulin resistance thematic. PMID:25257998

Frontal cortical mitochondrial dysfunction and mitochondria-related β-amyloid accumulation by chronic sleep restriction in mice.

PubMed

Zhao, Hongyi; Wu, Huijuan; He, Jialin; Zhuang, Jianhua; Liu, Zhenyu; Yang, Yang; Huang, Liuqing; Zhao, Zhongxin

2016-08-17

Mitochondrial dysfunction induced by mitochondria-related β-amyloid (Aβ) accumulation is increasingly being considered a novel risk factor for sporadic Alzheimer's disease pathophysiology. The close relationship between chronic sleep restriction (CSR) and cortical Aβ elevation was confirmed recently. By assessing frontal cortical mitochondrial function (electron microscopy manifestation, cytochrome C oxidase concentration, ATP level, and mitochondrial membrane potential) and the levels of mitochondria-related Aβ in 9-month-old adult male C57BL/6J mice subjected to CSR and as an environmental control (CO) group, we aimed to evaluate the association of CSR with mitochondrial dysfunction and mitochondria-related Aβ accumulation. In this study, frontal cortical mitochondrial dysfunction was significantly more severe in CSR mice compared with CO animals. Furthermore, CSR mice showed higher mitochondria-associated Aβ, total Aβ, and mitochondria-related β-amyloid protein precursor (AβPP) levels compared with CO mice. In the CSR model, mouse frontal cortical mitochondrial dysfunction was correlated with mitochondria-associated Aβ and mitochondria-related AβPP levels. However, frontal cortical mitochondria-associated Aβ levels showed no significant association with cortical total Aβ and mitochondrial AβPP concentrations. These findings indicated that CSR-induced frontal cortical mitochondrial dysfunction and mitochondria-related Aβ accumulation, which was closely related to mitochondrial dysfunction under CSR.

Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells.

PubMed

Martinez-Outschoorn, Ubaldo E; Balliet, Renee M; Rivadeneira, Dayana B; Chiavarina, Barbara; Pavlides, Stephanos; Wang, Chenguang; Whitaker-Menezes, Diana; Daumer, Kristin M; Lin, Zhao; Witkiewicz, Agnieszka K; Flomenberg, Neal; Howell, Anthony; Pestell, Richard G; Knudsen, Erik S; Sotgia, Federica; Lisanti, Michael P

2010-08-15

Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor micro-environment." Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the "Reverse Warburg Effect"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use "oxidative stress" in adjacent fibroblasts (i) as an "engine" to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the "field effect" in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively "contagious"--spread from cell-to-cell like a virus--creating an "oncogenic/mutagenic" field promoting widespread DNA damage.

Differential programming of p53-deficient embryonic cells during rotenone block

EPA Science Inventory

Mitochondrial dysfunction has been implicated in chemical toxicities. The present study used an in vitro model to investigate the differential expression of metabolic pathways during cellular stress in p53- efficient embryonic fibroblasts compared to p53-deficient cells. These c...

Tryptamine-Gallic Acid Hybrid Prevents Non-steroidal Anti-inflammatory Drug-induced Gastropathy

PubMed Central

Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd. Shameel; Sarkar, Souvik; Kumar, Rahul; Halder, Kamal Krishna; Debnath, Mita Chatterjee; Adhikari, Susanta; Bandyopadhyay, Uday

2012-01-01

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O2˙̄) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled (99mTc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy. PMID:22157011

Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR.

PubMed

Veiga, Sonia Rosa; Ge, Xuemei; Mercer, Carol A; Hernández-Alvarez, María Isabel; Thomas, Hala Elnakat; Hernández-Losa, Javier; Ramón Y Cajal, Santiago; Zorzano, Antonio; Thomas, George; Kozma, Sara C

2018-04-24

Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC. Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC. Copyright ©2018, American Association for Cancer Research.

The Effect of Bornyl cis-4-Hydroxycinnamate on Melanoma Cell Apoptosis Is Associated with Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

PubMed Central

Yang, Tzu-Yen; Wu, Yu-Jen; Chang, Chi-I; Wu, Mei-Li

2018-01-01

Bornyl cis-4-hydroxycinnamate, an active compound isolated from Piper betle stems, was investigated in terms of its effects on A2058 and A375 melanoma cell proliferation and protein expression in this study. We used flow cytometric analysis to examine the early stages of apoptosis induced by bornyl cis-4-hydroxycinnamate in the two melanoma cell lines and employed comparative proteomic analysis to investigate the effects of this compound on protein expression in A375 cells. Master maps generated by PDQuest software from two-dimensional electrophoresis (2-DE) analysis of A375 cells showed that the expression levels of 35 proteins were significantly altered, with 18 proteins upregulated and 17 downregulated. The proteomics study identified several proteins that are involved in mitochondrial dysfunction and endoplasmic reticulum stress (ER stress), in addition to apoptosis-associated proteins, including prohibitin, hypoxia-upregulated protein 1, stress 70 protein, 78 kDa glucose-regulated protein (GRP78), and protein deglycase DJ-1 (protein DJ-1) in melanoma cells exposed to bornyl cis-4-hydroxycinnamate. The treatment also resulted in a marked decline of the mitochondrial membrane potential, in cytochrome C release into the cytosol, in the activation of Bcl-2-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad), caspase-3, and caspase-9, and in the decreased expression of p-Bad, B-cell lymphoma 2 (Bcl-2), Bcl-xl, and induced myeloid leukemia cell differentiation protein-1 (Mcl-1), indicating that apoptosis induced by bornyl cis-4-hydroxycinnamate was mediated by the mitochondria through the caspase-dependent pathway. Also, salubrinal (an eukaryotic initiation factor 2α inhibitor; eIF2α inhibitor) was able to protect the cells from bornyl cis-4-hydroxycinnamate-induced apoptosis. Bornyl cis-4-hydroxycinnamate-related cell death also implied that the protein kinase R-like endoplasmic reticulum kinase (PERK)–eIF2α–ATF4–CHOP signal pathways was activated upon bornyl cis-4-hydroxycinnamate treatment. Altogether, our results support the conclusion that bornyl cis-4-hydroxycinnamate-induced apoptosis in melanoma cells is associated with mechanisms correlated with the activation of caspase cascades, mitochondrial dysfunction, and endoplasmic reticulum stress, and indicate that this molecule has the potential to be developed as a chemotherapeutic agent for human melanoma. PMID:29734677

Coenzyme Q10 Prevents Mitochondrial Dysfunction and Facilitates Pharmacological Activity of Atorvastatin in 6-OHDA Induced Dopaminergic Toxicity in Rats.

PubMed

Prajapati, Santosh Kumar; Garabadu, Debapriya; Krishnamurthy, Sairam

2017-05-01

Atorvastatin (ATV) generally used to treat dyslipidemia is also reported to have effect against 6-hydroxydopamine (6-OHDA) induced neurotoxicity. Additionally, atorvastatin can interfere with mitochondrial function by reducing the level of Q10. Therefore, the therapeutic effect of atorvastatin (20 mg/kg) could be compromised. In this context, the present study evaluated the effect of ATV supplemented with Q10. 6-OHDA was unilaterally injected into the right striatum of male rats. On day 8 of 6-OHDA infusion, ATV (20 mg/kg), Q10 (200 mg/kg), and their combination were administered per oral for 14 days. On day 21, there was significant loss of striatal dopamine indicating neurotoxicity. The combination of ATV+Q10 showed significant amelioration of dopamine (DA) toxicity compared to individual treatments. Similarly, ATV+Q10 compared to individual treatment significantly decreased the motor deficits induced by 6-OHDA. Further, 6-OHDA induced mitochondrial dysfunction in the substantia nigra pars compacta (SNpc). There was significant decrease in mitochondrial complex enzyme activities and mitochondrial membrane potential (MMP). Treatment with ATV and ATV+Q10 ameliorated mitochondrial dysfunction by increasing complex enzyme activities; however, only ATV+Q10 were able to stabilize MMP and maintained mitochondrial integrity. Moreover, there was significant induction of oxidative stress as observed from increase in lipid peroxidases (LPO) and nitrite (NO), and decrease in super oxide dismutase (SOD). Treatment with ATV+Q10 significantly altered the above effects indicating antioxidant activity. Furthermore, only combination of ATV and Q10 decreased the 6-OHDA induced expression of cytochrome-C, caspase-9 and caspase-3. Therefore, current results provide evidence that supplementation of Q10 with ATV shows synergistic effect in reducing dopamine toxicity.

Enhanced J-protein interaction and compromised protein stability of mtHsp70 variants lead to mitochondrial dysfunction in Parkinson's disease.

PubMed

Goswami, Arvind Vittal; Samaddar, Madhuja; Sinha, Devanjan; Purushotham, Jaya; D'Silva, Patrick

2012-08-01

Parkinson's disease (PD) is the second most prevalent progressive neurological disorder commonly associated with impaired mitochondrial function in dopaminergic neurons. Although familial PD is multifactorial in nature, a recent genetic screen involving PD patients identified two mitochondrial Hsp70 variants (P509S and R126W) that are suggested in PD pathogenesis. However, molecular mechanisms underlying how mtHsp70 PD variants are centrally involved in PD progression is totally elusive. In this article, we provide mechanistic insights into the mitochondrial dysfunction associated with human mtHsp70 PD variants. Biochemically, the R126W variant showed severely compromised protein stability and was found highly susceptible to aggregation at physiological conditions. Strikingly, on the other hand, the P509S variant exhibits significantly enhanced interaction with J-protein cochaperones involved in folding and import machinery, thus altering the overall regulation of chaperone-mediated folding cycle and protein homeostasis. To assess the impact of mtHsp70 PD mutations at the cellular level, we developed yeast as a model system by making analogous mutations in Ssc1 ortholog. Interestingly, PD mutations in yeast (R103W and P486S) exhibit multiple in vivo phenotypes, which are associated with 'mitochondrial dysfunction', including compromised growth, impairment in protein translocation, reduced functional mitochondrial mass, mitochondrial DNA loss, respiratory incompetency and increased susceptibility to oxidative stress. In addition to that, R103W protein is prone to aggregate in vivo due to reduced stability, whereas P486S showed enhanced interaction with J-proteins, thus remarkably recapitulating the cellular defects that are observed in human PD variants. Taken together, our findings provide evidence in favor of direct involvement of mtHsp70 as a susceptibility factor in PD.

Mitochondrial Contribution to Parkinson's Disease Pathogenesis

PubMed Central

Schapira, Anthony H. V.; Gegg, Matthew

2011-01-01

The identification of the etiologies and pathogenesis of Parkinson's disease (PD) should play an important role in enabling the development of novel treatment strategies to prevent or slow the progression of the disease. The last few years have seen enormous progress in this respect. Abnormalities of mitochondrial function and increased free radical mediated damage were described in post mortem PD brain before the first gene mutations causing familial PD were published. Several genetic causes are now known to induce loss of dopaminergic cells and parkinsonism, and study of the mechanisms by which these mutations produce this effect has provided important insights into the pathogenesis of PD and confirmed mitochondrial dysfunction and oxidative stress pathways as central to PD pathogenesis. Abnormalities of protein metabolism including protein mis-folding and aggregation are also crucial to the pathology of PD. Genetic causes of PD have specifically highlighted the importance of mitochondrial dysfunction to PD: PINK1, parkin, DJ-1 and most recently alpha-synuclein proteins have been shown to localise to mitochondria and influence function. The turnover of mitochondria by autophagy (mitophagy) has also become a focus of attention. This review summarises recent discoveries in the contribution of mitochondrial abnormalities to PD etiology and pathogenesis. PMID:21687805

Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females

PubMed Central

Ribas, Vicent; Drew, Brian G.; Zhou, Zhenqi; Phun, Jennifer; Kalajian, Nareg Y.; Soleymani, Teo; Daraei, Pedram; Widjaja, Kevin; Wanagat, Jonathan; de Aguiar Vallim, Thomas Q.; Fluitt, Amy H.; Bensinger, Steven; Le, Thuc; Radu, Caius; Whitelegge, Julian P.; Beaven, Simon W.; Tontonoz, Peter; Lusis, Aldons J.; Parks, Brian W.; Vergnes, Laurent; Reue, Karen; Singh, Harpreet; Bopassa, Jean C.; Toro, Ligia; Stefani, Enrico; Watt, Matthew J.; Schenk, Simon; Akerstrom, Thorbjorn; Kelly, Meghan; Pedersen, Bente K.; Hewitt, Sylvia C.; Korach, Kenneth S.; Hevener, Andrea L.

2016-01-01

Impaired estrogen receptor α(ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERαexpression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERαknockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A–regulator of calcineurin 1–calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERαdeficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERαin the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women. PMID:27075628

Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria.

PubMed

Xiao, Mengqing; Zhong, Huiqin; Xia, Lin; Tao, Yongzhen; Yin, Huiyong

2017-10-01

Mitochondrial lipids are essential for maintaining the integrity of mitochondrial membranes and the proper functions of mitochondria. As the "powerhouse" of a cell, mitochondria are also the major cellular source of reactive oxygen species (ROS). Oxidative stress occurs when the antioxidant system is overwhelmed by overproduction of ROS. Polyunsaturated fatty acids in mitochondrial membranes are primary targets for ROS attack, which may lead to lipid peroxidation (LPO) and generation of reactive lipids, such as 4-hydroxynonenal. When mitochondrial lipids are oxidized, the integrity and function of mitochondria may be compromised and this may eventually lead to mitochondrial dysfunction, which has been associated with many human diseases including cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases. How mitochondrial lipids are oxidized and the underlying molecular mechanisms and pathophysiological consequences associated with mitochondrial LPO remain poorly defined. Oxidation of the mitochondria-specific phospholipid cardiolipin and generation of bioactive lipids through mitochondrial LPO has been increasingly recognized as an important event orchestrating apoptosis, metabolic reprogramming of energy production, mitophagy, and immune responses. In this review, we focus on the current understanding of how mitochondrial LPO and generation of bioactive lipid mediators in mitochondria are involved in the modulation of mitochondrial functions in the context of relevant human diseases associated with oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.

High-Dialysate-Glucose-Induced Oxidative Stress and Mitochondrial-Mediated Apoptosis in Human Peritoneal Mesothelial Cells

PubMed Central

Hung, Kuan-Yu; Liu, Shin-Yun; Yang, Te-Cheng; Liao, Tien-Ling; Kao, Shu-Huei

2014-01-01

Human peritoneal mesothelial cells (HPMCs) are a critical component of the peritoneal membrane and play a pivotal role in dialysis adequacy. Loss of HPMCs can contribute to complications in peritoneal dialysis. Compelling evidence has shown that high-dialysate glucose is a key factor causing functional changes and cell death in HPMCs. We investigated the mechanism of HPMC apoptosis induced by high-dialysate glucose, particularly the role of mitochondria in the maintenance of HPMCs. HPMCs were incubated at glucose concentrations of 5 mM, 84 mM, 138 mM, and 236 mM. Additionally, N-acetylcysteine (NAC) was used as an antioxidant to clarify the mechanism of high-dialysate-glucose-induced apoptosis. Exposing HPMCs to high-dialysate glucose resulted in substantial apoptosis with cytochrome c release, followed by caspase activation and poly(ADP-ribose) polymerase cleavage. High-dialysate glucose induced excessive reactive oxygen species production and lipid peroxidation as well as oxidative damage to DNA. Mitochondrial fragmentation, multiple mitochondrial DNA deletions, and dissipation of the mitochondrial membrane potential were also observed. The mitochondrial dysfunction and cell death were suppressed using NAC. These results indicated that mitochondrial dysfunction is one of the main causes of high-dialysate-glucose-induced HPMC apoptosis. PMID:24891925

Role of mitochondrial dysfunction in neurotoxicity of MPP+: partial protection of PC12 cells by acetyl-L-carnitine.

PubMed

Virmani, Ashraf; Gaetani, Franco; Binienda, Zbigniew; Xu, Alex; Duhart, Helen; Ali, Syed F

2004-10-01

The damage to the central nervous system that is observed after administration of either methamphetamine (METH) or 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is known to be linked to dopamine (DA). The underlying neurotoxicity mechanism for both METH and MPP+ seem to involve free radical formation and impaired mitochondrial function. The MPP+ is thought to selectively kill nigrostriatal dopaminergic neurons by inhibiting mitochondrial complex I, with cell death being attributed to oxidative stress damage to these vulnerable DA neurons. In the present study, MPP+ was shown to significantly inhibit the response to MTT by cultured PC12 cells. This inhibitory action of MPP+ could be partially reversed by the co-incubation of the cells with the acetylated form of carnitine, acetyl-L-carnitine (ALC). Since at least part of the toxic action of MPP+ is related to mitochondrial inhibition, the partial reversal of the inhibition of MTT response by ALC could involve a partial restoration of mitochondrial function. The role carnitine derivatives, such as ALC, play in attenuating MPP+ and METH-evoked toxicity is still under investigation to elucidate the contribution of mitochondrial dysfunction in mechanisms of neurotoxicity.

Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.

PubMed

Yu, Emma P K; Reinhold, Johannes; Yu, Haixiang; Starks, Lakshi; Uryga, Anna K; Foote, Kirsty; Finigan, Alison; Figg, Nichola; Pung, Yuh-Fen; Logan, Angela; Murphy, Michael P; Bennett, Martin

2017-12-01

Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis. Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE -/- ) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE -/- mice overexpressing the mitochondrial helicase Twinkle (Tw + /ApoE -/- ). Tw + /ApoE -/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw + /ApoE -/- mice had decreased necrotic core and increased fibrous cap areas, and Tw + /ApoE -/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis. Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis. © 2017 The Authors.

S-52, a novel nootropic compound, protects against β-amyloid induced neuronal injury by attenuating mitochondrial dysfunction.

PubMed

Gao, Xin; Zheng, Chun Yan; Qin, Guo Wei; Tang, Xi Can; Zhang, Hai Yan

2012-10-01

Accumulating evidence suggests that β-amyloid (Aβ)-induced oxidative DNA damage and mitochondrial dysfunction may initiate and contribute to the progression of Alzheimer's disease (AD). This study evaluated the neuroprotective effects of S-52, a novel nootropic compound, on Aβ-induced mitochondrial failure. In an established paradigm of moderate cellular injury induced by Aβ, S-52 was observed to attenuate the toxicity of Aβ to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain and tricarboxylic acid cycle. In addition, S-52 also effectively inhibited reactive oxygen species accumulation dose dependently not only in Aβ-harmed cells but also in unharmed, normal cells. The role of S-52 as a scavenger of free radicals is involved in the antioxidative effect of this compound. The beneficial effects on mitochondria and oxidative stress extend the neuroprotective effects of S-52. The present study provides crucial information for better understanding the beneficial profiles of this compound and discovering novel potential drug candidates for AD therapy. Copyright © 2012 Wiley Periodicals, Inc.

High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II

PubMed Central

Sverdlov, Aaron L.; Elezaby, Aly; Behring, Jessica B.; Bachschmid, Markus M.; Luptak, Ivan; Tu, Vivian H.; Siwik, Deborah A.; Miller, Edward J.; Liesa, Marc; Shirihai, Orian S; Pimentel, David R.; Cohen, Richard A.; Colucci, Wilson S.

2014-01-01

Background Diet-induced obesity leads to metabolic heart disease (MHD) characterized by increased oxidative stress that may cause oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins. The functional consequences of OPTM of cardiac mitochondrial proteins in MHD are unknown. Our objective was to determine whether cardiac mitochondrial dysfunction in MHD due to diet-induced obesity is associated with cysteine OPTM. Methods and results Male C57Bl/6J mice were fed either a high-fat, high-sucrose (HFHS) or control diet for 8 months. Cardiac mitochondria from HFHS-fed mice (vs. control diet) had an increased rate of H2O2 production, a decreased GSH/GSSG ratio, a decreased rate of complex II substrate-driven ATP synthesis and decreased complex II activity. Complex II substrate-driven ATP synthesis and complex II activity were partially restored ex-vivo by reducing conditions. A biotin switch assay showed that HFHS feeding increased cysteine OPTM in complex II subunits A (SDHA) and B (SDHB). Using iodo-TMT multiplex tags we found that HFHS feeding is associated with reversible oxidation of cysteines 89 and 231 in SDHA, and 100, 103 and 115 in SDHB. Conclusions MHD due to consumption of a HFHS “Western” diet causes increased H2O2 production and oxidative stress in cardiac mitochondria associated with decreased ATP synthesis and decreased complex II activity. Impaired complex II activity and ATP production are associated with reversible cysteine OPTM of complex II. Possible sites of reversible cysteine OPTM in SDHA and SDHB were identified by iodo-TMT tag labeling. Mitochondrial ROS may contribute to the pathophysiology of MHD by impairing the function of complex II. PMID:25109264

Fullerenol Cytotoxicity in Kidney Cells is Associated with Cytoskeleton Disruption, Autophagic Vacuole Accumulation, and Mitochondrial Dysfunction

PubMed Central

Johnson-Lyles, Denise N.; Peifley, Kimberly; Lockett, Stephen; Neun, Barry W.; Hansen, Matthew; Clogston, Jeffrey; Stern, Stephan T.; McNeil, Scott E.

2010-01-01

Water soluble fullerenes, such as the hydroxylated fullerene, fullerenol (C60OHx), are currently under development for diagnostic and therapeutic biomedical applications in the field of nanotechnology. These molecules have been shown to undergo urinary clearance, yet there is limited data available on their renal biocompatibility. Here we examine the biological responses of renal proximal tubule cells (LLC-PK1) exposed to fullerenol. Fullerenol was found to be cytotoxic in the millimolar range, with viability assessed by the sulforhodamine B and trypan blue assays. Fullerenol-induced cell death was associated with cytoskeleton disruption and autophagic vacuole accumulation. Interaction with the autophagy pathway was evaluated in vitro by Lysotracker Red dye uptake, LC3-II marker expression and TEM. Fullerenol treatment also resulted in coincident loss of cellular mitochondrial membrane potential and ATP depletion, as measured by the Mitotracker Red dye and the luciferin-luciferase assays, respectively. Fullerenol-induced ATP depletion and loss of mitochondrial potential were partially ameliorated by co-treatment with the autophagy inhibitor, 3-methyladenine. In vitro fullerenol treatment did not result in appreciable oxidative stress, as measured by lipid peroxide and glutathione content. Based on these data, it is hypothesized that cytoskeleton disruption may be an initiating event in fullerenol cytotoxicity, leading to subsequent autophagy dysfunction and loss of mitochondrial capacity. As nanoparticle-induced cytoskeleton disruption, autophagic vacuole accumulation and mitochondrial dysfunction are commonly reported in the literature, the proposed mechanism may be relevant for a variety of nanomaterials. PMID:20713077

Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes.

PubMed

Ansari, M Y; Khan, N M; Ahmad, I; Haqqi, T M

2017-08-08

Mitochondrial dysfunction, oxidative stress and chondrocyte death are important contributors to the development and pathogenesis of osteoarthritis (OA). In this study, we determined the expression and role of Parkin in the clearance of damaged/dysfunctional mitochondria, regulation of reactive oxygen species (ROS) levels and chondrocyte survival under pathological conditions. Human chondrocytes were from the unaffected area of knee OA cartilage (n = 12) and were stimulated with IL-1β to mimic pathological conditions. Mitochondrial membrane depolarization and ROS levels were determined using specific dyes and flow cytometry. Autophagy was determined by Western blotting for ATG5, Beclin1, immunofluorescence staining and confocal microscopy. Gene expression was determined by RT-qPCR. siRNA, wild-type and mutant Parkin plasmids were transfected using Amaxa system. Apoptosis was determined by PI staining of chondrocytes and TUNEL assay. IL-1β-stimulated OA chondrocytes showed high levels of ROS generation, mitochondrial membrane damage, accumulation of damaged mitochondria and higher incidence of apoptosis. IL-1β stimulation of chondrocytes with depleted Parkin expression resulted in sustained high levels of ROS, accumulation of damaged/dysfunctional mitochondria and enhanced apoptosis. Parkin translocation to depolarized/damaged mitochondria and recruitment of p62/SQSTM1 was required for the elimination of damaged/dysfunctional mitochondria in IL-1β-stimulated OA chondrocytes. Importantly we demonstrate that Parkin elimination of depolarized/damaged mitochondria required the Parkin ubiquitin ligase activity and resulted in reduced ROS levels and inhibition of apoptosis in OA chondrocytes under pathological conditions. Our data demonstrates that Parkin functions to eliminate depolarized/damaged mitochondria in chondrocytes which is necessary for mitochondrial quality control, regulation of ROS levels and chondrocyte survival under pathological conditions. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Mitochondria, cognitive impairment, and Alzheimer's disease.

PubMed

Mancuso, M; Calsolaro, V; Orsucci, D; Carlesi, C; Choub, A; Piazza, S; Siciliano, G

2009-07-06

To date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic, and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress, and accumulation of Abeta, which in a vicious cycle reinforce the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria, and especially of the mtDNA, in the cascade of events leading to neurodegeneration, dementia, and AD.

Mitochondria, Cognitive Impairment, and Alzheimer's Disease

PubMed Central

Mancuso, M.; Calsolaro, V.; Orsucci, D.; Carlesi, C.; Choub, A.; Piazza, S.; Siciliano, G.

2009-01-01

To date, the beta amyloid (Aβ) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The “mitochondrial cascade hypothesis” could explain many of the biochemical, genetic, and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress, and accumulation of Aβ, which in a vicious cycle reinforce the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria, and especially of the mtDNA, in the cascade of events leading to neurodegeneration, dementia, and AD. PMID:20798880

Downregulation of the psychiatric susceptibility gene Cacna1c promotes mitochondrial resilience to oxidative stress in neuronal cells.

PubMed

Michels, Susanne; Ganjam, Goutham K; Martins, Helena; Schratt, Gerhard M; Wöhr, Markus; Schwarting, Rainer K W; Culmsee, Carsten

2018-01-01

Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness and their etiologies involve complex interactions between genetic and environmental risk factors. Over the past ten years, several genome wide association studies (GWAS) have identified CACNA1C as one of the strongest genetic risk factors for the development of affective disorders. However, its role in disease pathogenesis is still largely unknown. Vulnerability to affective disorders also involves diverse environmental risk factors such as perinatal insults, childhood maltreatment, and other adverse pathophysiological or psychosocial life events. At the cellular level, such environmental influences may activate oxidative stress pathways, thereby altering neuronal plasticity and function. Mitochondria are the key organelles of energy metabolism and, further, highly important for the adaptation to oxidative stress. Accordingly, multiple lines of evidence including post-mortem brain and neuro-imaging studies suggest that psychiatric disorders are accompanied by mitochondrial dysfunction. In this study, we investigated the effects of Cacna1c downregulation in combination with glutamate-induced oxidative stress on mitochondrial function, Ca 2+ homeostasis, and cell viability in mouse hippocampal HT22 cells. We found that the siRNA-mediated knockdown of Cacna1c preserved mitochondrial morphology, mitochondrial membrane potential, and ATP levels after glutamate treatment. Further, Cacna1c silencing inhibited excessive mitochondrial reactive oxygen species formation and calcium influx, and protected the HT22 cells from oxidative cell death. Overall, our findings suggest that the GWAS-confirmed psychiatric risk gene CACNA1C plays a major role in oxidative stress pathways with particular impact on mitochondrial integrity and function.

Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress.

PubMed

Dehdashtian, Ehsan; Mehrzadi, Saeed; Yousefi, Bahman; Hosseinzadeh, Azam; Reiter, Russel J; Safa, Majid; Ghaznavi, Habib; Naseripour, Masood

2018-01-15

Diabetic retinopathy (DR), a microvascular complication of diabetes mellitus (DM), remains as one of the major causes of vision loss worldwide. The release of pro-inflammatory cytokines and the adhesion of leukocytes to retinal capillaries are initial events in DR development. Inflammation, ER stress, oxidative stress and autophagy are major causative factors involved in the pathogenesis of DR. Diabetes associated hyperglycemia leads to mitochondrial electron transport chain dysfunction culminating in a rise in ROS generation. Since mitochondria are the major source of ROS production, oxidative stress induced by mitochondrial dysfunction also contributes to the development of diabetic retinopathy. Autophagy increases in the retina of diabetic patients and is regulated by ER stress, oxidative stress and inflammation-related pathways. Autophagy functions as a double-edged sword in DR. Under mild stress, autophagic activity can lead to cell survival while during severe stress, dysregulated autophagy results in massive cell death and may have a role in initiation and exacerbation of DR. Melatonin and its metabolites play protective roles against inflammation, ER stress and oxidative stress due to their direct free radical scavenger activities and indirect antioxidant activity via the stimulation antioxidant enzymes including glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase. Melatonin also acts as a cell survival agent by modulating autophagy in various cell types and under different conditions through amelioration of oxidative stress, ER stress and inflammation. Herein, we review the possible effects of melatonin on diabetic retinopathy, focusing on its ability to regulate autophagy processes. Copyright © 2017. Published by Elsevier Inc.

Calcium-mediated oxidative stress: a common mechanism in tight junction disruption by different types of cellular stress.

PubMed

Gangwar, Ruchika; Meena, Avtar S; Shukla, Pradeep K; Nagaraja, Archana S; Dorniak, Piotr L; Pallikuth, Sandeep; Waters, Christopher M; Sood, Anil; Rao, RadhaKrishna

2017-02-20

The role of reactive oxygen species (ROS) in osmotic stress, dextran sulfate sodium (DSS) and cyclic stretch-induced tight junction (TJ) disruption was investigated in Caco-2 cell monolayers in vitro and restraint stress-induced barrier dysfunction in mouse colon in vivo Live cell imaging showed that osmotic stress, cyclic stretch and DSS triggered rapid production of ROS in Caco-2 cell monolayers, which was blocked by depletion of intracellular Ca 2+ by 1,2-bis-( o -aminophenoxy)ethane- N , N , N ', N '-tetraacetic acid. Knockdown of Ca V 1.3 or TRPV6 channels blocked osmotic stress and DSS-induced ROS production and attenuated TJ disruption and barrier dysfunction. N -Acetyl l-cysteine (NAC) and l- N G -Nitroarginine methyl ester (l-NAME) blocked stress-induced TJ disruption and barrier dysfunction. NAC and l-NAME also blocked stress-induced activation of c-Jun N -terminal kinase (JNK) and c-Src. ROS was colocalized with the mitochondrial marker in stressed cells. Cyclosporin A blocked osmotic stress and DSS-induced ROS production, barrier dysfunction, TJ disruption and JNK activation. Mitochondria-targeted Mito-TEMPO blocked osmotic stress and DSS-induced barrier dysfunction and TJ disruption. Chronic restraint stress in mice resulted in the elevation of intracellular Ca 2+ , activation of JNK and c-Src, and disruption of TJ in the colonic epithelium. Furthermore, corticosterone administration induced JNK and c-Src activation, TJ disruption and protein thiol oxidation in colonic mucosa. The present study demonstrates that oxidative stress is a common signal in the mechanism of TJ disruption in the intestinal epithelium by different types of cellular stress in vitro and bio behavioral stress in vivo . © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Calcium-Mediated Oxidative Stress: a Common Mechanism in Tight Junction Disruption by Different Types of Cellular Stress

PubMed Central

Gangwar, Ruchika; Meena, Avtar S.; Shukla, Pradeep K.; Nagaraja, Archana S.; Dorniak, Piotr L.; Pallikuth, Sandeep; Waters, Christopher M.; Sood, Anil; Rao, RadhaKrishna

2017-01-01

The role of reactive oxygen species (ROS) in osmotic stress, dextran sulfate sodium (DSS) and cyclic stretch-induced tight junction disruption was investigated in Caco-2 cell monolayers in vitro, and restraint stress-induced barrier dysfunction in mouse colon in vivo. Live cell imaging showed that osmotic stress, cyclic stretch and DSS triggered rapid production of ROS in Caco-2 cell monolayers, which was blocked by depletion of intracellular Ca2+ by BAPTA. Knockdown of CaV1.3 or TRPV6 channels blocked osmotic stress and DSS-induced ROS production and attenuated tight junction disruption and barrier dysfunction. N-acetyl L-cysteine (NAC) and L-nitroarginine methyl ester (L-NAME) blocked stress-induced tight junction disruption and barrier dysfunction. NAC and L-NAME also blocked stress-induced activation of JNK and c-Src. ROS was co-localized with the mitochondrial marker in stressed cells. Cyclosporin A blocked osmotic stress and DSS-induced ROS production, barrier dysfunction, tight junction disruption and JNK activation. Mitochondria-targeted Mito-TEMPO blocked osmotic stress and DSS-induced barrier dysfunction and tight junction disruption. Chronic restraint stress in mice resulted in the elevation of intracellular Ca2+, activation of JNK and c-Src, and disruption of tight junction in the colonic epithelium. Furthermore, corticosterone administration induced JNK and c-Src activation, tight junction disruption and protein thiol oxidation in colonic mucosa. This study demonstrates that oxidative stress is a common signal in the mechanism of tight junction disruption in the intestinal epithelium by different types of cellular stress in vitro and bio behavioral stress in vivo. PMID:28057718

Hydrogen sulfide epigenetically attenuates homocysteine-induced mitochondrial toxicity mediated through NMDA receptor in mouse brain endothelial (bEnd3) cells†

PubMed Central

Kamat, Pradip K.; Kalani, Anuradha; Tyagi, Suresh C.; Tyagi, Neetu

2014-01-01

Previously we have showed that homocysteine (Hcy) caused oxidative stress and altered mitochondrial function. Hydrogen sulphide (H2S) has potent anti-inflammatory, anti-oxidative and anti-apoptotic effects. Therefore, in the present study we examined whether H2S ameliorates Hcy-induced mitochondrial toxicity which led to endothelial dysfunction in part, by epigenetic alterations in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to 100μM Hcy treatment in the presence or absence of 30μM NaHS (donor of H2S) for 24hrs. Hcy-activate NMDA receptor and induced mitochondrial toxicity by increased levels of Ca2+, NADPH-oxidase-4 (NOX-4) expression, mitochondrial dehydrogenase activity and decreased the level of nitrate, superoxide dismutase (SOD-2) expression, mitochondria membrane potentials, ATP production. To confirm the role of epigenetic, 5′-azacitidine (an epigenetic modulator) treatment was given to the cells. Pretreatment with NaHS (30μM) attenuated the Hcy-induced increased expression of DNMT1, DNMT3a, Ca2+ and decreased expression of DNMT3b in bEND3 cells. Furthermore, NaHS treatment also enhanced mitochondrial oxidative stress (NOX4, ROS, and NO) and restored ATP that indicates its protective effects against mitochondrial toxicity. Additional, NaHS significantly alleviated Hcy-induced LC3-I/II, CSE, Atg3/7 and low p62 expression which confirm its effect on mitophagy. Likewise, NaHS also restored level of eNOS, CD31, VE-Cadherin and ET-1 and maintains endothelial function in Hcy treated cells. Molecular inhibition of NMDA receptor by using small interfering RNA showed protective effect whereas inhibition of H2S production by propargylglycine (PG) (inhibitor of enzyme CSE) showed mitotoxic effect. Taken together, results demonstrate that, administration of H2S protected the cells from HHcy-induced mitochondrial toxicity and endothelial dysfunction. PMID:25056869

Hydrogen Sulfide Epigenetically Attenuates Homocysteine-Induced Mitochondrial Toxicity Mediated Through NMDA Receptor in Mouse Brain Endothelial (bEnd3) Cells.

PubMed

Kamat, Pradip K; Kalani, Anuradha; Tyagi, Suresh C; Tyagi, Neetu

2015-02-01

Previously we have shown that homocysteine (Hcy) caused oxidative stress and altered mitochondrial function. Hydrogen sulfide (H2S) has potent anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Therefore, in the present study we examined whether H2S ameliorates Hcy-induced mitochondrial toxicity which led to endothelial dysfunction in part, by epigenetic alterations in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to 100 μM Hcy treatment in the presence or absence of 30 μM NaHS (donor of H2S) for 24 h. Hcy-activate NMDA receptor and induced mitochondrial toxicity by increased levels of Ca(2+), NADPH-oxidase-4 (NOX-4) expression, mitochondrial dehydrogenase activity and decreased the level of nitrate, superoxide dismutase (SOD-2) expression, mitochondria membrane potentials, ATP production. To confirm the role of epigenetic, 5'-azacitidine (an epigenetic modulator) treatment was given to the cells. Pretreatment with NaHS (30 μM) attenuated the Hcy-induced increased expression of DNMT1, DNMT3a, Ca(2+), and decreased expression of DNMT3b in bEND3 cells. Furthermore, NaHS treatment also mitigated mitochondrial oxidative stress (NOX4, ROS, and NO) and restored ATP that indicates its protective effects against mitochondrial toxicity. Additional, NaHS significantly alleviated Hcy-induced LC3-I/II, CSE, Atg3/7, and low p62 expression which confirm its effect on mitophagy. Likewise, NaHS also restored level of eNOS, CD31, VE-cadherin and ET-1 and maintains endothelial function in Hcy treated cells. Molecular inhibition of NMDA receptor by using small interfering RNA showed protective effect whereas inhibition of H2S production by propargylglycine (PG) (inhibitor of enzyme CSE) showed mitotoxic effect. Taken together, results demonstrate that, administration of H2S protected the cells from HHcy-induced mitochondrial toxicity and endothelial dysfunction. © 2014 Wiley Periodicals, Inc.

Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure.

PubMed

Shirakabe, Akihiro; Zhai, Peiyong; Ikeda, Yoshiyuki; Saito, Toshiro; Maejima, Yasuhiro; Hsu, Chiao-Po; Nomura, Masatoshi; Egashira, Kensuke; Levine, Beth; Sadoshima, Junichi

2016-03-29

Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload. © 2016 American Heart Association, Inc.

Measurement of Oxidative Stress: Mitochondrial Function Using the Seahorse System.

PubMed

Leung, Dilys T H; Chu, Simon

2018-01-01

The Seahorse XFp Analyzer is a powerful tool for the assessment of various parameters of cellular respiration. Here we describe the process of the Seahorse Cell Phenotype Test using the Seahorse XFp Analyzer to characterize the metabolic phenotype of live cells. The Seahorse XFp Analyzer can also be coupled with other assays to measure cellular energetics. Given that mitochondrial dysfunction is implicated in preeclampsia, the Seahorse XFp Analyzer will serve as a useful tool for the understanding of pathological metabolism in this disorder.

Targeted Overexpression of Mitochondrial Catalase Prevents Radiation-Induced Cognitive Dysfunction

PubMed Central

Parihar, Vipan K.; Allen, Barrett D.; Tran, Katherine K.; Chmielewski, Nicole N.; Craver, Brianna M.; Martirosian, Vahan; Morganti, Josh M.; Rosi, Susanna; Vlkolinsky, Roman; Acharya, Munjal M.; Nelson, Gregory A.; Allen, Antiño R.

2015-01-01

Abstract Aims: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. Results: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. Innovation: Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. Conclusion: Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain. Antioxid. Redox Signal. 22, 78–91. PMID:24949841

Inhibition of mTOR Prevents ROS Production Initiated by Ethidium Bromide-Induced Mitochondrial DNA Depletion

PubMed Central

Nacarelli, Timothy; Azar, Ashley; Sell, Christian

2014-01-01

The regulation of mitochondrial mass and DNA content involves a complex interaction between mitochondrial DNA replication machinery, functional components of the electron transport chain, selective clearance of mitochondria, and nuclear gene expression. In order to gain insight into cellular responses to mitochondrial stress, we treated human diploid fibroblasts with ethidium bromide at concentrations that induced loss of mitochondrial DNA over a period of 7 days. The decrease in mitochondrial DNA was accompanied by a reduction in steady state levels of the mitochondrial DNA binding protein, TFAM, a reduction in several electron transport chain protein levels, increased mitochondrial and total cellular ROS, and activation of p38 MAPK. However, there was an increase in mitochondrial mass and voltage dependent anion channel levels. In addition, mechanistic target of rapamycin (mTOR) activity, as judged by p70S6K targets, was decreased while steady state levels of p62/SQSTM1 and Parkin were increased. Treatment of cells with rapamycin created a situation in which cells were better able to adapt to the mitochondrial dysfunction, resulting in decreased ROS and increased cell viability but did not prevent the reduction in mitochondrial DNA. These effects may be due to a more efficient flux through the electron transport chain, increased autophagy, or enhanced AKT signaling, coupled with a reduced growth rate. Together, the results suggest that mTOR activity is affected by mitochondrial stress, which may be part of the retrograde signal system required for normal mitochondrial homeostasis. PMID:25104948

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

PubMed Central

Rossignol, D A; Frye, R E

2012-01-01

A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (∼0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD. PMID:21263444

MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging.

PubMed

Lustgarten, Michael S; Jang, Youngmok C; Liu, Yuhong; Qi, Wenbo; Qin, Yuejuan; Dahia, Patricia L; Shi, Yun; Bhattacharya, Arunabh; Muller, Florian L; Shimizu, Takahiko; Shirasawa, Takuji; Richardson, Arlan; Van Remmen, Holly

2011-06-01

In a previous study, we reported that a deficiency in MnSOD activity (approximately 80% reduction) targeted to type IIB skeletal muscle fibers was sufficient to elevate oxidative stress and to reduce muscle function in young adult mice (TnIFastCreSod2(fl/fl) mice). In this study, we used TnIFastCreSod2(fl/fl) mice to examine the effect of elevated oxidative stress on mitochondrial function and to test the hypothesis that elevated oxidative stress and decreased mitochondrial function over the lifespan of the TnIFastCreSod2(fl/fl) mice would be sufficient to accelerate muscle atrophy associated with aging. We found that mitochondrial function is reduced in both young and old TnIFastCreSod2(fl/fl) mice, when compared with control mice. Complex II activity is reduced by 47% in young and by approximately 90% in old TnIFastCreSod2(fl/fl) mice, and was found to be associated with reduced levels of the catalytic subunits for complex II, SDHA and SDHB. Complex II-linked mitochondrial respiration is reduced by approximately 70% in young TnIFastCreSod2(fl/fl) mice. Complex II-linked mitochondrial Adenosine-Tri-Phosphate (ATP) production is reduced by 39% in young and was found to be almost completely absent in old TnIFastCreSod2(fl/fl) mice. Furthermore, in old TnIFastCreSod2(fl/fl) mice, aconitase activity is almost completely abolished; mitochondrial superoxide release remains > 2-fold elevated; and oxidative damage (measured as F(2) - isoprostanes) is increased by 30% relative to age-matched controls. These data show that despite elevated skeletal muscle-specific mitochondrial oxidative stress, oxidative damage, and complex II-linked mitochondrial dysfunction, age-related muscle atrophy was not accelerated in old TnIFastCreSod2(fl/fl) mice, suggesting mitochondrial oxidative stress may not be causal for age-related muscle atrophy. No claim to original US government works. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

PubMed Central

Cole, Nelson B.; DiEuliis, Diane; Leo, Paul; Mitchell, Drake C.; Nussbaum, Robert L.

2008-01-01

Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson’s disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis. PMID:18440504

Ameliorative efficacy of quercetin against cisplatin‑induced mitochondrial dysfunction: Study on isolated rat liver mitochondria.

PubMed

Waseem, Mohammad; Tabassum, Heena; Bhardwaj, Monica; Parvez, Suhel

2017-09-01

The present study aimed to investigate the hepatoprotective effects of the bioflavonoid quercetin (QR) on cisplatin (CP)‑induced mitochondrial oxidative stress in the livers of rats, to elucidate the role of mitochondria in CP‑induced hepatotoxicity, and its underlying mechanism. Isolated liver mitochondria were incubated with 100 µg/ml CP and/or 50 µM QR in vitro. CP treatment triggered a significant increase in membrane lipid peroxidation (LPO) levels, protein carbonyl (PC) contents, and a decrease in reduced glutathione (GSH) and non‑protein thiol (NP‑SH) levels. In addition, CP caused a marked decline in the activities of enzymatic antioxidants and mitochondrial complexes (I, II, III and V) in liver mitochondria. QR pre‑treatment significantly modulated the activities of enzymatic antioxidants and mitochondrial complex enzymes. Furthermore, QR reversed the alterations in LPO and PC levels, and GSH and NP‑SH contents in liver mitochondria. The results of the present study suggested that QR supplementation may suppress CP‑induced mitochondrial toxicity during chemotherapy, and provides a potential prophylactic and defensive candidate for anticancer agent‑induced oxidative stress.

Rapamycin protects the mitochondria against oxidative stress and apoptosis in a rat model of Parkinson's disease.

PubMed

Jiang, Jianhua; Jiang, Juean; Zuo, Yuanyi; Gu, Zhenlun

2013-04-01

Parkinson's disease (PD) is a neurodegenerative disease, in which oxidative stress and mitochondrial dysfunction are responsible for neuronal apoptosis. Rapamycin plays a crucial role in reducing oxidative stress and protecting the mitochondria. However, its protective role in PD has not yet been fully elucidated. In this study, we report that pre-treatment with rapamycin provides behavioral improvements, protects against the loss of dopaminergic neurons, and alleviates mitochondrial ultrastructural injuries in a rat model of PD. Peroxide levels were lower and antioxidant activities were higher in PD rats pre-treated with rapamycin compared to the PD rats pre-treated with the vehicle. Furthermore, pre-treatment with rapamycin significantly elevated the expression of anti-apoptotic markers and reduced the levels of pro-apoptotic markers compared to pre-treatment with the vehicle. In conclusion, our results demonstrated that rapamycin reduced oxidative stress and alleviated mitochondrial injuries in the 6-hydroxydopamine (6-OHDA)-induced rat model of PD, which may subsequently contribute to its anti-apoptotic effects. The ability of rapamycin to exhibit neuroprotection in a rat model of PD may be related to its antioxidant capabilities.

ROLE OF CENTRAL NERVOUS SYSTEM INSULIN RESISTANCE IN FETAL ALCOHOL SPECTRUM DISORDERS

PubMed Central

de la Monte, Suzanne M; Wands, Jack R

2011-01-01

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of mental retardation in the USA. Ethanol impairs neuronal survival and function by two major mechanisms: 1) it inhibits insulin signaling required for viability, metabolism, synapse formation, and acetylcholine production; and 2) it functions as a neurotoxicant, causing oxidative stress, DNA damage and mitochondrial dysfunction. Ethanol inhibition of insulin signaling is mediated at the insulin receptor (IR) level and caused by both impaired receptor binding and increased activation of phosphatases that reverse IR tyrosine kinase activity. As a result, insulin activation of PI3K-Akt, which mediates neuronal survival, motility, energy metabolism, and plasticity, is impaired. The neurotoxicant effects of ethanol promote DNA damage, which could contribute to mitochondrial dysfunction and oxidative stress. Therefore, chronic in utero ethanol exposure produces a dual state of CNS insulin resistance and oxidative stress, which we postulate plays a major role in ethanol neurobehavioral teratogenesis. We propose that many of the prominent adverse effects of chronic prenatal exposure to ethanol on CNS development and function may be prevented or reduced by treatment with peroxisome-proliferated activated receptor (PPAR) agonists which enhance insulin sensitivity by increasing expression and function of insulin-responsive genes, and reducing cellular oxidative stress. PMID:21063035

Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway

PubMed Central

Wang, Sheng-Fan; Chen, Meng-Shian; Chou, Yueh-Ching; Ueng, Yune-Fang; Yin, Pen-Hui; Yeh, Tien-Shun; Lee, Hsin-Chen

2016-01-01

Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin. Clinically, the high expression of xCT was associated with a poorer prognosis for gastric cancer patients under adjuvant chemotherapy. Moreover, we found that mitochondrial dysfunction enhanced cisplatin resistance and up-regulated xCT expression, as well as intracellular glutathione (GSH). The xCT inhibitors, siRNA against xCT or BSO decreased mitochondrial dysfunction-enhanced cisplatin resistance. We further demonstrated that the upregulation of the eIF2α-ATF4 pathway contributed to mitochondrial dysfunction-induced xCT expression, and activated eIF2α kinase GCN2, but not PERK, stimulated the eIF2α-ATF4-xCT pathway in response to mitochondrial dysfunction-increased reactive oxygen species (ROS) levels. In conclusion, our results suggested that the ROS-activated GCN2-eIF2α-ATF4-xCT pathway might contribute to mitochondrial dysfunction-enhanced cisplatin resistance and could be a potential target for gastric cancer therapy. PMID:27708226

Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway.

PubMed

Wang, Sheng-Fan; Chen, Meng-Shian; Chou, Yueh-Ching; Ueng, Yune-Fang; Yin, Pen-Hui; Yeh, Tien-Shun; Lee, Hsin-Chen

2016-11-08

Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin. Clinically, the high expression of xCT was associated with a poorer prognosis for gastric cancer patients under adjuvant chemotherapy. Moreover, we found that mitochondrial dysfunction enhanced cisplatin resistance and up-regulated xCT expression, as well as intracellular glutathione (GSH). The xCT inhibitors, siRNA against xCT or BSO decreased mitochondrial dysfunction-enhanced cisplatin resistance. We further demonstrated that the upregulation of the eIF2α-ATF4 pathway contributed to mitochondrial dysfunction-induced xCT expression, and activated eIF2α kinase GCN2, but not PERK, stimulated the eIF2α-ATF4-xCT pathway in response to mitochondrial dysfunction-increased reactive oxygen species (ROS) levels. In conclusion, our results suggested that the ROS-activated GCN2-eIF2α-ATF4-xCT pathway might contribute to mitochondrial dysfunction-enhanced cisplatin resistance and could be a potential target for gastric cancer therapy.

Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone.

PubMed

Shokrzadeh, Mohammad; Mirshafa, Atefeh; Yekta Moghaddam, Niusha; Birjandian, Behnoosh; Shaki, Fatemeh

2018-04-18

Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice. Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E-treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria. Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia. UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity.

Role and Treatment of Mitochondrial DNA-Related Mitochondrial Dysfunction in Sporadic Neurodegenerative Diseases

PubMed Central

Swerdlow, Russell H.

2012-01-01

Several sporadic neurodegenerative diseases display phenomena that directly or indirectly relate to mitochondrial function. Data suggesting altered mitochondrial function in these diseases could arise from mitochondrial DNA (mtDNA) are reviewed. Approaches for manipulating mitochondrial function and minimizing the downstream consequences of mitochondrial dysfunction are discussed. PMID:21902672

Investigating Mitochondrial Dysfunction in Human Lung Cells Exposed to Redox-Active PM Components

EPA Science Inventory

Exposure to ambient particulate matter (PM) causes cardiopulmonary morbidity and mortality through mechanisms that involve oxidative stress. 1,2-naphthoquinone (1,2-NQ) is a ubiquitous component of PM and a potent redox-active electrophile. We previously reported that 1,2-NQ incr...

Ischemia-induced endothelial cell swelling and mitochondrial dysfunction are attenuated by dietary polyphenols in vitro

USDA-ARS?s Scientific Manuscript database

Polyphenols possess anti-oxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular uni...

C-Phycocyanin protects against mitochondrial dysfunction and oxidative stress in parthenogenetic porcine embryos.

PubMed

Niu, Ying-Jie; Zhou, Wenjun; Guo, Jing; Nie, Zheng-Wen; Shin, Kyung-Tae; Kim, Nam-Hyung; Lv, Wen-Fa; Cui, Xiang-Shun

2017-12-05

C-Phycocyanin (CP) is a biliprotein enriched in blue-green algae that is known to possess antioxidant, anti-apoptosis, anti-inflammatory, and radical-scavenging properties in somatic cells. However, the protective effect of CP on porcine embryo developmental competence in vitro remains unclear. In the present study, we investigated the effect of CP on the development of early porcine embryos as well as its underlying mechanisms. Different concentrations of CP (2, 5, 8, 10 μg/mL) were added to porcine zygote medium 5 during in vitro culture. The results showed that 5 μg/mL CP significantly increased blastocyst formation and hatching rate. Blastocyst formation and quality were significantly increased in the 50 μM H 2 O 2 treatment group following 5 μg/mL CP addition. CP prevented the H 2 O 2 -induced compromise of mitochondrial membrane potential, release of cytochrome c from the mitochondria, and reactive oxygen species generation. Furthermore, apoptosis, DNA damage level, and autophagy in the blastocysts were attenuated by supplementation of CP in the H 2 O 2 -induced oxidative injury group compared to in controls. These results suggest that CP has beneficial effects on the development of porcine parthenotes by attenuating mitochondrial dysfunction and oxidative stress.

The Emerging Role of Disturbed CoQ Metabolism in Nonalcoholic Fatty Liver Disease Development and Progression

PubMed Central

Botham, Kathleen M.; Napolitano, Mariarosaria; Bravo, Elena

2015-01-01

Although non-alcoholic fatty liver disease (NAFLD), characterised by the accumulation of triacylglycerol in the liver, is the most common liver disorder, the causes of its development and progression to the more serious non-alcoholic steatohepatitis (NASH) remain incompletely understood. Oxidative stress has been implicated as a key factor in both these processes, and mitochondrial dysfunction and inflammation are also believed to play a part. Coenzyme Q (CoQ) is a powerful antioxidant found in all cell membranes which has an essential role in mitochondrial respiration and also has anti-inflammatory properties. NAFLD has been shown to be associated with disturbances in plasma and liver CoQ concentrations, but the relationship between these changes and disease development and progression is not yet clear. Dietary supplementation with CoQ has been found to be hepatoprotective and to reduce oxidative stress and inflammation as well as improving mitochondrial dysfunction, suggesting that it may be beneficial in NAFLD. However, studies using animal models or patients with NAFLD have given inconclusive results. Overall, evidence is now emerging to indicate that disturbances in CoQ metabolism are involved in NAFLD development and progression to NASH, and this highlights the need for further studies with human subjects to fully clarify its role. PMID:26633474

Anticancer effect of a curcumin derivative B63: ROS production and mitochondrial dysfunction.

PubMed

Zheng, Adi; Li, Hao; Wang, Xun; Feng, Zhihui; Xu, Jie; Cao, Ke; Zhou, Bo; Wu, Jing; Liu, Jiankang

2014-01-01

Curcumin, a polyphenol isolated from the plant Curcuma longa, displays chemotherapeutic and chemopreventive effects in diverse cancers, including colorectal cancer. A mono-carbonyl analogue B63 was synthesized through several chemical modifications of the basic structure of curcumin to increase its biological activity and bioavailability. In vitro assays showed potent anti-proliferative effects of B63 on colon cancer cells (about 2 fold more effective than curcumin based on IC50). B63 treatment also induced significant necrosis, apoptosis, and S phase cell cycle arrest in SW620 colon cancer cells. The pro-apoptotic proteins Bad and Bim were up-regulated, and cytochrome c release from the mitochondria into the cytosol was enhanced, resulting in pro-caspase-3 and PARP-1 cleavage. Furthermore, the anticancer activity of B63 was dependent on intracellular ROS from damaged mitochondrial function and induced endoplasmic reticulum (ER) stress. In vivo, 50 mg/kg of B63 inhibit tumor growth similarly to 100 mg/kg curcumin in a mouse xenograft model using SW620 cells. These results suggest that the curcumin derivative B63 has a greater anticancer capacity than the parent curcumin in colon cancer cells and that the necrotic and apoptotic effects of B63 are mediated by ROS resulting from ER stress and mitochondrial dysfunction.

RIP1-mediated mitochondrial dysfunction and ROS production contributed to tumor necrosis factor alpha-induced L929 cell necroptosis and autophagy.

PubMed

Ye, Yuan-Chao; Wang, Hong-Ju; Yu, Lu; Tashiro, Shin-Ichi; Onodera, Satoshi; Ikejima, Takashi

2012-12-01

Tumor necrosis factor alpha (TNFα) induces necroptosis and autophagy; however, the detailed molecular mechanism is not fully understood. In this study, we found that TNFα administration caused mitochondrial dysfunction and reactive oxygen species (ROS) production, which led to necroptosis and autophagy in murine fibrosarcoma L929 cells. Notably, the RIP1 (serine-threonine kinase receptor-interacting protein 1, a main adaptor protein of necroptosis) specific inhibitor necrostatin-1 (Nec-1) recovered mitochondrial dysfunction and ROS production due to TNFα administration. Moreover, pan-caspase inhibitor z-VAD-fmk (zVAD) increased RIP1 expression and exacerbated TNFα-induced mitochondrial dysfunction and ROS production, indicating that RIP1 led to mitochondrial dysfunction and ROS production. In addition, cytochrome c release from mitochondria was accompanied with TNFα administration, and Nec-1 blocked the release of cytochrome c upon TNFα administration, while zVAD enhanced the release. These further suggested that RIP1 induced mitochondrial dysfunction accompanied with cytochrome c release. Furthermore, autophagy inhibitor 3-methyladenine (3MA) did not affect RIP1 expression as well as mitochondrial dysfunction and ROS production. Together with our previous publication that autophagy was a downstream consequence of necroptosis, we concluded that TNFα induced mitochondrial dysfunction accompanied with ROS production and cytochrome c release via RIP1, leading to necroptosis and resulting autophagic cell death. Copyright © 2012 Elsevier B.V. All rights reserved.

Retrograde Signaling as a Mechanism of Yeast Adaptation to Unfavorable Factors.

PubMed

Trendeleva, T A; Zvyagilskaya, R A

2018-02-01

Mitochondria perform many essential functions in eukaryotic cells. Being the main producers of ATP and the site of many catabolic and anabolic reactions, they participate in intracellular signaling, proliferation, aging, and formation of reactive oxygen species. Mitochondrial dysfunction is the cause of many diseases and even cell death. The functioning of mitochondria in vivo is impossible without interaction with other cellular compartments. Mitochondrial retrograde signaling is a signaling pathway connecting mitochondria and the nucleus. The major signal transducers in the yeast retrograde response are Rtg1p, Rtg2p, and Rtg3p proteins, as well as four additional negative regulatory factors - Mks1p, Lst8p, and two 14-3-3 proteins (Bmh1/2p). In this review, we analyze current information on the retrograde signaling in yeast that is regarded as a stress or homeostatic response mechanism to changes in various metabolic and biosynthetic activities that occur upon mitochondrial dysfunction. We also discuss relations between retrograde signaling and other signaling pathways in the cell.

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells.

PubMed

Ribeiro, Márcio; Rosenstock, Tatiana R; Oliveira, Ana M; Oliveira, Catarina R; Rego, A Cristina

2014-09-01

Oxidative stress and mitochondrial dysfunction have been described in Huntington's disease, a disorder caused by expression of mutant huntingtin (mHtt). IGF-1 was previously shown to protect HD cells, whereas insulin prevented neuronal oxidative stress. In this work we analyzed the role of insulin and IGF-1 in striatal cells derived from HD knock-in mice on mitochondrial production of reactive oxygen species (ROS) and related antioxidant and signaling pathways influencing mitochondrial function. Insulin and IGF-1 decreased mitochondrial ROS induced by mHtt and normalized mitochondrial SOD activity, without affecting intracellular glutathione levels. IGF-1 and insulin promoted Akt phosphorylation without changing the nuclear levels of phosphorylated Nrf2 or Nrf2/ARE activity. Insulin and IGF-1 treatment also decreased mitochondrial Drp1 phosphorylation, suggesting reduced mitochondrial fragmentation, and ameliorated mitochondrial function in HD cells in a PI-3K/Akt-dependent manner. This was accompanied by increased total and phosphorylated Akt, Tfam, and mitochondrial-encoded cytochrome c oxidase II, as well as Tom20 and Tom40 in mitochondria of insulin- and IGF-1-treated mutant striatal cells. Concomitantly, insulin/IGF-1-treated mutant cells showed reduced apoptotic features. Hence, insulin and IGF-1 improve mitochondrial function and reduce mitochondrial ROS caused by mHtt by activating the PI-3K/Akt signaling pathway, in a process independent of Nrf2 transcriptional activity, but involving enhanced mitochondrial levels of Akt and mitochondrial-encoded complex IV subunit. Copyright © 2014 Elsevier Inc. All rights reserved.

Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons.

PubMed

Lopez-Gonzalez, Rodrigo; Lu, Yubing; Gendron, Tania F; Karydas, Anna; Tran, Helene; Yang, Dejun; Petrucelli, Leonard; Miller, Bruce L; Almeida, Sandra; Gao, Fen-Biao

2016-10-19

GGGGCC repeat expansions in C9ORF72 are the most common genetic cause of both ALS and FTD. To uncover underlying pathogenic mechanisms, we found that DNA damage was greater, in an age-dependent manner, in motor neurons differentiated from iPSCs of multiple C9ORF72 patients than control neurons. Ectopic expression of the dipeptide repeat (DPR) protein (GR) 80 in iPSC-derived control neurons increased DNA damage, suggesting poly(GR) contributes to DNA damage in aged C9ORF72 neurons. Oxidative stress was also increased in C9ORF72 neurons in an age-dependent manner. Pharmacological or genetic reduction of oxidative stress partially rescued DNA damage in C9ORF72 neurons and control neurons expressing (GR) 80 or (GR) 80 -induced cellular toxicity in flies. Moreover, interactome analysis revealed that (GR) 80 preferentially bound to mitochondrial ribosomal proteins and caused mitochondrial dysfunction. Thus, poly(GR) in C9ORF72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress, revealing another pathogenic mechanism in C9ORF72-related ALS and FTD. Copyright © 2016 Elsevier Inc. All rights reserved.

Pathogenic mechanisms in systemic lupus erythematosus.

PubMed

Perl, Andras

2010-02-01

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by the dysfunction of T cells, B cells, and dendritic cells and by the production of antinuclear autoantibodies. This editorial provides a synopsis of newly discovered genetic factors and signaling pathways in lupus pathogenesis that are documented in 11 state-of-the-art reviews and original articles. Mitochondrial hyperpolarization underlies mitochondrial dysfunction, depletion of ATP, oxidative stress, abnormal activation, and death signal processing in lupus T cells. The mammalian target of rapamycin, which is a sensor of the mitochondrial transmembrane potential, has been successfully targeted for treatment of SLE with rapamycin or sirolimus in both patients and animal models. Inhibition of oxidative stress, nitric oxide production, expression of endogenous retroviral and repetitive elements such as HRES-1, the long interspersed nuclear elements 1, Trex1, interferon alpha (IFN-alpha), toll-like receptors 7 and 9 (TLR-7/9), high-mobility group B1 protein, extracellular signal-regulated kinase, DNA methyl transferase 1, histone deacetylase, spleen tyrosine kinase, proteasome function, lysosome function, endosome recycling, actin cytoskeleton formation, the nuclear factor kappa B pathway, and activation of cytotoxic T cells showed efficacy in animal models of lupus. Although B cell depletion and blockade of anti-DNA antibodies and T-B cell interaction have shown success in animal models, human studies are currently ongoing to establish the value of several target molecules for treatment of patients with lupus. Ongoing oxidative stress and inflammation lead to accelerated atherosclerosis that emerged as a significant cause of mortality in SLE.

Caspase-2 resides in the mitochondria and mediates apoptosis directly from the mitochondrial compartment.

PubMed

Lopez-Cruzan, M; Sharma, R; Tiwari, M; Karbach, S; Holstein, D; Martin, C R; Lechleiter, J D; Herman, B

2016-02-15

Caspase-2 plays an important role in apoptosis induced by several stimuli, including oxidative stress. However, the subcellular localization of caspase-2, particularly its presence in the mitochondria, is unclear. It is also not known if cytosolic caspase-2 translocates to the mitochondria to trigger the intrinsic pathway of apoptosis or if caspase-2 is constitutively present in the mitochondria that then selectively mediates this apoptotic effect. Here, we demonstrate the presence of caspase-2 in purified mitochondrial fractions from in vitro -cultured cells and in liver hepatocytes using immunoblots and confocal microscopy. We show that mitochondrial caspase-2 is functionally active by performing fluorescence resonance energy transfer analyses using a mitochondrially targeted substrate flanked by donor and acceptor fluorophores. Cell-free apoptotic assays involving recombination of nuclear, cytosolic and mitochondrial fractions from the livers of wild type and Casp2 -/- mice clearly point to a direct functional role for mitochondrial caspase-2 in apoptosis. Furthermore, cytochrome c release from Casp2 -/- cells is decreased as compared with controls upon treatment with agents inducing mitochondrial dysfunction. Finally, we show that Casp2 -/- primary skin fibroblasts are protected from oxidants that target the mitochondrial electron transport chain. Taken together, our results demonstrate that caspase-2 exists in the mitochondria and that it is essential for mitochondrial oxidative stress-induced apoptosis.

Involvement of Dopamine Receptors in Binge Methamphetamine-Induced Activation of Endoplasmic Reticulum and Mitochondrial Stress Pathways

PubMed Central

Beauvais, Genevieve; Atwell, Kenisha; Jayanthi, Subramaniam; Ladenheim, Bruce; Cadet, Jean Lud

2011-01-01

Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D1 receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D1 and D2 receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D1 or D2 receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58IPK, in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D2-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors. PMID:22174933

Mitochondrial oxidative stress and cardiac ageing.

PubMed

Martín-Fernández, Beatriz; Gredilla, Ricardo

According with different international organizations, cardiovascular diseases are becoming the first cause of death in western countries. Although exposure to different risk factors, particularly those related to lifestyle, contribute to the etiopathogenesis of cardiac disorders, the increase in average lifespan and aging are considered major determinants of cardiac diseases events. Mitochondria and oxidative stress have been pointed out as relevant factors both in heart aging and in the development of cardiac diseases such as heart failure, cardiac hypertrophy and diabetic cardiomyopathy. During aging, cellular processes related with mitochondrial function, such as bioenergetics, apoptosis and inflammation are altered leading to cardiac dysfunction. Increasing our knowledge about the mitochondrial mechanisms related with the aging process, will provide new strategies in order to improve this process, particularly the cardiovascular ones. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress.

PubMed

Haj-Mirzaian, Arya; Amiri, Shayan; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Kordjazy, Nastaran; Olson, Carl O; Rastegar, Mojgan; Naserzadeh, Parvaneh; Marzban, Hassan; Dehpour, Ahmad Reza; Hosseini, Mir-Jamal; Samiei, Elika; Mehr, Shahram Ejtemaei

2016-06-01

Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20mg/kg) augmented the protective effects of tropisetron (1mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex. Copyright © 2016 Elsevier Inc. All rights reserved.

Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress

PubMed Central

Dai, Chongshan; Ciccotosto, Giuseppe D.; Cappai, Roberto; Wang, Yang; Tang, Shusheng; Xiao, Xilong; Velkov, Tony

2017-01-01

Background: Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity. Methods: The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells. Results: Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells. Conclusions: To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy. PMID:28204513

The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease.

PubMed

Ng, Li Fang; Gruber, Jan; Cheah, Irwin K; Goo, Chong Kit; Cheong, Wei Fun; Shui, Guanghou; Sit, Kim Ping; Wenk, Markus R; Halliwell, Barry

2014-06-01

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II.

PubMed

Sverdlov, Aaron L; Elezaby, Aly; Behring, Jessica B; Bachschmid, Markus M; Luptak, Ivan; Tu, Vivian H; Siwik, Deborah A; Miller, Edward J; Liesa, Marc; Shirihai, Orian S; Pimentel, David R; Cohen, Richard A; Colucci, Wilson S

2015-01-01

Diet-induced obesity leads to metabolic heart disease (MHD) characterized by increased oxidative stress that may cause oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins. The functional consequences of OPTM of cardiac mitochondrial proteins in MHD are unknown. Our objective was to determine whether cardiac mitochondrial dysfunction in MHD due to diet-induced obesity is associated with cysteine OPTM. Male C57BL/6J mice were fed either a high-fat, high-sucrose (HFHS) or control diet for 8months. Cardiac mitochondria from HFHS-fed mice (vs. control diet) had an increased rate of H2O2 production, a decreased GSH/GSSG ratio, a decreased rate of complex II substrate-driven ATP synthesis and decreased complex II activity. Complex II substrate-driven ATP synthesis and complex II activity were partially restored ex-vivo by reducing conditions. A biotin switch assay showed that HFHS feeding increased cysteine OPTM in complex II subunits A (SDHA) and B (SDHB). Using iodo-TMT multiplex tags we found that HFHS feeding is associated with reversible oxidation of cysteines 89 and 231 in SDHA, and 100, 103 and 115 in SDHB. MHD due to consumption of a HFHS "Western" diet causes increased H2O2 production and oxidative stress in cardiac mitochondria associated with decreased ATP synthesis and decreased complex II activity. Impaired complex II activity and ATP production are associated with reversible cysteine OPTM of complex II. Possible sites of reversible cysteine OPTM in SDHA and SDHB were identified by iodo-TMT tag labeling. Mitochondrial ROS may contribute to the pathophysiology of MHD by impairing the function of complex II. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". Copyright © 2014 Elsevier Ltd. All rights reserved.

ALDH2 restores exhaustive exercise-induced mitochondrial dysfunction in skeletal muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Qiuping; Zheng, Jianheng; Qiu, Jun

Background: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is highly expressed in heart and skeletal muscles, and is the major enzyme that metabolizes acetaldehyde and toxic aldehydes. The cardioprotective effects of ALDH2 during cardiac ischemia/reperfusion injury have been recognized. However, less is known about the function of ALDH2 in skeletal muscle. This study was designed to evaluate the effect of ALDH2 on exhaustive exercise-induced skeletal muscle injury. Methods: We created transgenic mice expressing ALDH2 in skeletal muscles. Male wild-type C57/BL6 (WT) and ALDH2 transgenic mice (ALDH2-Tg), 8-weeks old, were challenged with exhaustive exercise for 1 week to induce skeletal muscle injury. Animalsmore » were sacrificed 24 h post-exercise and muscle tissue was excised. Results: ALDH2-Tg mice displayed significantly increased treadmill exercise capacity compared to WT mice. Exhaustive exercise caused an increase in mRNA levels of the muscle atrophy markers, Atrogin-1 and MuRF1, and reduced mitochondrial biogenesis and fusion in WT skeletal muscles; these effects were attenuated in ALDH2-Tg mice. Exhaustive exercise also enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of Beclin1 and Bnip3; the effects of which were mitigated by ALDH2 overexpression. In addition, ALDH2-Tg reversed the increase of an oxidative stress biomarker (4-hydroxynonenal) and decreased levels of mitochondrial antioxidant proteins, including manganese superoxide dismutase and NAD(P)H:quinone oxidoreductase 1, in skeletal muscle induced by exhaustive exercise. Conclusion: ALDH2 may reverse skeletal muscle mitochondrial dysfunction due to exhaustive exercise by regulating mitochondria dynamic remodeling and enhancing the quality of mitochondria. - Highlights: • Skeletal muscle ALDH2 expression and activity declines during exhaustive exercise. • ALDH2 overexpression enhances physical performance and restores muscle atrophy. • ALDH2 overexpression attenuates exercise-induced mitochondrial oxidative stress.« less

Protective effects of physical exercise on MDMA-induced cognitive and mitochondrial impairment.

PubMed

Taghizadeh, Ghorban; Pourahmad, Jalal; Mehdizadeh, Hajar; Foroumadi, Alireza; Torkaman-Boutorabi, Anahita; Hassani, Shokoufeh; Naserzadeh, Parvaneh; Shariatmadari, Reyhaneh; Gholami, Mahdi; Rouini, Mohammad Reza; Sharifzadeh, Mohammad

2016-10-01

Debate continues about the effect of 3, 4-methylenedioxymethamphetamine (MDMA) on cognitive and mitochondrial function through the CNS. It has been shown that physical exercise has an important protective effect on cellular damage and death. Therefore, we investigated the effect of physical exercise on MDMA-induced impairments of spatial learning and memory as well as MDMA effects on brain mitochondrial function in rats. Male wistar rats underwent short-term (2 weeks) or long-term (4 weeks) treadmill exercise. After completion of exercise duration, acquisition and retention of spatial memory were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally (I.P) injected with MDMA (5, 10, and 15mg/kg) 30min before the first training trial in 4 training days of MWM. Different parameters of brain mitochondrial function were measured including the level of ROS production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outermembrane damage, the amount of cytochrome c release from the mitochondria, and ADP/ATP ratio. MDMA damaged the spatial learning and memory in a dose-dependent manner. Brain mitochondria isolated from the rats treated with MDMA showed significant increase in ROS formation, collapse of MMP, mitochondrial swelling, and outer membrane damage, cytochrome c release from the mitochondria, and finally increased ADP/ATP ratio. This study also found that physical exercise significantly decreased the MDMA-induced impairments of spatial learning and memory and also mitochondrial dysfunction. The results indicated that MDMA-induced neurotoxicity leads to brain mitochondrial dysfunction and subsequent oxidative stress is followed by cognitive impairments. However, physical exercise could reduce these deleterious effects of MDMA through protective effects on brain mitochondrial function. Copyright © 2016 Elsevier Inc. All rights reserved.

Naringin Ameliorates HIV-1 Nucleoside Reverse Transcriptase Inhibitors- Induced Mitochondrial Toxicity.

PubMed

Oluwafeyisetan, Adebiyi; Olubunmi, Adebiyi; Peter, Owira

2016-01-01

Mitochondrial reactive oxygen species (ROS) generation and defective oxidative phosphorylation (OXPHOS) have been proposed as possible mechanisms underlying the development of nucleoside reverse transcriptase inhibitors (NRTIs)-induced mitochondrial toxicities. Available options in managing these complications have, so far, produced controversial results, thus necessitating further research into newer agents with promise. Antioxidant and free-radical scavenging effects of naringin, a plant-derived flavonoid, have previously been demonstrated. This study was designed to investigate the effects of naringin on NRTIs-induced mitochondrial toxicity. Wistar rats were randomly divided into Zidovudine (AZT)-only (100 mg/kg body weight BW); AZT+Naringin (100+50 mg/kg BW); AZT+Vitamin E (100+100 mg/kg BW); Stavudine (d4T)- only (50 mg/kg BW); d4T+Naringin (50+50 mg/kg BW); d4T+Vitamin E (50+100 mg/kg BW) and Vehicle (3.0 mL/kg BW)-treated groups, respectively. After 56 days of oral daily dosing, rats were euthanized by halothane overdose, blood collected by cardiac puncture and livers promptly excised for further biochemical and ultrastructural analyses. </p> Results: AZT- or d4T-only caused significant mitochondrial dysfunction and mitochondrial ultrastructural damage compared to controls, while either naringin or vitamin E reversed indices of mitochondrial dysfunction evidenced by significantly reduced mitochondrial malondialdehyde (MDA) and blood lactate concentrations, increased liver manganese superoxide dismutase (MnSOD) activity and upregulate expression of mitochondrial-encoded subunit of electron transport chain (ETC) complex IV protein compared to AZT- or d4T-only treated rats. Furthermore, naringin or vitamin E, respectively, ameliorated mitochondrial damage observed in AZT- or d4T-only treated rats. Naringin ameliorated oxidative stress and NRTI-induced mitochondrial damage and might, therefore, be beneficial in managing toxicities and complications arising from NRTI use.

Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease.

PubMed

Fetterman, Jessica L; Holbrook, Monica; Westbrook, David G; Brown, Jamelle A; Feeley, Kyle P; Bretón-Romero, Rosa; Linder, Erika A; Berk, Brittany D; Weisbrod, Robert M; Widlansky, Michael E; Gokce, Noyan; Ballinger, Scott W; Hamburg, Naomi M

2016-03-31

Prior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease. We assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (β = 0.14 ± 0.13, P = 0.04 and β = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function. We found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

PubMed Central

Mittal, Anubhav; Hickey, Anthony JR; Chai, Chau C; Loveday, Benjamin PT; Thompson, Nichola; Dare, Anna; Delahunt, Brett; Cooper, Garth JS; Windsor, John A; Phillips, Anthony RJ

2011-01-01

Introduction Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. Methods Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n = 8), saline control; Group 2 (n = 6), caerulein-induced mild acute pancreatitis; Group 3 (n = 7) sham surgical controls; and Group 4 (n = 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. Results Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. Conclusions The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis. PMID:21492333

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

PubMed Central

Marzetti, Emanuele; Csiszar, Anna; Dutta, Debapriya; Balagopal, Gauthami; Calvani, Riccardo

2013-01-01

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD. PMID:23748424

Mitochondrial DNA as a non-invasive biomarker: Accurate quantification using real time quantitative PCR without co-amplification of pseudogenes and dilution bias

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malik, Afshan N., E-mail: afshan.malik@kcl.ac.uk; Shahni, Rojeen; Rodriguez-de-Ledesma, Ana

2011-08-19

Highlights: {yields} Mitochondrial dysfunction is central to many diseases of oxidative stress. {yields} 95% of the mitochondrial genome is duplicated in the nuclear genome. {yields} Dilution of untreated genomic DNA leads to dilution bias. {yields} Unique primers and template pretreatment are needed to accurately measure mitochondrial DNA content. -- Abstract: Circulating mitochondrial DNA (MtDNA) is a potential non-invasive biomarker of cellular mitochondrial dysfunction, the latter known to be central to a wide range of human diseases. Changes in MtDNA are usually determined by quantification of MtDNA relative to nuclear DNA (Mt/N) using real time quantitative PCR. We propose that themore » methodology for measuring Mt/N needs to be improved and we have identified that current methods have at least one of the following three problems: (1) As much of the mitochondrial genome is duplicated in the nuclear genome, many commonly used MtDNA primers co-amplify homologous pseudogenes found in the nuclear genome; (2) use of regions from genes such as {beta}-actin and 18S rRNA which are repetitive and/or highly variable for qPCR of the nuclear genome leads to errors; and (3) the size difference of mitochondrial and nuclear genomes cause a 'dilution bias' when template DNA is diluted. We describe a PCR-based method using unique regions in the human mitochondrial genome not duplicated in the nuclear genome; unique single copy region in the nuclear genome and template treatment to remove dilution bias, to accurately quantify MtDNA from human samples.« less

Estrogen-related receptor α is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury.

PubMed

Tsushida, Keigo; Tanabe, Katsuyuki; Masuda, Kana; Tanimura, Satoshi; Miyake, Hiromasa; Arata, Yuka; Sugiyama, Hitoshi; Wada, Jun

2018-04-15

Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin. Male C57BL/6 J wild-type and ERRα -/- mice received a single intraperitoneal injection of 20 mg/kg cisplatin. Seventy-two hours after the injection, kidney function and morphology were evaluated. ERRα expression was observed in renal tubules, and cisplatin inhibited its translocation into nuclei. ERRα deficiency exacerbated cisplatin-induced renal dysfunction and tubular injury, as well as oxidative stress and apoptosis. ERRα -/- mice kidneys revealed lower mitochondrial DNA content and swollen mitochondria with reduced cristae. In addition, these mice had lower expression of the mitochondrial fusion protein mitofusin-2. The cisplatin-induced decrease in mitochondrial DNA and altered mitochondrial structure were more severe in ERRα -/- mice. In cultured mouse proximal tubular epithelial cells, the ERRα inverse agonist XCT-790 significantly inhibited mitofusin-2 expression and induced mitochondrial fragmentation. Taken together, our findings suggest the involvement of ERRα in the progression of cisplatin-induced AKI probably through impaired mitochondrial dynamics. Copyright © 2018 Elsevier Inc. All rights reserved.

Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics.

PubMed

Kou, Xianjuan; Li, Jie; Liu, Xingran; Chang, Jingru; Zhao, Qingxia; Jia, Shaohui; Fan, Jingjing; Chen, Ning

2017-06-01

microRNAs (miRNAs) have been reported to be involved in many neurodegenerative diseases. To explore the regulatory role of miR-34a in aging-related diseases such as Alzheimer's disease (AD) during exercise intervention, we constructed a rat model with d-galactose (d-gal)-induced oxidative stress and cognitive impairment coupled with dysfunctional autophagy and abnormal mitochondrial dynamics, determined the mitigation of cognitive impairment of d-gal-induced aging rats during swimming intervention, and evaluated miR-34a-mediated functional status of autophagy and abnormal mitochondrial dynamics. Meanwhile, whether the upregulation of miR-34a can lead to dysfunctional autophagy and abnormal mitochondrial dynamics was confirmed in human SH-SY5Y cells with silenced miR-34a by the transfection of a miR-34a inhibitor. Results indicated that swimming intervention could significantly attenuate cognitive impairment, prevent the upregulation of miR-34a, mitigate the dysfunctional autophagy, and inhibit the increase of dynamin-related protein 1 (DRP1) in d-gal-induced aging model rats. In contrast, the miR-34a inhibitor in cell model not only attenuated D-gal-induced the impairment of autophagy but also decreased the expression of DRP1 and mitofusin 2 (MFN2). Therefore, swimming training can delay brain aging of d-gal-induced aging rats through attenuating the impairment of miR-34a-mediated autophagy and abnormal mitochondrial dynamics, and miR-34a could be the novel therapeutic target for aging-related diseases such as AD. NEW & NOTEWORTHY In the present study, we have found that the upregulation of miR-34a is the hallmark of aging or aging-related diseases, which can result in dysfunctional autophagy and abnormal mitochondrial dynamics. In contrast, swimming intervention can delay the aging process by rescuing the impaired functional status of autophagy and abnormal mitochondrial dynamics via the suppression of miR-34a. Copyright © 2017 the American Physiological Society.

Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts

PubMed Central

Van Beersel, Guillaume; Tihon, Eliane; Demine, Stéphane; Hamer, Isabelle; Jadot, Michel; Arnould, Thierry

2012-01-01

NCLs (neuronal ceroid lipofuscinoses) form a group of eight inherited autosomal recessive diseases characterized by the intralysosomal accumulation of autofluorescent pigments, called ceroids. Recent data suggest that the pathogenesis of NCL is associated with the appearance of fragmented mitochondria with altered functions. However, even if an impairement in the autophagic pathway has often been evoked, the molecular mechanisms leading to mitochondrial fragmentation in response to a lysosomal dysfunction are still poorly understood. In this study, we show that fibroblasts that are deficient for the TPP-1 (tripeptidyl peptidase-1), a lysosomal hydrolase encoded by the gene mutated in the LINCL (late infantile NCL, CLN2 form) also exhibit a fragmented mitochondrial network. This morphological alteration is accompanied by an increase in the expression of the protein BNIP3 (Bcl2/adenovirus E1B 19 kDa interacting protein 3) as well as a decrease in the abundance of mitofusins 1 and 2, two proteins involved in mitochondrial fusion. Using RNAi (RNA interference) and quantitative analysis of the mitochondrial morphology, we show that the inhibition of BNIP3 expression does not result in an increase in the reticulation of the mitochondrial population in LINCL cells. However, this protein seems to play a key role in cell response to mitochondrial oxidative stress as it sensitizes mitochondria to antimycin A-induced fragmentation. To our knowledge, our results bring the first evidence of a mechanism that links TPP-1 deficiency and oxidative stress-induced changes in mitochondrial morphology. PMID:23249249

Targeting Endoplasmic Reticulum and/or Mitochondrial Ca2+ Fluxes as Therapeutic Strategy for HCV Infection.

PubMed

Scrima, Rosella; Piccoli, Claudia; Moradpour, Darius; Capitanio, Nazzareno

2018-01-01

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca 2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

Targeting endoplasmic reticulum and/or mitochondrial Ca2+ fluxes as therapeutic strategy for HCV infection

NASA Astrophysics Data System (ADS)

Scrima, Rosella; Piccoli, Claudia; Moradpour, Darius; Capitanio, Nazzareno

2018-03-01

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females.

PubMed

Ribas, Vicent; Drew, Brian G; Zhou, Zhenqi; Phun, Jennifer; Kalajian, Nareg Y; Soleymani, Teo; Daraei, Pedram; Widjaja, Kevin; Wanagat, Jonathan; de Aguiar Vallim, Thomas Q; Fluitt, Amy H; Bensinger, Steven; Le, Thuc; Radu, Caius; Whitelegge, Julian P; Beaven, Simon W; Tontonoz, Peter; Lusis, Aldons J; Parks, Brian W; Vergnes, Laurent; Reue, Karen; Singh, Harpreet; Bopassa, Jean C; Toro, Ligia; Stefani, Enrico; Watt, Matthew J; Schenk, Simon; Akerstrom, Thorbjorn; Kelly, Meghan; Pedersen, Bente K; Hewitt, Sylvia C; Korach, Kenneth S; Hevener, Andrea L

2016-04-13

Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERα expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERα knockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A-regulator of calcineurin 1-calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERα deficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women. Copyright © 2016, American Association for the Advancement of Science.

Oleuropein isolated from Fraxinus rhynchophylla inhibits glutamate-induced neuronal cell death by attenuating mitochondrial dysfunction.

PubMed

Kim, Mi Hye; Min, Ju-Sik; Lee, Joon Yeop; Chae, Unbin; Yang, Eun-Ju; Song, Kyung-Sik; Lee, Hyun-Shik; Lee, Hong Jun; Lee, Sang-Rae; Lee, Dong-Seok

2017-04-27

Glutamate-induced neurotoxicity is related to excessive oxidative stress accumulation and results in the increase of neuronal cell death. In addition, glutamate has been reported to lead to neurodegenerative diseases, including Parkinson's and Alzheimer's diseases.It is well known that Fraxinus rhynchophylla contains a significant level of oleuropein (Ole), which exerts various pharmacological effects. However, the mechanism of neuroprotective effects of Ole is still poorly defined. In this study, we aimed to investigate whether Ole prevents glutamate-induced toxicity in HT-22 hippocampal neuronal cells. The exposure of the glutamate treatment caused neuronal cell death through an alteration of Bax/Bcl-2 expression and translocation of mitochondrial apoptosis-inducing factor (AIF) to the cytoplasm of HT-22 cells. In addition, glutamate induced an increase in dephosphorylation of dynamin-related protein 1 (Drp1), mitochondrial fragmentation, and mitochondrial dysfunction. The pretreatment of Ole decreased Bax expression, increased Bcl-2 expression, and inhibited the translocation of mitochondrial AIF to the cytoplasm. Furthermore, Ole amended a glutamate-induced mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria, regulating the phosphorylation of Drp1 at amino acid residue serine 637. In conclusion, our results show that Ole has a preventive effect against glutamate-induced toxicity in HT-22 hippocampal neuronal cells. Therefore, these data imply that Ole may be an efficient approach for the treatment of neurodegenerative diseases.

Oxidative Stress and Mitochondrial Functions in the Intestinal Caco-2/15 Cell Line

PubMed Central

Taha, Rame; Seidman, Ernest; Mailhot, Genevieve; Boudreau, François; Gendron, Fernand-Pierre; Beaulieu, Jean-François; Ménard, Daniel; Delvin, Edgard; Amre, Devendra; Levy, Emile

2010-01-01

Background Although mitochondrial dysfunction and oxidative stress are central mechanisms in various pathological conditions, they have not been extensively studied in the gastrointestinal tract, which is known to be constantly exposed to luminal oxidants from ingested foods. Key among these is the simultaneous consumption of iron salts and ascorbic acid, which can cause oxidative damage to biomolecules. Methodology/Principal Findings The objective of the present work was to evaluate how iron-ascorbate (FE/ASC)-mediated lipid peroxidation affects mitochondrion functioning in Caco-2/15 cells. Our results show that treatment of Caco-2/15 cells with FE/ASC (0.2 mM/2 mM) (1) increased malondialdehyde levels assessed by HPLC; (2) reduced ATP production noted by luminescence assay; (3) provoked dysregulation of mitochondrial calcium homeostasis as evidenced by confocal fluorescence microscopy; (4) upregulated the protein expression of cytochrome C and apoptotic inducing factor, indicating exaggerated apoptosis; (5) affected mitochondrial respiratory chain complexes I, II, III and IV; (6) elicited mtDNA lesions as illustrated by the raised levels of 8-OHdG; (7) lowered DNA glycosylase, one of the first lines of defense against 8-OHdG mutagenicity; and (8) altered the gene expression and protein mass of mitochondrial transcription factors (mtTFA, mtTFB1, mtTFB2) without any effects on RNA Polymerase. The presence of the powerful antioxidant BHT (50 µM) prevented the occurrence of oxidative stress and most of the mitochondrial abnormalities. Conclusions/Significance Collectively, our findings indicate that acute exposure of Caco-2/15 cells to FE/ASC-catalyzed peroxidation produces harmful effects on mitochondrial functions and DNA integrity, which are abrogated by the powerful exogenous BHT antioxidant. Functional derangements of mitochondria may have implications in oxidative stress-related disorders such as inflammatory bowel diseases. PMID:20676402

Oxidative stress and mitochondrial functions in the intestinal Caco-2/15 cell line.

PubMed

Taha, Rame; Seidman, Ernest; Mailhot, Genevieve; Boudreau, François; Gendron, Fernand-Pierre; Beaulieu, Jean-François; Ménard, Daniel; Delvin, Edgard; Amre, Devendra; Levy, Emile

2010-07-27

Although mitochondrial dysfunction and oxidative stress are central mechanisms in various pathological conditions, they have not been extensively studied in the gastrointestinal tract, which is known to be constantly exposed to luminal oxidants from ingested foods. Key among these is the simultaneous consumption of iron salts and ascorbic acid, which can cause oxidative damage to biomolecules. The objective of the present work was to evaluate how iron-ascorbate (FE/ASC)-mediated lipid peroxidation affects mitochondrion functioning in Caco-2/15 cells. Our results show that treatment of Caco-2/15 cells with FE/ASC (0.2 mM/2 mM) (1) increased malondialdehyde levels assessed by HPLC; (2) reduced ATP production noted by luminescence assay; (3) provoked dysregulation of mitochondrial calcium homeostasis as evidenced by confocal fluorescence microscopy; (4) upregulated the protein expression of cytochrome C and apoptotic inducing factor, indicating exaggerated apoptosis; (5) affected mitochondrial respiratory chain complexes I, II, III and IV; (6) elicited mtDNA lesions as illustrated by the raised levels of 8-OHdG; (7) lowered DNA glycosylase, one of the first lines of defense against 8-OHdG mutagenicity; and (8) altered the gene expression and protein mass of mitochondrial transcription factors (mtTFA, mtTFB1, mtTFB2) without any effects on RNA Polymerase. The presence of the powerful antioxidant BHT (50 microM) prevented the occurrence of oxidative stress and most of the mitochondrial abnormalities. Collectively, our findings indicate that acute exposure of Caco-2/15 cells to FE/ASC-catalyzed peroxidation produces harmful effects on mitochondrial functions and DNA integrity, which are abrogated by the powerful exogenous BHT antioxidant. Functional derangements of mitochondria may have implications in oxidative stress-related disorders such as inflammatory bowel diseases.

Redox imbalance and mitochondrial abnormalities in the diabetic lung.

PubMed

Wu, Jinzi; Jin, Zhen; Yan, Liang-Jun

2017-04-01

Although the lung is one of the least studied organs in diabetes, increasing evidence indicates that it is an inevitable target of diabetic complications. Nevertheless, the underlying biochemical mechanisms of lung injury in diabetes remain largely unexplored. Given that redox imbalance, oxidative stress, and mitochondrial dysfunction have been implicated in diabetic tissue injury, we set out to investigate mechanisms of lung injury in diabetes. The objective of this study was to evaluate NADH/NAD + redox status, oxidative stress, and mitochondrial abnormalities in the diabetic lung. Using STZ induced diabetes in rat as a model, we measured redox-imbalance related parameters including aldose reductase activity, level of poly ADP ribose polymerase (PAPR-1), NAD + content, NADPH content, reduced form of glutathione (GSH), and glucose 6-phophate dehydrogenase (G6PD) activity. For assessment of mitochondrial abnormalities in the diabetic lung, we measured the activities of mitochondrial electron transport chain complexes I to IV and complex V as well as dihydrolipoamide dehydrogenase (DLDH) content and activity. We also measured the protein content of NAD + dependent enzymes such as sirtuin3 (sirt3) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Our results demonstrate that NADH/NAD + redox imbalance occurs in the diabetic lung. This redox imbalance upregulates the activities of complexes I to IV, but not complex V; and this upregulation is likely the source of increased mitochondrial ROS production, oxidative stress, and cell death in the diabetic lung. These results, together with the findings that the protein contents of DLDH, sirt3, and NQO1 all are decreased in the diabetic lung, demonstrate that redox imbalance, mitochondrial abnormality, and oxidative stress contribute to lung injury in diabetes. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Melatonin reverses H-89 induced spatial memory deficit: Involvement of oxidative stress and mitochondrial function.

PubMed

Sharif, Rojin; Aghsami, Mehdi; Gharghabi, Mehdi; Sanati, Mehdi; Khorshidahmad, Tina; Vakilzadeh, Gelareh; Mehdizadeh, Hajar; Gholizadeh, Shervin; Taghizadeh, Ghorban; Sharifzadeh, Mohammad

2017-01-01

Oxidative stress and mitochondrial dysfunction play indispensable role in memory and learning impairment. Growing evidences have shed light on anti-oxidative role for melatonin in memory deficit. We have previously reported that inhibition of protein kinase A by H-89 can induce memory impairment. Here, we investigated the effect of melatonin on H-89 induced spatial memory deficit and pursued their interactive consequences on oxidative stress and mitochondrial function in Morris Water Maze model. Rats received melatonin (50 and 100μg/kg/side) and H-89(10μM) intra-hippocampally 30min before each day of training. Animals were trained for 4 consecutive days, each containing one block from four trials. Oxidative stress indices, including thiobarbituric acid (TBARS), reactive oxygen species (ROS), thiol groups, and ferric reducing antioxidant power (FRAP) were assessed using spectrophotometer. Mitochondrial function was evaluated through measuring ROS production, mitochondrial membrane potential (MMP), swelling, outer membrane damage, and cytochrome c release. As expected from our previous report, H-89 remarkably impaired memory by increasing the escape latency and traveled distance. Intriguingly, H-89 significantly augmented TBARS and ROS levels, caused mitochondrial ROS production, swelling, outer membrane damage, and cytochrome c release. Moreover, H-89 lowered thiol, FRAP, and MMP values. Intriguingly, melatonin pre-treatment not only effectively hampered H-89-mediated spatial memory deficit at both doses, but also reversed the H-89 effects on mitochondrial and biochemical indices upon higher dose. Collectively, these findings highlight a protective role for melatonin against H-89-induced memory impairment and indicate that melatonin may play a therapeutic role in the treatment of oxidative- related neurodegenerative disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Ecstasy produces left ventricular dysfunction and oxidative stress in rats

PubMed Central

Shenouda, Sylvia K.; Lord, Kevin C.; McIlwain, Elizabeth; Lucchesi, Pamela A.; Varner, Kurt J.

2008-01-01

Aims Our aim was to determine whether the repeated, binge administration of 3,4-methylenedioxymethamphetamine (ecstasy; MDMA) produces structural and/or functional changes in the myocardium that are associated with oxidative stress. Methods and results Echocardiography and pressure–volume conductance catheters were used to assess left ventricular (LV) structure and function in rats subjected to four ecstasy binges (9 mg/kg i.v. for 4 days, separated by a 10 day drug-free period). Hearts from treated and control rats were used for either biochemical and proteomic analysis or the isolation of adult LV myocytes. After the fourth binge, treated hearts showed eccentric LV dilation and diastolic dysfunction. Systolic function was not altered in vivo; however, the magnitude of the contractile responses to electrical stimulation was significantly smaller in myocytes from rats treated in vivo with ecstasy compared with myocytes from control rats. The magnitude of the peak increase in intracellular calcium (measured by Fura-2) was also significantly smaller in myocytes from ecstasy-treated vs. control rats. The relaxation kinetics of the intracellular calcium transients were significantly longer in myocytes from ecstasy-treated rats. Ecstasy significantly increased nitrotyrosine content in the left ventricle. Proteomic analysis revealed increased nitration of contractile proteins (troponin-T, tropomyosin alpha-1 chain, myosin light polypeptide, and myosin regulatory light chain), mitochondrial proteins (Ub-cytochrome-c reductase and ATP synthase), and sarcoplasmic reticulum calcium ATPase. Conclusion The repeated binge administration of ecstasy produces eccentric LV dilation and dysfunction that is accompanied by oxidative stress. These functional responses may result from the redox modification of proteins involved in excitation-contraction coupling and/or mitochondrial energy production. Together, these results indicate that ecstasy has the potential to produce serious cardiac toxicity and ventricular dysfunction. PMID:18495670

Mitochondrial dysfunction precedes depression of AMPK/AKT signaling in insulin resistance induced by high glucose in primary cortical neurons.

PubMed

Peng, Yunhua; Liu, Jing; Shi, Le; Tang, Ying; Gao, Dan; Long, Jiangang; Liu, Jiankang

2016-06-01

Recent studies have demonstrated brain insulin signaling impairment and mitochondrial dysfunction in diabetes. Hyperinsulinemia and hyperlipidemia arising from diabetes have been linked to neuronal insulin resistance, and hyperglycemia induces peripheral sensory neuronal impairment and mitochondrial dysfunction. However, how brain glucose at diabetic conditions elicits cortical neuronal insulin signaling impairment and mitochondrial dysfunction remains unknown. In the present study, we cultured primary cortical neurons with high glucose levels and investigated the neuronal mitochondrial function and insulin response. We found that mitochondrial function was declined in presence of 10 mmol/L glucose, prior to the depression of AKT signaling in primary cortical neurons. We further demonstrated that the cerebral cortex of db/db mice exhibited both insulin resistance and loss of mitochondrial complex components. Moreover, we found that adenosine monophosphate-activated protein kinase (AMPK) inactivation is involved in high glucose-induced mitochondrial dysfunction and insulin resistance in primary cortical neurons and neuroblastoma cells, as well as in cerebral cortex of db/db mice, and all these impairments can be rescued by mitochondrial activator, resveratrol. Taken together, our results extend the finding that high glucose (≥10 mmol/L) comparable to diabetic brain extracellular glucose level leads to neuronal mitochondrial dysfunction and resultant insulin resistance, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. We found that high glucose (≥10 mmol/L), comparable to diabetic brain extracellular glucose level, leads to neuronal mitochondrial dysfunction and resultant insulin resistance in an AMPK-dependent manner, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. © 2016 International Society for Neurochemistry.

γ-Tocotrienol Protects against Mitochondrial Dysfunction and Renal Cell Death

PubMed Central

Bakajsova, Diana; Hayes, Corey; Hauer-Jensen, Martin; Compadre, Cesar M.

2012-01-01

Oxidative stress is a major mechanism of a variety of renal diseases. Tocopherols and tocotrienols are well known antioxidants. This study aimed to determine whether γ-tocotrienol (GT3) protects against mitochondrial dysfunction and renal proximal tubular cell (RPTC) injury caused by oxidants. Primary cultures of RPTCs were injured by using tert-butyl hydroperoxide (TBHP) in the absence and presence of GT3 or α-tocopherol (AT). Reactive oxygen species (ROS) production increased 300% in TBHP-injured RPTCs. State 3 respiration, oligomycin-sensitive respiration, and respiratory control ratio (RCR) decreased 50, 63, and 47%, respectively. The number of RPTCs with polarized mitochondria decreased 54%. F0F1-ATPase activity and ATP content decreased 31 and 65%, respectively. Cell lysis increased from 3% in controls to 26 and 52% at 4 and 24 h, respectively, after TBHP exposure. GT3 blocked ROS production, ameliorated decreases in state 3 and oligomycin-sensitive respirations and F0F1-ATPase activity, and maintained RCR and mitochondrial membrane potential (ΔΨm) in injured RPTCs. GT3 maintained ATP content, blocked RPTC lysis at 4 h, and reduced it to 13% at 24 h after injury. Treatment with equivalent concentrations of AT did not block ROS production and cell lysis and moderately improved mitochondrial respiration and coupling. This is the first report demonstrating the protective effects of GT3 against RPTC injury by: 1) decreasing production of ROS, 2) improving mitochondrial respiration, coupling, ΔΨm, and F0F1-ATPase function, 3) maintaining ATP levels, and 4) preventing RPTC lysis. Our data suggest that GT3 is superior to AT in protecting RPTCs against oxidant injury and may prove therapeutically valuable for preventing renal injury associated with oxidative stress. PMID:22040679

Effects of different acute high ambient temperatures on function of hepatic mitochondrial respiration, antioxidative enzymes, and oxidative injury in broiler chickens.

PubMed

Tan, G-Y; Yang, L; Fu, Y-Q; Feng, J-H; Zhang, M-H

2010-01-01

This study investigated the effects of different acute high ambient temperatures on dysfunction of hepatic mitochondrial respiration, the antioxidative enzyme system, and oxidative injury in broiler chickens. One hundred twenty-eight 6-wk-old broiler chickens were assigned randomly to 4 groups and subsequently exposed to 25 (control), 32, 35, and 38 degrees C (RH, 70 +/- 5%) for 3 h, respectively. The rectal temperatures, activity of antioxidative enzymes (superoxide dismutase, catalase, and glutathione peroxidase), content of malondialdehyde and protein carbonyl, and the activity of mitochondrial respiratory enzymes were determined. The results showed that exposure to high ambient temperature induced a significant elevation of rectal temperature, antioxidative enzyme activity, and formation of malondialdehyde and protein carbonyl, as well as dysfunction of the mitochondrial respiratory chain in comparison with control (P < 0.05). Almost all of the indicators changed in a temperature-dependent manner with the gradual increase of ambient temperature from 32 to 38 degrees C; differences in each parameter (except catalase) among the groups exposed to different high ambient temperatures were also statistically significant (P < 0.05). The results of the present study suggest that, in the broiler chicken model used here, acute exposure to high temperatures may depress the activity of the mitochondrial respiratory chain. This inactivation results subsequently in overproduction of reactive oxygen species, which ultimately results in oxidative injury. However, this hypothesis needs to be evaluated more rigorously in future studies. It has also been shown that, with the gradual increase in temperature, the oxidative injury induced by heat stress in broiler chickens becomes increasingly severe, and this stress response presents in a temperature-dependent manner in the temperature range of 32 to 38 degrees C.

Effects of argan oil on the mitochondrial function, antioxidant system and the activity of NADPH- generating enzymes in acrylamide treated rat brain.

PubMed

Aydın, Birsen

2017-03-01

Argan oil (AO) is rich in minor compounds such as polyphenols and tocopherols which are powerful antioxidants. Acrylamide (ACR) has been classified as a neurotoxic agent in animals and humans. Mitochondrial oxidative stress and dysfunction is one of the most probable molecular mechanisms of neurodegenerative diseases. Female Sprague Dawley rats were exposed to ACR (50mg/kg i.p. three times a week), AO (6ml/kg,o.p, per day) or together for 30days. The activities of cytosolic enzymes such as xanthine oxidase (XO), glucose 6-phosphate dehydrogenase (G6PDH), glutathione-S-transferase (GST), mitochondrial oxidative stress, oxidative phosphorylation (OXPHOS) and tricarboxylic acid cycle (TCA) enzymes, mitochondrial metabolic function, adenosine triphosphate (ATP) level and acetylcholinesterase (AChE) activity were assessed in rat brain. Cytosolic and mitochondrial antioxidant enzymes were significantly diminished in the brains of rats treated with ACR compared to those in control. Besides, ACR treatment resulted in a significant reduction in brain ATP level, mitochondrial metabolic function, OXPHOS and TCA enzymes. Administration of AO restored both the cytosolic and mitochondrial oxidative stress by normalizing nicotinamide adenine dinucleotide phosphate (NADPH) generating enzymes. In addition, improved mitochondrial function primarily enhancing nicotinamide adenine dinucleotide (NADH) generated enzymes activities and ATP level in the mitochondria. The reason for AO's obvious beneficial effects in this study may be due to synergistic effects of its different bioactive compounds which is especially effective on mitochondria. Modulation of the brain mitochondrial functions and antioxidant systems by AO may lead to the development of new mitochondria-targeted antioxidants in the future. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview.

PubMed

Liu, Jiankang

2008-01-01

We have identified a group of nutrients that can directly or indirectly protect mitochondria from oxidative damage and improve mitochondrial function and named them "mitochondrial nutrients". The direct protection includes preventing the generation of oxidants, scavenging free radicals or inhibiting oxidant reactivity, and elevating cofactors of defective mitochondrial enzymes with increased Michaelis-Menten constant to stimulate enzyme activity, and also protect enzymes from further oxidation, and the indirect protection includes repairing oxidative damage by enhancing antioxidant defense systems either through activation of phase 2 enzymes or through increase in mitochondrial biogenesis. In this review, we take alpha-lipoic acid (LA) as an example of mitochondrial nutrients by summarizing the protective effects and possible mechanisms of LA and its derivatives on age-associated cognitive and mitochondrial dysfunction of the brain. LA and its derivatives improve the age-associated decline of memory, improve mitochondrial structure and function, inhibit the age-associated increase of oxidative damage, elevate the levels of antioxidants, and restore the activity of key enzymes. In addition, co-administration of LA with other mitochondrial nutrients, such as acetyl-L: -carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction. Therefore, administrating mitochondrial nutrients, such as LA and its derivatives in combination with other mitochondrial nutrients to aged people and patients suffering from neurodegenerative diseases, may be an effective strategy for improving mitochondrial and cognitive dysfunction.

Silica nanoparticles mediated neuronal cell death in corpus striatum of rat brain: implication of mitochondrial, endoplasmic reticulum and oxidative stress

NASA Astrophysics Data System (ADS)

Parveen, Arshiya; Rizvi, Syed Husain Mustafa; Mahdi, Farzana; Tripathi, Sandeep; Ahmad, Iqbal; Shukla, Rajendra K.; Khanna, Vinay K.; Singh, Ranjana; Patel, Devendra K.; Mahdi, Abbas Ali

2014-11-01

Extensive uses of silica nanoparticles (SiNPs) in biomedical and industrial fields have increased the risk of exposure, resulting concerns about their safety. We focussed on some of the safety aspects by studying neurobehavioural impairment, oxidative stress (OS), neurochemical and ultrastructural changes in corpus striatum (CS) of male Wistar rats exposed to 80-nm SiNPs. Moreover, its role in inducing mitochondrial and endoplasmic reticulum (ER) stress-mediated neuronal apoptosis was also investigated. The results demonstrated impairment in neurobehavioural indices, and a significant increase in lipid peroxide levels (LPO), hydrogen peroxide (H2O2), superoxide (O2 -) and protein carbonyl content, whereas there was a significant decrease in the activities of the enzymes, manganese superoxide dismutase (Mn SOD), glutathione peroxidase (GPx), catalase (CAT) and reduced glutathione (GSH) content, suggesting impaired antioxidant defence system. Protein (cytochrome c, Bcl-2, Bax, p53, caspase-3, caspase 12 and CHOP/Gadd153) and mRNA (Bcl-2, Bax, p53 and CHOP/Gadd153, cytochrome c) expression studies of mitochondrial and ER stress-related apoptotic factors suggested that both the cell organelles were involved in OS-mediated apoptosis in treated rat brain CS. Moreover, electron microscopic studies clearly showed mitochondrial and ER dysfunction. In conclusion, the result of the study suggested that subchronic SiNPs' exposure has the potential to alter the behavioural activity and also to bring about changes in biochemical, neurochemical and ultrastructural profiles in CS region of rat brain. Furthermore, we also report SiNPs-induced apoptosis in CS, through mitochondrial and ER stress-mediated signalling.

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases.

PubMed

Matsuhashi, Tetsuro; Sato, Takeya; Kanno, Shin-Ichiro; Suzuki, Takehiro; Matsuo, Akihiro; Oba, Yuki; Kikusato, Motoi; Ogasawara, Emi; Kudo, Tai; Suzuki, Kosuke; Ohara, Osamu; Shimbo, Hiroko; Nanto, Fumika; Yamaguchi, Hiroaki; Saigusa, Daisuke; Mukaiyama, Yasuno; Watabe, Akiko; Kikuchi, Koichi; Shima, Hisato; Mishima, Eikan; Akiyama, Yasutoshi; Oikawa, Yoshitsugu; Hsin-Jung, H O; Akiyama, Yukako; Suzuki, Chitose; Uematsu, Mitsugu; Ogata, Masaki; Kumagai, Naonori; Toyomizu, Masaaki; Hozawa, Atsushi; Mano, Nariyasu; Owada, Yuji; Aiba, Setsuya; Yanagisawa, Teruyuki; Tomioka, Yoshihisa; Kure, Shigeo; Ito, Sadayoshi; Nakada, Kazuto; Hayashi, Ken-Ichiro; Osaka, Hitoshi; Abe, Takaaki

2017-06-01

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences.

PubMed

de Ferranti, Sarah; Mozaffarian, Dariush

2008-06-01

As the prevalence of adiposity soars in both developed and developing nations, appreciation of the close links between obesity and disease increases. The strong relationships between excess adipose tissue and poor health outcomes, including cardiovascular disease, diabetes, and cancer, mandate elucidation of the complex cellular, hormonal, and molecular pathophysiology whereby adiposity initiates and maintains adverse health effects. In this report we review adipocyte metabolism and function in the context of energy imbalance and postprandial nutrient excess, including adipocyte hypertrophy and hyperplasia, adipocyte dysfunction, and other systemic consequences. We also discuss implications for laboratory evaluation and clinical care, including the role of lifestyle modifications. Chronic energy imbalance produces adipocyte hypertrophy and hyperplasia, endoplasmic reticulum stress, and mitochondrial dysfunction. These processes lead to increased intracellular and systemic release of adipokines, free fatty acids, and inflammatory mediators that cause adipocyte dysfunction and induce adverse effects in the liver, pancreatic beta-cells, and skeletal muscle as well as the heart and vascular beds. Several specialized laboratory tests can quantify these processes and predict clinical risk, but translation to the clinical setting is premature. Current and future pharmacologic interventions may target these pathways; modest changes in diet, physical activity, weight, and smoking are likely to have the greatest impact. Adipocyte endoplasmic reticulum and mitochondrial stress, and associated changes in circulating adipokines, free fatty acids, and inflammatory mediators, are central to adverse health effects of adiposity. Future investigation should focus on these pathways and on reversing the adverse lifestyle behaviors that are the fundamental causes of adiposity.

Mitochondrial medicine for neurodegenerative diseases.

PubMed

Du, Heng; Yan, Shirley ShiDu

2010-05-01

Mitochondrial dysfunction has been reported in a wide array of neurological disorders ranging from neuromuscular to neurodegenerative diseases. Recent studies on neurodegenerative diseases have revealed that mitochondrial pathology is generally found in inherited or sporadic neurodegenerative diseases and is believed to be involved in the pathophysiological process of these diseases. Commonly seen types of mitochondrial dysfunction in neurodegenerative diseases include excessive free radical generation, lowered ATP production, mitochondrial permeability transition, mitochondrial DNA lesions, perturbed mitochondrial dynamics and apoptosis. Mitochondrial medicine as an emerging therapeutic strategy targeted to mitochondrial dysfunction in neurodegenerative diseases has been proven to be of value, though this area of research is still at in its early stage. In this article, we report on recent progress in the development of several mitochondrial therapies including antioxidants, blockade of mitochondrial permeability transition, and mitochondrial gene therapy as evidence that mitochondrial medicine has promise in the treatment of neurodegenerative diseases. 2010 Elsevier Ltd. All rights reserved.

Effect of polyphenols on oxidative stress and mitochondrial dysfunction in neuronal death, brain edema, and cell swelling in cerebral ischemia

USDA-ARS?s Scientific Manuscript database

Polyphenols are natural substances with variable phenolic structures and are elevated in vegetables, fruits, grains, bark, roots, tea, and wine. while there are over 8000 polyphenolic structures identified in plants, edible plants contain only several hundred polyphenolic structures. In addition t...

Mitochondrial Dysfunction in Lysosomal Storage Disorders

PubMed Central

de la Mata, Mario; Cotán, David; Villanueva-Paz, Marina; de Lavera, Isabel; Álvarez-Córdoba, Mónica; Luzón-Hidalgo, Raquel; Suárez-Rivero, Juan M.; Tiscornia, Gustavo; Oropesa-Ávila, Manuel

2016-01-01

Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS), where neuronal dysfunction or loss results in progressive neurodegeneration and premature death. Many LSDs exhibit signs of mitochondrial dysfunction, which include mitochondrial morphological changes, decreased mitochondrial membrane potential (ΔΨm), diminished ATP production and increased generation of reactive oxygen species (ROS). Furthermore, reduced autophagic flux may lead to the persistence of dysfunctional mitochondria. Gaucher disease (GD), the LSD with the highest prevalence, is caused by mutations in the GBA1 gene that results in defective and insufficient activity of the enzyme β-glucocerebrosidase (GCase). Decreased catalytic activity and/or instability of GCase leads to accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in the lysosomes of macrophage cells and visceral organs. Mitochondrial dysfunction has been reported to occur in numerous cellular and mouse models of GD. The aim of this manuscript is to review the current knowledge and implications of mitochondrial dysfunction in LSDs. PMID:28933411

Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watanabe, Tomoyuki; Saotome, Masao, E-mail: msaotome@hama-med.ac.jp; Nobuhara, Mamoru

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}),more » they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance. • Inhibition of DRP or ROS failed to improve palmitate-induced insulin-resistance. • Mitochondrial dysfunction by lipid metabolites would induce insulin-resistance.« less

Association between mitochondrial DNA variations and Alzheimer's Disease in the ADNI cohort

PubMed Central

Lakatos, Anita; Derbeneva, Olga; Younes, Danny; Keator, David; Bakken, Trygve; Lvova, Maria; Brandon, Marty; Guffanti, Guia; Reglodi, Dora; Saykin, Andrew; Weiner, Michael; Macciardi, Fabio; Schork, Nicholas; Wallace, Douglas C.; Potkin, Steven G.

2010-01-01

Despite the central role of amyloid deposition in the development of Alzheimer's disease (AD), the pathogenesis of AD still remains elusive at the molecular level. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species (ROS) which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. Because the brain relies on aerobic metabolism, it is apparent that mitochondria are critical for the cerebral function. Mitochondrial DNA sequence-changes could shift cell dynamics and facilitate neuronal vulnerability. Therefore we postulated that mitochondrial DNA sequence polymorphisms may increase the risk of AD. We evaluated the role of mitochondrial haplogroups derived from 138 mitochondrial polymorphisms in 358 Caucasian ADNI subjects. Our results indicate that the mitochondrial haplogroup UK may confer genetic susceptibility to AD independently of the APOE4 allele. PMID:20538375

Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging.

PubMed

Lemasters, John J

2005-01-01

In autophagy, portions of cytoplasm are sequestered into autophagosomes and delivered to lysosomes for degradation. Long assumed to be a random process, increasing evidence suggests that autophagy of mitochondria, peroxisomes, and possibly other organelles is selective. A recent paper (Kissova et al., J. Biol. Chem. 2004;279:39068-39074) shows in yeast that a specific outer membrane protein, Uth1p, is required for efficient mitochondrial autophagy. For this selective autophagy of mitochondria, we propose the term "mitophagy" to emphasize the non-random nature of the process. Mitophagy may play a key role in retarding accumulation of somatic mutations of mtDNA with aging.

Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ.

PubMed

Vergeade, Aurélia; Mulder, Paul; Vendeville-Dehaudt, Cathy; Estour, François; Fortin, Dominique; Ventura-Clapier, Renée; Thuillez, Christian; Monteil, Christelle

2010-09-01

The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. Copyright 2010 Elsevier Inc. All rights reserved.

Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis.

PubMed

Miquel, Ernesto; Cassina, Adriana; Martínez-Palma, Laura; Souza, José M; Bolatto, Carmen; Rodríguez-Bottero, Sebastián; Logan, Angela; Smith, Robin A J; Murphy, Michael P; Barbeito, Luis; Radi, Rafael; Cassina, Patricia

2014-05-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron degeneration that ultimately results in progressive paralysis and death. Growing evidence indicates that mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in ALS. To further explore the hypothesis that mitochondrial dysfunction and nitroxidative stress contribute to disease pathogenesis at the in vivo level, we assessed whether the mitochondria-targeted antioxidant [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methane sulfonate (MitoQ) can modify disease progression in the SOD1(G93A) mouse model of ALS. To do this, we administered MitoQ (500 µM) in the drinking water of SOD1(G93A) mice from a time when early symptoms of neurodegeneration become evident at 90 days of age until death. This regime is a clinically plausible scenario and could be more easily translated to patients as this corresponds to initiating treatment of patients after they are first diagnosed with ALS. MitoQ was detected in all tested tissues by liquid chromatography/mass spectrometry after 20 days of administration. MitoQ treatment slowed the decline of mitochondrial function, in both the spinal cord and the quadriceps muscle, as measured by high-resolution respirometry. Importantly, nitroxidative markers and pathological signs in the spinal cord of MitoQ-treated animals were markedly reduced and neuromuscular junctions were recovered associated with a significant increase in hindlimb strength. Finally, MitoQ treatment significantly prolonged the life span of SOD1(G93A) mice. Our results support a role for mitochondrial nitroxidative damage and dysfunction in the pathogenesis of ALS and suggest that mitochondria-targeted antioxidants may be of pharmacological use for ALS treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC-1 and roGFP1 Fluorescence

PubMed Central

Bebensee, Dörthe F.

2017-01-01

Rett syndrome (RTT) is a neurodevelopmental disorder with mutations in the MECP2 gene. Mostly girls are affected, and an apparently normal development is followed by cognitive impairment, motor dysfunction, epilepsy, and irregular breathing. Various indications suggest mitochondrial dysfunction. In Rett mice, brain ATP levels are reduced, mitochondria are leaking protons, and respiratory complexes are dysregulated. Furthermore, we found in MeCP2-deficient mouse (Mecp2−/y) hippocampus an intensified mitochondrial metabolism and ROS generation. We now used emission ratiometric 2-photon imaging to assess mitochondrial morphology, mass, and membrane potential (ΔΨm) in Mecp2−/y hippocampal astrocytes. Cultured astrocytes were labeled with the ΔΨm marker JC-1, and semiautomated analyses yielded the number of mitochondria per cell, their morphology, and ΔΨm. Mecp2−/y astrocytes contained more mitochondria than wild-type (WT) cells and were more oxidized. Mitochondrial size, ΔΨm, and vulnerability to pharmacological challenge did not differ. The antioxidant Trolox opposed the oxidative burden and decreased the mitochondrial mass, thereby dampening the differences among WT and Mecp2−/y astrocytes; mitochondrial size and ΔΨm were not markedly affected. In conclusion, mitochondrial alterations and redox imbalance in RTT also involve astrocytes. Mitochondria are more numerous in Mecp2−/y than in WT astrocytes. As this genotypic difference is abolished by Trolox, it seems linked to the oxidative stress in RTT. PMID:28894505

Hyperoxia activates ATM independent from mitochondrial ROS and dysfunction.

PubMed

Resseguie, Emily A; Staversky, Rhonda J; Brookes, Paul S; O'Reilly, Michael A

2015-08-01

High levels of oxygen (hyperoxia) are often used to treat individuals with respiratory distress, yet prolonged hyperoxia causes mitochondrial dysfunction and excessive reactive oxygen species (ROS) that can damage molecules such as DNA. Ataxia telangiectasia mutated (ATM) kinase is activated by nuclear DNA double strand breaks and delays hyperoxia-induced cell death through downstream targets p53 and p21. Evidence for its role in regulating mitochondrial function is emerging, yet it has not been determined if mitochondrial dysfunction or ROS activates ATM. Because ATM maintains mitochondrial homeostasis, we hypothesized that hyperoxia induces both mitochondrial dysfunction and ROS that activate ATM. In A549 lung epithelial cells, hyperoxia decreased mitochondrial respiratory reserve capacity at 12h and basal respiration by 48 h. ROS were significantly increased at 24h, yet mitochondrial DNA double strand breaks were not detected. ATM was not required for activating p53 when mitochondrial respiration was inhibited by chronic exposure to antimycin A. Also, ATM was not further activated by mitochondrial ROS, which were enhanced by depleting manganese superoxide dismutase (SOD2). In contrast, ATM dampened the accumulation of mitochondrial ROS during exposure to hyperoxia. Our findings suggest that hyperoxia-induced mitochondrial dysfunction and ROS do not activate ATM. ATM more likely carries out its canonical response to nuclear DNA damage and may function to attenuate mitochondrial ROS that contribute to oxygen toxicity. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

mPGES-1 (Microsomal Prostaglandin E Synthase-1) Mediates Vascular Dysfunction in Hypertension Through Oxidative Stress.

PubMed

Avendaño, María S; García-Redondo, Ana B; Zalba, Guillermo; González-Amor, María; Aguado, Andrea; Martínez-Revelles, Sonia; Beltrán, Luis M; Camacho, Mercedes; Cachofeiro, Victoria; Alonso, María J; Salaices, Mercedes; Briones, Ana M

2018-06-11

mPGES-1 (microsomal prostaglandin E synthase-1), the downstream enzyme responsible for PGE 2 (prostaglandin E 2 ) synthesis in inflammatory conditions and oxidative stress are increased in vessels from hypertensive animals. We evaluated the role of mPGES-1-derived PGE 2 in the vascular dysfunction and remodeling in hypertension and the possible contribution of oxidative stress. We used human peripheral blood mononuclear cells from asymptomatic patients, arteries from untreated and Ang II (angiotensin II)-infused mPGES-1 -/- and mPGES-1 +/+ mice, and vascular smooth muscle cells exposed to PGE 2 In human cells, we found a positive correlation between mPGES-1 mRNA and carotid intima-media thickness ( r =0.637; P <0.001) and with NADPH oxidase-dependent superoxide production ( r =0.417; P <0.001). In Ang II-infused mice, mPGES-1 deletion prevented all of the following: (1) the augmented wall:lumen ratio, vascular stiffness, and altered elastin structure; (2) the increased gene expression of profibrotic and proinflammatory markers; (3) the increased vasoconstrictor responses and endothelial dysfunction; (4) the increased NADPH oxidase activity and the diminished mitochondrial membrane potential; and (5) the increased reactive oxygen species generation and reduced NO bioavailability. In vascular smooth muscle cells or aortic segments, PGE 2 increased NADPH oxidase expression and activity and reduced mitochondrial membrane potential, effects that were abolished by antagonists of the PGE 2 receptors (EP), EP1 and EP3, and by JNK (c-Jun N-terminal kinase) and ERK1/2 (extracellular-signal-regulated kinases 1/2) inhibition. Deletion of mPGES-1 augmented vascular production of PGI 2 suggesting rediversion of the accumulated PGH 2 substrate. In conclusion, mPGES-1-derived PGE 2 is involved in vascular remodeling, stiffness, and endothelial dysfunction in hypertension likely through an increase of oxidative stress produced by NADPH oxidase and mitochondria. © 2018 American Heart Association, Inc.

Rat liver mitochondrial dysfunction by addition of copper(II) or iron(III) ions.

PubMed

Saporito-Magriñá, Christian; Musacco-Sebio, Rosario; Acosta, Juan M; Bajicoff, Sofía; Paredes-Fleitas, Paola; Boveris, Alberto; Repetto, Marisa G

2017-01-01

Increased copper (Cu) and iron (Fe) levels in liver and brain are associated to oxidative stress and damage with increased phospholipid oxidation process. The aim of this work was to assess the toxic effects of Cu 2+ and Fe 3+ addition to rat liver mitochondria by determining mitochondrial respiration in states 3 (active respiration) and 4 (resting respiration), and phospholipid peroxidation. Both, Cu 2+ and Fe 3+ produced decreases in O 2 consumption in a concentration-dependent manner in active state 3: both ions by 42% with malate-glutamate as complex I substrate (concentration for half maximal response (C 50 ) 60μM Cu 2+ and 1.25mM Fe 3+ ), and with succinate as complex II substrate: 64-69% with C 50 of 50μM Cu 2+ and with C 50 of 1.25mM of Fe 3+ . Respiratory control decreased with Cu 2+ (C 50 50μM) and Fe 3+ (C 50 1.25-1-75mM) with both substrates. Cu 2+ produced a 2-fold increase and Fe 3+ a 5-fold increase of thiobarbituric acid-reactive substances (TBARS) content from 25μM Cu 2+ (C 50 40μM) and from 100μM Fe 3+ (C 50 1.75mM). Supplementations with Cu 2+ and Fe 3+ ions induce mitochondrial dysfunction with phospholipid peroxidation in rat liver mitochondria. Although is proved that a Fenton/Haber Weiss mechanism of oxidative damage occurs in metal-ion induced mitochondrial toxicity, slightly different responses to the metal ions suggest some differences in the mechanism of intracellular toxicity. The decreased rates of mitochondrial respiration and the alteration of mitochondrial function by phospholipid and protein oxidations lead to mitochondrial dysfunction, cellular dyshomeostasis and cell death. Copyright © 2016 Elsevier Inc. All rights reserved.

Dimethoxycurcumin-induced cell death in human breast carcinoma MCF7 cells: evidence for pro-oxidant activity, mitochondrial dysfunction, and apoptosis.

PubMed

Kunwar, A; Jayakumar, S; Srivastava, A K; Priyadarsini, K I

2012-04-01

The factors responsible for the induction of cell death by dimethoxycurcumin (Dimc), a synthetic analog of curcumin, were assessed in human breast carcinoma MCF7 cells. Initial cytotoxic studies with both curcumin and Dimc using MTT assay indicated their comparable effects. Further, the mechanism of action was explored in terms of oxidative stress, mitochondrial dysfunction, and modulation in the expression of proteins involved in cell cycle regulation and apoptosis. Dimc (5-50 μM) caused generation of reactive oxygen species, reduction in glutathione level, and induction of DNA damage. The mitochondrial dysfunction induced by Dimc was evidenced by the reduction in mitochondrial membrane potential and decrease in cellular energy status (ATP/ADP) monitored by HPLC analysis. The observed decrease in ATP was also supported by the significant suppression of different (α, β, γ, and ε) subunits of ATP synthase. The cytotoxic effect of Dimc was further characterized in terms of induction of S-phase cell cycle arrest and apoptosis, and their relative contribution was found to vary with the treatment concentration of Dimc. The S-phase arrest and apoptosis could also be correlated with the changes in the expressions of cell cycle proteins like p53, p21, CDK4, and cyclin-D1 and apoptotic markers like Bax and Bcl-2. Overall, the results demonstrated that Dimc induced cell death in MCF7 cells through S-phase arrest and apoptosis.

Further Commentary on Mitochondrial Dysfunction in Autism Spectrum Disorder: Assessment and Treatment Considerations

ERIC Educational Resources Information Center

Dager, Stephen R.; Corrigan, Neva M.; Estes, Annette; Shaw, Dennis W. W.

2012-01-01

The authors respond to a recent letter (Rossignol and Frye 2011) critical of their paper, "Proton magnetic resonance spectroscopy and MRI reveal no evidence for brain mitochondrial dysfunction in children with autism spectrum disorder" (Corrigan et al. 2011). Further considerations regarding the assessment of mitochondrial dysfunction in autism…

Controlled curcumin release via conjugation into PBAE nanogels enhances mitochondrial protection against oxidative stress.

PubMed

Gupta, Prachi; Jordan, Carolyn T; Mitov, Mihail I; Butterfield, D Allan; Hilt, J Zach; Dziubla, Thomas D

2016-09-25

Mitochondria are considered to be the "power plants" of the cell, but can also initiate and execute cell death, stimulated by oxidative stress (OS). OS induced mitochondrial dysfunction is characterized by a loss in oxygen consumption and reduced ATP production. Curcumin, as a potential therapeutic, has been explored as a candidate for mitochondrial OS suppression, but rapid metabolism and aqueous insolubility has prevented it from being effective. Further, efficient delivery of curcumin via the incorporation into nanocarriers has again been limited due to low drug loading capacities and/or significant burst release, resulting in acute cytotoxicity. Hence, to increase the therapeutic potential and reduce the toxic effects of curcumin, curcumin conjugated poly(β-amino ester) nanogels (CNGs) were synthesized using Michael addition chemistry. This approach provided easy control over the nanogel size, with CNGs showing a uniform release of active curcumin over 48h with no burst release. This controlled release system significantly increased the safety limit for curcumin, with a ten fold increase in the cytotoxic threshold, as compared to free curcumin. Further, real-time mitochondrial response analysis with the Seahorse XF96 showed effective and prolonged suppression of H2O2 induced mitochondrial oxidative stress upon pre-treating endothelial cells with CNGs and this potential of nanogels was studied at different pre-treatment times prior to H2O2 exposure. Copyright © 2016 Elsevier B.V. All rights reserved.

Pathogenesis of Chronic Cardiorenal Syndrome: Is There a Role for Oxidative Stress?

PubMed Central

Rubattu, Speranza; Mennuni, Silvia; Testa, Marco; Mennuni, Mara; Pierelli, Giorgia; Pagliaro, Beniamino; Gabriele, Erica; Coluccia, Roberta; Autore, Camillo; Volpe, Massimo

2013-01-01

Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental studies have identified several dysregulated pathways in heart failure and in chronic kidney disease that lead to increased oxidative stress. A decrease in mitochondrial oxidative metabolism has been reported in cardiomyocytes during heart failure. This is balanced by a compensatory increase in glucose uptake and glycolysis with consequent decrease in myocardial ATP content. In the kidneys, both NADPH oxidase and mitochondrial metabolism are important sources of TGF-β1-induced cellular ROS. NOX-dependent oxidative activation of transcription factors such as NF-kB and c-jun leads to increased expression of renal target genes (phospholipaseA2, MCP-1 and CSF-1, COX-2), thus contributing to renal interstitial fibrosis and inflammation. In the present article, we postulate that, besides contributing to both cardiac and renal dysfunction, increased oxidative stress may also play a crucial role in cardiorenal syndrome development and progression. In particular, an imbalance between the renin-angiotensin-aldosterone system, the sympathetic nervous system, and inflammation may favour cardiorenal syndrome through an excessive oxidative stress production. This article also discusses novel therapeutic strategies for their potential use in the treatment of patients affected by cardiorenal syndrome. PMID:24264044

Lowered iPLA2γ activity causes increased mitochondrial lipid peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson's disease.

PubMed

Chao, Honglu; Liu, Yinlong; Fu, Xian; Xu, Xiupeng; Bao, Zhongyuan; Lin, Chao; Li, Zheng; Liu, Yan; Wang, Xiaoming; You, Yongping; Liu, Ning; Ji, Jing

2018-02-01

iPLA 2 γ, calcium-independent phospholipase A 2 γ, discerningly hydrolyses glycerophospholipids to liberate free fatty acids. iPLA 2 γ-deficiency has been associated with abnormal mitochondrial function. More importantly, the iPLA 2 family is causative proteins in mitochondrial neurodegenerative disorders such as parkinsonian disorders. However, the mechanisms by which iPLA 2 γ affects Parkinson's disease (PD) remain unknown. Mitochondrion stress has a key part in rotenone-induced dopaminergic neuronal degeneration. The present evaluation revealed that lowered iPLA 2 γ function provokes the parkinsonian phenotype and leads to the reduction of dopamine and its metabolites, lowered survival, locomotor deficiencies, and organismal hypersensitivity to rotenone-induced oxidative stress. In addition, lowered iPLA 2 γ function escalated the amount of mitochondrial irregularities, including mitochondrial reactive oxygen species (ROS) regeneration, reduced ATP synthesis, reduced glutathione levels, and abnormal mitochondrial morphology. Further, lowered iPLA 2 γ function was tightly linked with strengthened lipid peroxidation and mitochondrial membrane flaws following rotenone treatment, which can cause cytochrome c release and eventually apoptosis. These results confirmed the important role of iPLA 2 γ, whereby decreasing iPLA 2 γ activity aggravates mitochondrial degeneration to induce neurodegenerative disorders in a rotenone rat model of Parkinson's disease. These findings may be useful in the design of rational approaches for the prevention and treatment of PD-associated symptoms. Copyright © 2017 Elsevier Inc. All rights reserved.

Mitochondrial energy metabolism dysfunction involved in reproductive toxicity of mice caused by endosulfan and protective effects of vitamin E.

PubMed

Wang, Na; Qian, Hong-Yan; Zhou, Xian-Qing; Li, Yan-Bo; Sun, Zhi-Wei

2012-08-01

The experiment was designed to study the mechanism of reproductive toxicity caused by endosulfan in mice and protective effects of vitamin E. The experiment was composed of three groups: the control group did not receive any endosulfan and vitamin E; the endosulfan exposed group received 0.8 mg/kg/d endosulfan and 0mg/kg/d vitamin E; and the endosulfan+vitamin E group received 0.8 mg/kg/d endosulfan and 100mg/kg/d vitamin E. The results showed that vitamin E significantly reversed the decline of the concentration and motility rate of sperm, and inhibited the increase of sperm abnormality rate caused by endosulfan. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and lactate dehydrogenase-C4 (LDH-C4) and the level of adenosine triphosphate (ATP) in the endosulfan+vitamin E group were higher while the malondialdehyde (MDA) content was significantly lower than those of the endosulfan exposed group. The results from pathology and electron microscope observed showed vitamin E decreased the cavities formation by desquamating of spermatogenic cells, stopped the ruptures and disappearances of mitochondrial cristaes in spermatogenic cells, and prevented the breakages and partial dissolvings of sperm tails induced by endosulfan. It is likely that endosulfan could directly damage sperm structures by oxidative stress, leading to a decrease in sperm quantity and quality. It also could indirectly cause a decline in reproductive function by damaging the structure of mitochondria, resulting in energy metabolism dysfunction, which could be one of the mechanisms behind the reproductive toxicity induced by endosulfan. It was inferred that vitamin E helps maintain the structural integrities of sperm architecture and prevent mitochondrial dysfunction through inhibiting oxidative stress, and thereby prevent the reproductive dysfunctions caused by endosulfan. Copyright © 2012 Elsevier Inc. All rights reserved.

Edaravone protects against hyperosmolarity-induced oxidative stress and apoptosis in primary human corneal epithelial cells.

PubMed

Li, Yanwei; Liu, Haifeng; Zeng, Wei; Wei, Jing

2017-01-01

An increase in the osmolarity of tears induced by excessive evaporation of the aqueous tear phase is a major pathological mechanism behind dry eye. Exposure of epithelial cells on the surface of the human eye to hyperosmolarity leads to oxidative stress, mitochondrial dysfunction, and apoptosis. Edaravone, a hydroxyl radical scavenging agent, is clinically used to reduce neuronal damage following ischemic stroke. In this study, we found that treatment with hyperosmotic media at 400 and 450 mOsM increased the levels of ROS and mitochondrial oxidative damage, which were ameliorated by edaravone treatment in a dose-dependent manner. We also found that edaravone could improve mitochondrial function in HCEpiCs by increasing the levels of ATP and mitochondrial membrane potential. MTT and LDH assays indicated that edaravone could attenuate hyperosmolarity-induced cell death. It was found that edaravone prevented apoptosis by decreasing the level of cleaved caspase-3, and attenuating the release of cytochrome C. Mechanistically, we found that edaravone augmented the expression of Nrf2 and its target genes, such as HO-1, GPx-1, and GCLC.

Edaravone protects against hyperosmolarity-induced oxidative stress and apoptosis in primary human corneal epithelial cells

PubMed Central

Li, Yanwei; Liu, Haifeng; Zeng, Wei; Wei, Jing

2017-01-01

An increase in the osmolarity of tears induced by excessive evaporation of the aqueous tear phase is a major pathological mechanism behind dry eye. Exposure of epithelial cells on the surface of the human eye to hyperosmolarity leads to oxidative stress, mitochondrial dysfunction, and apoptosis. Edaravone, a hydroxyl radical scavenging agent, is clinically used to reduce neuronal damage following ischemic stroke. In this study, we found that treatment with hyperosmotic media at 400 and 450 mOsM increased the levels of ROS and mitochondrial oxidative damage, which were ameliorated by edaravone treatment in a dose-dependent manner. We also found that edaravone could improve mitochondrial function in HCEpiCs by increasing the levels of ATP and mitochondrial membrane potential. MTT and LDH assays indicated that edaravone could attenuate hyperosmolarity-induced cell death. It was found that edaravone prevented apoptosis by decreasing the level of cleaved caspase-3, and attenuating the release of cytochrome C. Mechanistically, we found that edaravone augmented the expression of Nrf2 and its target genes, such as HO-1, GPx-1, and GCLC. PMID:28346481

Mild uncoupling of respiration and phosphorylation as a mechanism providing nephro- and neuroprotective effects of penetrating cations of the SkQ family.

PubMed

Plotnikov, E Y; Silachev, D N; Jankauskas, S S; Rokitskaya, T I; Chupyrkina, A A; Pevzner, I B; Zorova, L D; Isaev, N K; Antonenko, Y N; Skulachev, V P; Zorov, D B

2012-09-01

It is generally accepted that mitochondrial production of reactive oxygen species is nonlinearly related to the value of the mitochondrial membrane potential with significant increment at values exceeding 150 mV. Due to this, high values of the membrane potential are highly dangerous, specifically under pathological conditions associated with oxidative stress. Mild uncoupling of oxidative phosphorylation is an approach to preventing hyperpolarization of the mitochondrial membrane. We confirmed data obtained earlier in our group that dodecylrhodamine 19 (C(12)R1) (a penetrating cation from SkQ family not possessing a plastoquinone group) has uncoupling properties, this fact making it highly potent for use in prevention of pathologies associated with oxidative stress induced by mitochondrial hyperpolarization. Further experiments showed that C(12)R1 provided nephroprotection under ischemia/reperfusion of the kidney as well as under rhabdomyolysis through diminishing of renal dysfunction manifested by elevated level of blood creatinine and urea. Similar nephroprotective properties were observed for low doses (275 nmol/kg) of the conventional uncoupler 2,4-dinitrophenol. Another penetrating cation that did not demonstrate protonophorous activity (SkQR4) had no effect on renal dysfunction. In experiments with induced ischemic stroke, C(12)R1 did not have any effect on the area of ischemic damage, but it significantly lowered neurological deficit. We conclude that beneficial effects of penetrating cation derivatives of rhodamine 19 in renal pathologies and brain ischemia may be at least partially explained by uncoupling of oxidation and phosphorylation.

PKCδ knockout mice are protected from para-methoxymethamphetamine-induced mitochondrial stress and associated neurotoxicity in the striatum of mice.

PubMed

Shin, Eun-Joo; Dang, Duy-Khanh; Tran, Hai-Quyen; Nam, Yunsung; Jeong, Ji Hoon; Lee, Young Hun; Park, Kyung Tae; Lee, Yong Sup; Jang, Choon-Gon; Hong, Jau-Shyong; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2016-11-01

Para-methoxymethamphetamine (PMMA) is a para-ring-substituted amphetamine derivative sold worldwide as an illegal psychotropic drug. Although PMMA use has been reported to lead to severe intoxication and even death, little is known about the mechanism(s) by which PMMA exerts its neurotoxic effects. Here we found that PMMA treatment resulted in phosphorylation of protein kinase Cδ (PKCδ) and subsequent mitochondrial translocation of cleaved PKCδ. PMMA-induced oxidative stress was more pronounced in mitochondria than in the cytosol. Moreover, treatment with PMMA consistently resulted in significant reductions in mitochondrial membrane potential, mitochondrial complex I activity, and mitochondrial Mn superoxide dismutase-immunoreactivity. In contrast, PMMA treatment led to a significant increase in intramitochondrial Ca 2+ level. Treatment with PMMA also significantly increased ionized calcium binding adaptor molecule 1 (Iba-1)-labeled microglial activation and upregulated tumor necrosis factor alpha (TNF-α) gene expression. PKCδ knockout attenuated these mitochondrial effects and dampened the neurotoxic effects of PMMA. Importantly, TNF-α knockout mice were significantly protected from PMMA-induced increases in phospho-PKCδ expression, mitochondrial translocation of cleaved PKCδ, and Iba-1-labeled microgliosis. Both rottlerin, a pharmacological inhibitor of PKCδ, and etanercept, a pharmacological inhibitor of TNF-α, significantly protected against PMMA-mediated induction of apoptosis, as assessed by terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL) assays. In addition, PKCδ knockout and TNF-α knockout both resulted in decreased PMMA-mediated induction of dopaminergic loss. Therefore, our results suggest that PKCδ mediates PMMA-induced neurotoxicity by facilitating oxidative stress (mitochondria > cytosol), mitochondrial dysfunction, microglial activation, and pro-apoptotic signaling. Our results also indicate that PMMA-induced PKCδ activation requires the proinflammatory cytokine TNF-α. Copyright © 2016. Published by Elsevier Ltd.

Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications

PubMed Central

Vernochet, Cecile; Damilano, Federico; Mourier, Arnaud; Bezy, Olivier; Mori, Marcelo A.; Smyth, Graham; Rosenzweig, Anthony; Larsson, Nils-Göran; Kahn, C. Ronald

2014-01-01

Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75–81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.—Vernochet, C., Damilano, F., Mourier, A., Bezy, O., Mori, M. A., Smyth, G., Rosenzweig, A., Larsson, N.-G., Kahn, C. R. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. PMID:25005176

Sonic hedgehog promotes neurite outgrowth of cortical neurons under oxidative stress: Involving of mitochondria and energy metabolism.

PubMed

He, Weiliang; Cui, Lili; Zhang, Cong; Zhang, Xiangjian; He, Junna; Xie, Yanzhao; Chen, Yanxia

2017-01-01

Oxidative stress has been demonstrated to be involved in the etiology of several neurobiological disorders. Sonic hedgehog (Shh), a secreted glycoprotein factor, has been implicated in promoting several aspects of brain remodeling process. Mitochondria may play an important role in controlling fundamental processes in neuroplasticity. However, little evidence is available about the effect and the potential mechanism of Shh on neurite outgrowth in primary cortical neurons under oxidative stress. Here, we revealed that Shh treatment significantly increased the viability of cortical neurons in a dose-dependent manner, which was damaged by hydrogen peroxide (H 2 O 2 ). Shh alleviated the apoptosis rate of H 2 O 2 -induced neurons. Shh also increased neuritogenesis injuried by H 2 O 2 in primary cortical neurons. Moreover, Shh reduced the generation of reactive oxygen species (ROS), increased the activities of SOD and and decreased the productions of MDA. In addition, Shh protected mitochondrial functions, elevated the cellular ATP levels and amelioratesd the impairment of mitochondrial complex II activities of cortical neurons induced by H 2 O 2 . In conclusion, all these results suggest that Shh acts as a prosurvival factor playing an essential role to neurite outgrowth of cortical neuron under H 2 O 2 -induced oxidative stress, possibly through counteracting ROS release and preventing mitochondrial dysfunction and ATP as well as mitochondrial complex II activities against oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress.

PubMed

Dai, Chongshan; Ciccotosto, Giuseppe D; Cappai, Roberto; Wang, Yang; Tang, Shusheng; Xiao, Xilong; Velkov, Tony

2017-06-01

Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity. The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells. Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells. To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis

PubMed Central

2014-01-01

Background Renal ischemia-reperfusion injury (IRI) increases the rates of acute kidney failure, delayed graft function, and early mortality after kidney transplantation. The pathophysiology involved includes oxidative stress, mitochondrial dysfunction, and immune-mediated injury. The anti-oxidation, anti-apoptosis, and anti-inflammation properties of baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, have been verified. This study therefore assessed the effects of baicalin against renal IRI in rats. Methods Baicalin was intraperitoneally injected 30 min before renal ischemia. Serum and kidneys were harvested 24 h after reperfusion. Renal function and histological changes were assessed. Markers of oxidative stress, the Toll-like receptor (TLR)2 and TLR4 signaling pathway, mitochondrial stress, and cell apoptosis were also evaluated. Results Baicalin treatment decreased oxidative stress and histological injury, and improved kidney function, as well as inhibiting proinflammatory responses and tubular apoptosis. Baicalin pretreatment also reduced the expression of TLR2, TLR4, MyD88, p-NF-κB, and p-IκB proteins, as well as decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. Conclusions Baicalin may attenuate renal ischemia-reperfusion injury by inhibiting proinflammatory responses and mitochondria-mediated apoptosis. These effects are associated with the TLR2/4 signaling pathway and mitochondrial stress. PMID:24417870

The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis.

PubMed

Lin, Miao; Li, Long; Li, Liping; Pokhrel, Gaurab; Qi, Guisheng; Rong, Ruiming; Zhu, Tongyu

2014-01-13

Renal ischemia-reperfusion injury (IRI) increases the rates of acute kidney failure, delayed graft function, and early mortality after kidney transplantation. The pathophysiology involved includes oxidative stress, mitochondrial dysfunction, and immune-mediated injury. The anti-oxidation, anti-apoptosis, and anti-inflammation properties of baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, have been verified. This study therefore assessed the effects of baicalin against renal IRI in rats. Baicalin was intraperitoneally injected 30 min before renal ischemia. Serum and kidneys were harvested 24 h after reperfusion. Renal function and histological changes were assessed. Markers of oxidative stress, the Toll-like receptor (TLR)2 and TLR4 signaling pathway, mitochondrial stress, and cell apoptosis were also evaluated. Baicalin treatment decreased oxidative stress and histological injury, and improved kidney function, as well as inhibiting proinflammatory responses and tubular apoptosis. Baicalin pretreatment also reduced the expression of TLR2, TLR4, MyD88, p-NF-κB, and p-IκB proteins, as well as decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. Baicalin may attenuate renal ischemia-reperfusion injury by inhibiting proinflammatory responses and mitochondria-mediated apoptosis. These effects are associated with the TLR2/4 signaling pathway and mitochondrial stress.

Non-Exertional Heatstroke: A Case Report and Review of the Literature

PubMed Central

Mozzini, Chiara; Xotta, Giovanni; Garbin, Ulisse; Pasini, Anna Maria Fratta; Cominacini, Luciano

2017-01-01

Patient: Female, 41 Final Diagnosis: Heatstroke Symptoms: Coma Medication: — Clinical Procedure: Intensive Care Unit-Internal Medicine Specialty: Critical Care Medicine Objective: Rare co-existance of disease or pathology Background: Heatstroke (HS) is a life-threatening condition characterized by an elevation of the core body temperature above 40°C, central nervous system dysfunction, and possible multi-organ failure. HS can trigger systemic inflammation, disseminated intravascular coagulation (DIC), rhabdomyolysis, cerebral edema and seizures, pulmonary edema, heart dysfunctions, and renal and hepatic failure. Case Report: We report the case of a 41-year-old Romanian woman with a history of alcoholism who developed HS after arriving by bus in Verona, Italy in June 2016. The patient developed consecutive multi-organ dysfunction, including liver and renal failure, rhabdomyolysis, DIC, and arrhythmia. The patient was successfully treated with conservative measures. After 17 days, she recovered completely. Conclusions: The exact mechanism of HS-related multiple organ dysfunction is not completely understood and its pathogenesis is complex. It involves inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Development of a model in which chronic alcohol abuse alters oxidative, inflammatory, and ER stress response could also be a conceivable solution to the positive prognosis of severe HS patients, in which liver failure has a prominent role. PMID:28974669

Ionizing radiation accelerates Drp1-dependent mitochondrial fission, which involves delayed mitochondrial reactive oxygen species production in normal human fibroblast-like cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kobashigawa, Shinko, E-mail: kobashin@nagasaki-u.ac.jp; Suzuki, Keiji; Yamashita, Shunichi

2011-11-04

Highlights: Black-Right-Pointing-Pointer We report first time that ionizing radiation induces mitochondrial dynamic changes. Black-Right-Pointing-Pointer Radiation-induced mitochondrial fission was caused by Drp1 localization. Black-Right-Pointing-Pointer We found that radiation causes delayed ROS from mitochondria. Black-Right-Pointing-Pointer Down regulation of Drp1 rescued mitochondrial dysfunction after radiation exposure. -- Abstract: Ionizing radiation is known to increase intracellular level of reactive oxygen species (ROS) through mitochondrial dysfunction. Although it has been as a basis of radiation-induced genetic instability, the mechanism involving mitochondrial dysfunction remains unclear. Here we studied the dynamics of mitochondrial structure in normal human fibroblast like cells exposed to ionizing radiation. Delayed mitochondrial O{submore » 2}{sup {center_dot}-} production was peaked 3 days after irradiation, which was coupled with accelerated mitochondrial fission. We found that radiation exposure accumulated dynamin-related protein 1 (Drp1) to mitochondria. Knocking down of Drp1 expression prevented radiation induced acceleration of mitochondrial fission. Furthermore, knockdown of Drp1 significantly suppressed delayed production of mitochondrial O{sub 2}{sup {center_dot}-}. Since the loss of mitochondrial membrane potential, which was induced by radiation was prevented in cells knocking down of Drp1 expression, indicating that the excessive mitochondrial fission was involved in delayed mitochondrial dysfunction after irradiation.« less

Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease

PubMed Central

Swerdlow, Russell H.

2017-01-01

Decades of research indicate mitochondria from Alzheimer’s disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research. PMID:29036828

Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy.

PubMed

Griffiths, Lisa A; Flatters, Sarah J L

2015-10-01

Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle.

PubMed

Malkus, Kristen A; Tsika, Elpida; Ischiropoulos, Harry

2009-06-05

While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged. Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death. These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle" that may be considered the underlying cause of neurodegenerative pathogenesis.

Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle

PubMed Central

Malkus, Kristen A; Tsika, Elpida; Ischiropoulos, Harry

2009-01-01

While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged. Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death. These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle" that may be considered the underlying cause of neurodegenerative pathogenesis. PMID:19500376

The E3 ligase Mule protects the heart against oxidative stress and mitochondrial dysfunction through Myc-dependent inactivation of Pgc-1α and Pink1.

PubMed

Dadson, Keith; Hauck, Ludger; Hao, Zhenyue; Grothe, Daniela; Rao, Vivek; Mak, Tak W; Billia, Filio

2017-02-02

Cardiac homeostasis requires proper control of protein turnover. Protein degradation is principally controlled by the Ubiquitin-Proteasome System. Mule is an E3 ubiquitin ligase that regulates cellular growth, DNA repair and apoptosis to maintain normal tissue architecture. However, Mule's function in the heart has yet to be described. In a screen, we found reduced Mule expression in left ventricular samples from end-stage heart failure patients. Consequently, we generated conditional cardiac-specific Mule knockout (Mule  fl/fl(y) ;mcm) mice. Mule ablation in adult Mule  fl/fl(y) ;mcm mice prevented myocardial c-Myc polyubiquitination, leading to c-Myc accumulation and subsequent reduced expression of Pgc-1α, Pink1, and mitochondrial complex proteins. Furthermore, these mice developed spontaneous cardiac hypertrophy, left ventricular dysfunction, and early mortality. Co-deletion of Mule and c-Myc rescued this phenotype. Our data supports an indispensable role for Mule in cardiac homeostasis through the regulation of mitochondrial function via maintenance of Pgc-1α and Pink1 expression and persistent negative regulation of c-Myc.

Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function.

PubMed

Yang, Yang; Luo, Lan; Cai, Xueting; Fang, Yuan; Wang, Jiaqi; Chen, Gang; Yang, Jie; Zhou, Qian; Sun, Xiaoyan; Cheng, Xiaolan; Yan, Huaijiang; Lu, Wuguang; Hu, Chunping; Cao, Peng

2018-05-20

Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting toxicity associated with cancer chemotherapy. The efficacy of antioxidant administration in OIPN is debatable, as the promising preliminary results obtained with a number of antioxidants have not been confirmed in larger clinical trials. Besides its antioxidant activity, the transcription factor, nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2) plays a crucial role in the maintenance of mitochondrial homeostasis, and mitochondrial dysfunction is a key contributor to OIPN. Here, we have investigated the protective properties of Nrf2 in OIPN. Nrf2 -/- mice displayed severe mechanical allodynia and cold sensitivity and thus experienced increased peripheral nervous system injury compared to Nrf2 +/+ mice. Furthermore, Nrf2 knockout aggravated oxaliplatin-induced reactive oxygen species production, decreased the mitochondrial membrane potential, led to abnormal intracellular calcium levels, and induced cytochrome c-related apoptosis and overexpression of the TRP protein family. Sulforaphane-induced activation of the Nrf2 signaling pathway alleviated morphological alterations, mitochondrial dysfunction in dorsal root ganglion neurons, and nociceptive sensations in mice. Our findings reveal that Nrf2 may play a critical role in ameliorating OIPN, through protection of mitochondrial function by alleviating oxidative stress and inhibiting TRP protein family expression. This suggests that pharmacological or therapeutic activation of Nrf2 may be used to prevent or slow down the progression of OIPN. Copyright © 2018 Elsevier Inc. All rights reserved.

Genetic ablation of calcium-independent phospholipase A2gamma leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype.

PubMed

Mancuso, David J; Sims, Harold F; Han, Xianlin; Jenkins, Christopher M; Guan, Shao Ping; Yang, Kui; Moon, Sung Ho; Pietka, Terri; Abumrad, Nada A; Schlesinger, Paul H; Gross, Richard W

2007-11-30

Previously, we identified a novel calcium-independent phospholipase, designated calcium-independent phospholipase A(2) gamma (iPLA(2)gamma), which possesses dual mitochondrial and peroxisomal subcellular localization signals. To identify the roles of iPLA(2)gamma in cellular bioenergetics, we generated mice null for the iPLA(2)gamma gene by eliminating the active site of the enzyme through homologous recombination. Mice null for iPLA(2)gamma display multiple bioenergetic dysfunctional phenotypes, including 1) growth retardation, 2) cold intolerance, 3) reduced exercise endurance, 4) greatly increased mortality from cardiac stress after transverse aortic constriction, 5) abnormal mitochondrial function with a 65% decrease in ascorbate-induced Complex IV-mediated oxygen consumption, and 6) a reduction in myocardial cardiolipin content accompanied by an altered cardiolipin molecular species composition. We conclude that iPLA(2)gamma is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.

Role of Mitochondrial Homeostasis and Dynamics in Alzheimer’s Disease

PubMed Central

Selfridge, J. Eva; Lezi, E; Lu, Jianghua; Swerdlow, Russell H.

2012-01-01

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects a staggering percentage of the aging population and causes memory loss and cognitive decline. Mitochondrial abnormalities can be observed systemically and in brains of patients suffering from AD, and may account for part of the disease phenotype. In this review, we summarize some of the key findings that indicate mitochondrial dysfunction is present in AD-affected subjects, including cytochrome oxidase deficiency, endophenotype data, and altered mitochondrial morphology. Special attention is given to recently described perturbations in mitochondrial autophagy, fission-fusion dynamics, and biogenesis. We also briefly discuss how mitochondrial dysfunction may influence amyloidosis in Alzheimer’s disease, why mitochondria are a valid therapeutic target, and strategies for addressing AD-specific mitochondrial dysfunction. PMID:22266017

Reducing Mitochondrial ROS Improves Disease-related Pathology in a Mouse Model of Ataxia-telangiectasia

PubMed Central

D'Souza, Anthony D; Parish, Ian A; Krause, Diane S; Kaech, Susan M; Shadel, Gerald S

2013-01-01

The disease ataxia-telangiectasia (A-T) has no cure and few treatment options. It is caused by mutations in the ATM kinase, which functions in the DNA-damage response and redox sensing. In addition to severe cerebellar degeneration, A-T pathology includes cancer predisposition, sterility, immune system dysfunction, and bone marrow abnormalities. These latter phenotypes are recapitulated in the ATM null (ATM−/−) mouse model of the disease. Since oxidative stress and mitochondrial dysfunction are implicated in A-T, we determined whether reducing mitochondrial reactive oxygen species (ROS) via overexpression of catalase targeted to mitochondria (mCAT) alleviates A-T–related pathology in ATM−/− mice. We found that mCAT has many beneficial effects in this context, including reduced propensity to develop thymic lymphoma, improved bone marrow hematopoiesis and macrophage differentiation in vitro, and partial rescue of memory T-cell developmental defects. Our results suggest that positive effects observed on cancer development may be linked to mCAT reducing mitochondrial ROS, lactate production, and TORC1 signaling in transforming double-positive cells, whereas beneficial effects in memory T cells appear to be TORC1-independent. Altogether, this study provides proof-of-principle that reducing mitochondrial ROS production per se may be therapeutic for the disease, which may have advantages compared with more general antioxidant strategies. PMID:23011031

Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease

PubMed Central

2012-01-01

This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson's disease (PD). Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation, but as an integral part of this process, superoxides and other reactive oxygen species are also produced. Excessive free radical production contributes to oxidative stress. Cells have evolved to handle such stress via various endogenous anti-oxidant proteins. One such family of proteins is the mitochondrial uncoupling proteins (UCPs), which are anion carriers located in the mitochondrial inner membrane. There are five known homologues (UCP1 to 5), of which UCP4 and 5 are predominantly expressed in neural cells. In a series of previous publications, we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium (MPP+; toxic metabolite of MPTP) and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential, and reducing oxidative stress. We also showed how their expression can be influenced by nuclear factor kappa-B (NF-κB) signaling pathway specifically in UCP4. Furthermore, we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin (hormone produced by adipocytes) acting via UCP2 against MPP+-induced toxicity. There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD. Their expression, which can be induced, may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease. PMID:23210978

Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress

PubMed Central

Koncsos, Gábor; Varga, Zoltán V.; Boengler, Kerstin; Rohrbach, Susanne; Li, Ling; Schlüter, Klaus-Dieter; Schreckenberg, Rolf; Radovits, Tamás; Oláh, Attila; Mátyás, Csaba; Lux, Árpád; Al-Khrasani, Mahmoud; Komlódi, Tímea; Bukosza, Nóra; Máthé, Domokos; Deres, László; Barteková, Monika; Rajtík, Tomáš; Adameová, Adriana; Szigeti, Krisztián; Helyes, Zsuzsanna; Tretter, László; Pacher, Pál; Merkely, Béla; Schulz, Rainer; Ferdinandy, Péter

2016-01-01

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4. High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria. PMID:27521417

Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells.

PubMed

Song, Junna; Li, Jia; Hou, Fangjie; Wang, Xiaona; Liu, Baolin

2015-03-01

Endothelial dysfunction is tightly associated with cardiovascular complications in diabetic patients. This study aims to investigate the effects of mangiferin on the regulation of endothelial homeostasis under endoplasmic reticulum stress (ER stress) conditions. High glucose (25 mmol/L) exposure induced ER stress and promoted ROS production in endothelial cells. Mangiferin effectively inhibited ER stress-associated oxidative stress by attenuating IRE1α phosphorylation and reducing ROS production. In response to ER stress, thioredoxin-interacting protein (TXNIP) expression increased, followed by NLRP3 inflammasome activation and increased IL-1β secretion. Mangiferin treatment attenuated the expressions of TXNIP and NLRP3 and reduced IL-1β and IL-6 production, demonstrating its inhibitory effects on TXNIP/NLRP3 inflammasome activation. NLRP3 inflammasome activation is responsible for mitochondrial cell death. Mangiferin restored the loss of the mitochondrial membrane potential (Δψm) and inhibited caspase-3 activity, and thereby protected cells from high glucose-induced apoptosis. Moreover, mangiferin inhibited ET-1 secretion and restored the loss of NO production when cells were exposed to high glucose. Mangiferin enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished its beneficial effects, indicating the potential role of AMPK in its action. Our work showed the beneficial effects of mangiferin on the improvement of endothelial homeostasis and elucidated the molecular pathway through which mangiferin ameliorated endothelial dysfunction by inhibition of ER stress-associated TXNIP/NLRP3 inflammasome activation in endothelial cells. These findings demonstrated the beneficial effects of mangiferin on the regulation of endothelial homeostasis and indicated its potential application in the management of diabetic cardiovascular complications. Copyright © 2015 Elsevier Inc. All rights reserved.

Proton Magnetic Resonance Spectroscopy and MRI Reveal No Evidence for Brain Mitochondrial Dysfunction in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Corrigan, Neva M.; Shaw, Dennis. W. W.; Richards, Todd L.; Estes, Annette M.; Friedman, Seth D.; Petropoulos, Helen; Artru, Alan A.; Dager, Stephen R.

2012-01-01

Brain mitochondrial dysfunction has been proposed as an etiologic factor in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopic imaging ([superscript 1]HMRS) and MRI were used to assess for evidence of brain mitochondrial dysfunction in longitudinal samples of children with ASD or developmental delay (DD), and cross-sectionally…

Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications.

PubMed

Vernochet, Cecile; Damilano, Federico; Mourier, Arnaud; Bezy, Olivier; Mori, Marcelo A; Smyth, Graham; Rosenzweig, Anthony; Larsson, Nils-Göran; Kahn, C Ronald

2014-10-01

Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75-81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications. © FASEB.

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation*

PubMed Central

Agarwal, Swati; Yadav, Anuradha; Tiwari, Shashi Kant; Seth, Brashket; Chauhan, Lalit Kumar Singh; Khare, Puneet; Ray, Ratan Singh

2016-01-01

The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU- and β-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPA-mediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus. PMID:27252377

Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

PubMed

Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A

2016-09-01

Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function. Copyright © 2016 Elsevier Inc. All rights reserved.

Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

PubMed

Guo, Rui; Ren, Jun

2010-01-18

Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH). ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined. Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-). Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF. Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

Effects of Treating Old Rats with an Aqueous Agaricus blazei Extract on Oxidative and Functional Parameters of the Brain Tissue and Brain Mitochondria

PubMed Central

de Sá-Nakanishi, Anacharis B.; Soares, Andréia A.; de Oliveira, Andrea Luiza; Fernando Comar, Jurandir; Peralta, Rosane M.; Bracht, Adelar

2014-01-01

Dysfunction of the mitochondrial respiratory chain and increased oxidative stress is a striking phenomenon in the brain of aged individuals. For this reason there has been a constant search for drugs and natural products able to prevent or at least to mitigate these problems. In the present study the effects of an aqueous extract of Agaricus blazei, a medicinal mushroom, on the oxidative state and on the functionality of mitochondria from the brain of old rats (21 months) were conducted. The extract was administered intragastrically during 21 days at doses of 200 mg/kg. The administration of the A. blazei extract was protective to the brain of old rats against oxidative stress by decreasing the lipid peroxidation levels and the reactive oxygen species content and by increasing the nonenzymic and enzymic antioxidant capacities. Administration of the A. blazei extract also increased the activity of several mitochondrial respiratory enzymes and, depending on the substrate, the mitochondrial coupled respiration. PMID:24876914

Effects of treating old rats with an aqueous Agaricus blazei extract on oxidative and functional parameters of the brain tissue and brain mitochondria.

PubMed

de Sá-Nakanishi, Anacharis B; Soares, Andréia A; de Oliveira, Andrea Luiza; Comar, Jurandir Fernando; Peralta, Rosane M; Bracht, Adelar

2014-01-01

Dysfunction of the mitochondrial respiratory chain and increased oxidative stress is a striking phenomenon in the brain of aged individuals. For this reason there has been a constant search for drugs and natural products able to prevent or at least to mitigate these problems. In the present study the effects of an aqueous extract of Agaricus blazei, a medicinal mushroom, on the oxidative state and on the functionality of mitochondria from the brain of old rats (21 months) were conducted. The extract was administered intragastrically during 21 days at doses of 200 mg/kg. The administration of the A. blazei extract was protective to the brain of old rats against oxidative stress by decreasing the lipid peroxidation levels and the reactive oxygen species content and by increasing the nonenzymic and enzymic antioxidant capacities. Administration of the A. blazei extract also increased the activity of several mitochondrial respiratory enzymes and, depending on the substrate, the mitochondrial coupled respiration.

2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells.

PubMed

Bernhart, Eva; Kogelnik, Nora; Prasch, Jürgen; Gottschalk, Benjamin; Goeritzer, Madeleine; Depaoli, Maria Rosa; Reicher, Helga; Nusshold, Christoph; Plastira, Ioanna; Hammer, Astrid; Fauler, Günter; Malli, Roland; Graier, Wolfgang F; Malle, Ernst; Sattler, Wolfgang

2018-05-01

Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H 2 O 2 -chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA). In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) that form the morphological basis of the BBB. To follow subcellular trafficking of 2-ClHA we synthesized a 'clickable' alkyne derivative (2-ClHyA) that phenocopied the biological activity of the parent compound. Confocal and superresolution structured illumination microscopy revealed accumulation of 2-ClHyA in the endoplasmic reticulum (ER) and mitochondria of human BMVEC (hCMEC/D3 cell line). 2-ClHA and its alkyne analogue interfered with protein palmitoylation, induced ER-stress markers, reduced the ER ATP content, and activated transcription and secretion of interleukin (IL)-6 as well as IL-8. 2-ClHA disrupted the mitochondrial membrane potential and induced procaspase-3 and PARP cleavage. The protein kinase R-like ER kinase (PERK) inhibitor GSK2606414 suppressed 2-ClHA-mediated activating transcription factor 4 synthesis and IL-6/8 secretion, but showed no effect on endothelial barrier dysfunction and cleavage of procaspase-3. Our data indicate that 2-ClHA induces potent lipotoxic responses in brain endothelial cells and could have implications in inflammation-induced BBB dysfunction. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.

PubMed

Ehmke, Nadja; Graul-Neumann, Luitgard; Smorag, Lukasz; Koenig, Rainer; Segebrecht, Lara; Magoulas, Pilar; Scaglia, Fernando; Kilic, Esra; Hennig, Anna F; Adolphs, Nicolai; Saha, Namrata; Fauler, Beatrix; Kalscheuer, Vera M; Hennig, Friederike; Altmüller, Janine; Netzer, Christian; Thiele, Holger; Nürnberg, Peter; Yigit, Gökhan; Jäger, Marten; Hecht, Jochen; Krüger, Ulrike; Mielke, Thorsten; Krawitz, Peter M; Horn, Denise; Schuelke, Markus; Mundlos, Stefan; Bacino, Carlos A; Bonnen, Penelope E; Wollnik, Bernd; Fischer-Zirnsak, Björn; Kornak, Uwe

2017-11-02

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/P i carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H 2 O 2 ). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H 2 O 2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/P i transport to the development of skeletal and connective tissue. Copyright © 2017 American Society of Human Genetics. All rights reserved.

Ginsenoside Rg3 attenuates sepsis-induced injury and mitochondrial dysfunction in liver via AMPK-mediated autophagy flux.

PubMed

Xing, Wei; Yang, Lei; Peng, Yue; Wang, Qianlu; Gao, Min; Yang, Mingshi; Xiao, Xianzhong

2017-08-31

Sepsis-led mitochondrial dysfunction has become a critical pathophysiological procedure in sepsis. Since ginsenosides have been applied in the treatment of mitochondrial dysfunction, ginsenoside Rg3 was employed to study its effects on the mitochondrial dysfunction induced by sepsis. The apoptosis rate, oxygen consumption rate (OCR), reactive oxygen species (ROS), antioxidant glutathione (GSH) pools, and mitochondrial transmembrane potential (MTP) were determined in LPS-induced sepsis hepatocytes treated with different concentrations of Rg3. Then, the protein expression levels of mitochondrial biogenesis related transcription factors, autophagy-related proteins, and AMP-activated protein kinase (AMPK) signal pathway related proteins were determined by Western blotting in both in vitro and in vivo sepsis models. Rg3 shows functions of promotion of OCR, attenuation of ROS, and maintenance of GSH pools, and its conjugating activity in the in vitro sepsis models. Rg3-treated cells were observed to have a higher MTP value compared with the LPS only induced cells. Moreover, Rg3 treatment can inhibit mitochondrial dysfunction via increasing the protein expression levels of mitochondrial biogenesis related transcription factors. Rg3 treatment has the function of inhibitor of apoptosis of human primary hepatocytes, and Rg3 can up-regulate the autophagy-related proteins and activate AMPK signal pathway in sepsis models. Meanwhile, the mitochondrial protective function exerted by Rg3 decreased after the autophagy inhibitors or AMPK inhibitor treatment in LPS-induced human primary hepatocytes. Rg3 can improve mitochondrial dysfunction by regulating autophagy in mitochondria via activating the AMPK signal pathway, thus protecting cell and organ injuries caused by sepsis. © 2017 The Author(s).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, Hye Jin

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor within the Per-Arnt-Sim (PAS) domain superfamily. Exposure to the most potent AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is associated with various pathological effects including metabolic syndrome. While research over the last several years has demonstrated a role for oxidative stress and metabolic dysfunction in AHR-dependent TCDD-induced toxicity, the role of the mitochondria in this process has not been fully explored. Our previous research suggested that a portion of the cellular pool of AHR could be found in the mitochondria (mitoAHR). Using a protease protection assay with digitonin extraction, we have now shownmore » that this mitoAHR is localized to the inter-membrane space (IMS) of the organelle. TCDD exposure induced a degradation of mitoAHR similar to that of cytosolic AHR. Furthermore, siRNA-mediated knockdown revealed that translocase of outer-mitochondrial membrane 20 (TOMM20) was involved in the import of AHR into the mitochondria. In addition, TCDD altered cellular respiration in an AHR-dependent manner to maintain respiratory efficiency as measured by oxygen consumption rate (OCR). Stable isotope labeling by amino acids in cell culture (SILAC) identified a battery of proteins within the mitochondrial proteome influenced by TCDD in an AHR-dependent manner. Among these, 17 proteins with fold changes ≥ 2 are associated with various metabolic pathways, suggesting a role of mitochondrial retrograde signaling in TCDD-mediated pathologies. Collectively, these studies suggest that mitoAHR is localized to the IMS and AHR-dependent TCDD-induced toxicity, including metabolic dysfunction, wasting syndrome, and hepatic steatosis, involves mitochondrial dysfunction. - Highlights: • The mitoAHR is localized in the mitochondrial intermembrane space. • TOMM20 participates in mitoAHR translocation. • AHR contributes to the maintenance of respiratory control ratio following TCDD exposure. • TCDD-induced AHR-dependent changes in the mitochondrial proteome are identified.« less

Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25–35 peptide-injected mice, a nontransgenic Alzheimer’s disease model

PubMed Central

Lahmy, Valentine; Long, Romain; Morin, Didier; Villard, Vanessa; Maurice, Tangui

2015-01-01

Alzheimer’s disease (AD), the most prevalent dementia in the elderly, is characterized by progressive synaptic and neuronal loss. Mitochondrial dysfunctions have been consistently reported as an early event in AD and appear before Aβ deposition and memory decline. In order to define a new neuroprotectant strategy in AD targeting mitochondrial alterations, we develop tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (ANAVEX2-73, AE37), a mixed muscarinic receptor ligand and a sigma-1 receptor (σ1R) agonist. We previously reported that ANAVEX2-73 shows anti-amnesic and neuroprotective activities in mice injected intracerebroventricular (ICV) with oligomeric amyloid-β25–35 peptide (Aβ25–35). The σ1R is present at mitochondria-associated endoplasmic reticulum (ER) membranes, where it acts as a sensor/modulator of ER stress responses and local Ca2+ exchanges with the mitochondria. We therefore evaluated the effect of ANAVEX2-73 and PRE-084, a reference σ1R agonist, on preservation of mitochondrial integrity in Aβ25–35-injected mice. In isolated mitochondria from hippocampus preparations of Aβ25–35 injected animals, we measured respiration rates, complex activities, lipid peroxidation, Bax/Bcl-2 ratios and cytochrome c release into the cytosol. Five days after Aβ25–35 injection, mitochondrial respiration in mouse hippocampus was altered. ANAVEX2-73 (0.01–1 mg/kg IP) restored normal respiration and PRE-084 (0.5–1 mg/kg IP) increased respiration rates. Both compounds prevented Aβ25–35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, all indicators of increased toxicity. ANAVEX2-73 and PRE-084 efficiently prevented the mitochondrial respiratory dysfunction and resulting oxidative stress and apoptosis. The σ1R, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD. PMID:25653589

Mitochondrial Modulation by Epigallocatechin 3-Gallate Ameliorates Cisplatin Induced Renal Injury through Decreasing Oxidative/Nitrative Stress, Inflammation and NF-kB in Mice

PubMed Central

Wang, Xueping; Wang, Ping; Fu, Guanghou; Meng, Hongzhou; Wang, Yimin; Jin, Baiye

2015-01-01

Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for cisplatin. PMID:25875356

Aminoethyl nitrate – the novel super nitrate?

PubMed Central

Bauersachs, Johann

2009-01-01

Long-term use of most organic nitrates is limited by development of tolerance, induction of oxidative stress and endothelial dysfunction. In this issue of the BJP, Schuhmacher et al. characterized a novel class of organic nitrates with amino moieties (aminoalkyl nitrates). Aminoethyl nitrate was identified as a novel organic mononitrate with high potency but devoid of induction of mitochondrial oxidative stress. Cross-tolerance to nitroglycerin or the endothelium-dependent agonist acetylcholine after in vivo treatment was not observed. Like all nitrates, aminoethyl nitrate induced vasorelaxation by activation of soluble guanylate cyclase. Thus, in contrast to the prevailing view, high potency in an organic nitrate is not necessarily accompanied by induction of oxidative stress or endothelial dysfunction. This work from Daiber's group is an important step forward in the understanding of nitrate bioactivation, tolerance phenomena and towards the development of better organic nitrates for clinical use. PMID:19732062

Hypertrophic Cardiomyopathy: A Vicious Cycle Triggered by Sarcomere Mutations and Secondary Disease Hits.

PubMed

Wijnker, Paul J M; Sequeira, Vasco; Kuster, Diederik W D; Velden, Jolanda van der

2018-04-11

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction, and myocardial disarray. Disease onset occurs between 20 and 50 years of age, thus affecting patients in the prime of their life. HCM is caused by mutations in sarcomere proteins, the contractile building blocks of the heart. Despite increased knowledge of causal mutations, the exact path from genetic defect leading to cardiomyopathy is complex and involves additional disease hits. Recent Advances: Laboratory-based studies indicate that HCM development not only depends on the primary sarcomere impairment caused by the mutation but also on secondary disease-related alterations in the heart. Here we propose a vicious mutation-induced disease cycle, in which a mutation-induced energy depletion alters cellular metabolism with increased mitochondrial work, which triggers secondary disease modifiers that will worsen disease and ultimately lead to end-stage HCM. Evidence shows excessive cellular reactive oxygen species (ROS) in HCM patients and HCM animal models. Oxidative stress markers are increased in the heart (oxidized proteins, DNA, and lipids) and serum of HCM patients. In addition, increased mitochondrial ROS production and changes in endogenous antioxidants are reported in HCM. Mutant sarcomeric protein may drive excessive levels of cardiac ROS via changes in cardiac efficiency and metabolism, mitochondrial activation and/or dysfunction, impaired protein quality control, and microvascular dysfunction. Interventions restoring metabolism, mitochondrial function, and improved ROS balance may be promising therapeutic approaches. We discuss the effects of current HCM pharmacological therapies and potential future therapies to prevent and reverse HCM. Antioxid. Redox Signal. 00, 000-000.

Riboflavin Responsive Mitochondrial Dysfunction in Neurodegenerative Diseases

PubMed Central

Udhayabanu, Tamilarasan; Manole, Andreea; Rajeshwari, Mohan; Varalakshmi, Perumal; Houlden, Henry; Ashokkumar, Balasubramaniem

2017-01-01

Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment. PMID:28475111

Regulation of mitochondrial bioenergetics by the non-canonical roles of mitochondrial dynamics proteins in the heart.

PubMed

Wang, Wang; Fernandez-Sanz, Celia; Sheu, Shey-Shing

2018-05-01

Recent advancement in mitochondrial research has significantly extended our knowledge on the role and regulation of mitochondria in health and disease. One important breakthrough is the delineation of how mitochondrial morphological changes, termed mitochondrial dynamics, are coupled to the bioenergetics and signaling functions of mitochondria. In general, it is believed that fusion leads to an increased mitochondrial respiration efficiency and resistance to stress-induced dysfunction while fission does the contrary. This concept seems not applicable to adult cardiomyocytes. The mitochondria in adult cardiomyocytes exhibit fragmented morphology (tilted towards fission) and show less networking and movement as compared to other cell types. However, being the most energy-demanding cells, cardiomyocytes in the adult heart possess vast number of mitochondria, high level of energy flow, and abundant mitochondrial dynamics proteins. This apparent discrepancy could be explained by recently identified new functions of the mitochondrial dynamics proteins. These "non-canonical" roles of mitochondrial dynamics proteins range from controlling inter-organelle communication to regulating cell viability and survival under metabolic stresses. Here, we summarize the newly identified non-canonical roles of mitochondrial dynamics proteins. We focus on how these fission and fusion independent roles of dynamics proteins regulate mitochondrial bioenergetics. We also discuss potential molecular mechanisms, unique intracellular location, and the cardiovascular disease relevance of these non-canonical roles of the dynamics proteins. We propose that future studies are warranted to differentiate the canonical and non-canonical roles of dynamics proteins and to identify new approaches for the treatment of heart diseases. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. Copyright © 2017 Elsevier B.V. All rights reserved.

Mitochondrial Metabolism in Aging Heart

PubMed Central

Lesnefsky, Edward J.; Chen, Qun; Hoppel, Charles L.

2016-01-01

Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area there is an approximate 50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction. PMID:27174952

AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress.

PubMed

Koczor, Christopher A; Jiao, Zhe; Fields, Earl; Russ, Rodney; Ludaway, Tomika; Lewis, William

2015-10-01

Mitochondrial dysfunction causes oxidative stress and cardiomyopathy. Oxidative stress also is a side effect of dideoxynucleoside antiretrovirals (NRTI) and is observed in NRTI-induced cardiomyopathy. We show here that treatment with the NRTI AZT {1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione} modulates cardiac gene expression epigenetically through production of mitochondrially derived reactive oxygen species. Transgenic mice with ubiquitous expression of mitochondrially targeted catalase (MCAT) and C57Bl/6 wild-type mice littermates (WT) were administered AZT (0.22 mg/day po, 35 days), and cardiac DNA and mRNA were isolated. In AZT-treated WT, 95 cardiac genes were differentially expressed compared with vehicle-treated WTs. When MCAT mice were treated with AZT, each of those 95 genes reverted toward the expression of vehicle-treated WTs. In AZT-treated WT hearts, Mthfr [5,10-methylenetetrahydrofolate reductase; a critical enzyme in synthesis of methionine cycle intermediates including S-adenosylmethionine (SAM)], was overexpressed. Steady-state abundance of SAM in cardiac extracts from AZT-treated MCAT mice increased 60% above that of vehicle-treated MCAT. No such change occurred in WT. AZT caused hypermethylation (47%) and hypomethylation (53%) of differentially methylated DNA regions in WT cardiac DNA. AZT-treated MCAT heart DNA exhibited greater hypermethylation (91%) and less hypomethylation (9%) compared with vehicle-treated MCAT controls. The gene encoding protein kinase C-α displayed multifocal epigenetic regulation caused by oxidative stress. Results show that mitochondrially derived oxidative stress in the heart hinders cardiac DNA methylation, alters steady-state abundance of SAM, alters cardiac gene expression, and promotes characteristic pathophysiological changes of cardiomyopathy. This mechanism for NRTI toxicity offers insight into long-term side effects from these commonly used antiviral agents. Copyright © 2015 the American Physiological Society.

Ablation of PGC1 beta prevents mTOR dependent endoplasmic reticulum stress response

PubMed Central

Camacho, Alberto; Rodriguez-Cuenca, Sergio; Blount, Margaret; Prieur, Xavier; Barbarroja, Nuria; Fuller, Maria; Hardingham, Giles E.; Vidal-Puig, Antonio

2012-01-01

Mitochondria dysfunction contributes to the pathophysiology of obesity, diabetes, neurodegeneration and ageing. The peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) coordinates mitochondrial biogenesis and function as well as fatty acid metabolism. It has been suggested that endoplasmic reticulum (ER) stress may be one of the mechanisms linking mitochondrial dysfunction and these pathologies. Here we investigate whether PGC-1β ablation affects the ER stress response induced by specific nutritional and pharmacological challenges in the CNS. By using flow cytometry, western blot, real time PCR and several pharmacological and nutritional interventions in PGC-1β knock out and WT mice, we confirmed that PGC-1β coordinates mitochondria function in brain and reported for the first time that a) ablation of PGC-1β is associated with constitutive activation of mTORC1 pathway associated with increased basal GRP78 protein levels in hypothalamus and cortex of animals fed chow diet; and b) in animals fed chronically with high fat diet (HFD) or high protein diet (HPD), we observed a failure to appropriately induce ER stress response in the absence of PGC-1β, associated with an increase in mTOR pathway phosphorylation. This contrasted with the appropriate upregulation of ER stress response observed in wild type littermates. Additionally, inefficient in vitro induction of ER stress by thapsigargin seems result in apoptotic neuronal cell death in PGC-1β KO. Our data indicate that PGC-1β is required for a neuronal ER response to nutritional stress imposed by HFD and HPD diets and that genetic ablation of PGC-1β might increase the susceptibility to neuronal damage and cell death. PMID:22771762

Mitochondrial dysfunction, oxidative stress and apoptosis revealed by proteomic and transcriptomic analyses of the striata in two mouse models of Parkinson’s disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chin, Mark H.; Qian, Weijun; Wang, Haixing

2008-02-10

The molecular mechanisms underlying the changes in the nigrostriatal pathway in Parkinson disease (PD) are not completely understood. Here we use mass spectrometry and microarrays to study the proteomic and transcriptomic changes in the striatum of two mouse models of PD, induced by the distinct neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Proteomic analyses resulted in the identification and relative quantification of 912 proteins with two or more unique peptides and 85 proteins with significant abundance changes following neurotoxin treatment. Similarly, microarray analyses revealed 181 genes with significant changes in mRNA following neurotoxin treatment. The combined protein and gene list providesmore » a clearer picture of the potential mechanisms underlying neurodegeneration observed in PD. Functional analysis of this combined list revealed a number of significant categories, including mitochondrial dysfunction, oxidative stress response and apoptosis. Additionally, codon usage and miRNAs may play an important role in translational control in the striatum. These results constitute one of the largest datasets integrating protein and transcript changes for these neurotoxin models with many similar endpoint phenotypes but distinct mechanisms.« less

MIDAS/GPP34, a nuclear gene product, regulates total mitochondrial mass in response to mitochondrial dysfunction.

PubMed

Nakashima-Kamimura, Naomi; Asoh, Sadamitsu; Ishibashi, Yoshitomo; Mukai, Yuri; Shidara, Yujiro; Oda, Hideaki; Munakata, Kae; Goto, Yu-Ichi; Ohta, Shigeo

2005-11-15

To investigate the regulatory system in mitochondrial biogenesis involving crosstalk between the mitochondria and nucleus, we found a factor named MIDAS (mitochondrial DNA absence sensitive factor) whose expression was enhanced by the absence of mitochondrial DNA (mtDNA). In patients with mitochondrial diseases, MIDAS expression was increased only in dysfunctional muscle fibers. A majority of MIDAS localized to mitochondria with a small fraction in the Golgi apparatus in HeLa cells. To investigate the function of MIDAS, we stably transfected HeLa cells with an expression vector carrying MIDAS cDNA or siRNA. Cells expressing the MIDAS protein and the siRNA constitutively showed an increase and decrease in the total mass of mitochondria, respectively, accompanying the regulation of a mitochondria-specific phospholipid, cardiolipin. In contrast, amounts of the mitochondrial DNA, RNA and proteins did not depend upon MIDAS. Thus, MIDAS is involved in the regulation of mitochondrial lipids, leading to increases of total mitochondrial mass in response to mitochondrial dysfunction.

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1-Mediated Protein Kinase A/Uncoupling Protein 2 Pathway.

PubMed

Xiong, Shiqiang; Wang, Peijian; Ma, Liqun; Gao, Peng; Gong, Liuping; Li, Li; Li, Qiang; Sun, Fang; Zhou, Xunmei; He, Hongbo; Chen, Jing; Yan, Zhencheng; Liu, Daoyan; Zhu, Zhiming

2016-02-01

Coronary heart disease arising from atherosclerosis is a leading cause of cardiogenic death worldwide. Mitochondria are the principal source of reactive oxygen species (ROS), and defective oxidative phosphorylation by the mitochondrial respiratory chain contributes to ROS generation. Uncoupling protein 2 (UCP2), an adaptive antioxidant defense factor, protects against mitochondrial ROS-induced endothelial dysfunction in atherosclerosis. The activation of transient receptor potential vanilloid 1 (TRPV1) attenuates vascular dysfunction. Therefore, whether TRPV1 activation antagonizes coronary lesions by alleviating endothelial mitochondrial dysfunction and enhancing the activity of the protein kinase A/UCP2 pathway warrants examination. ApoE(-/-), ApoE(-/-)/TRPV1(-/-), and ApoE(-/-)/UCP2(-/-) mice were fed standard chow, a high-fat diet (HFD), or the HFD plus 0.01% capsaicin. HFD intake profoundly impaired coronary vasodilatation and myocardial perfusion and shortened the survival duration of ApoE(-/-) mice. TRPV1 or UCP2 deficiency exacerbated HFD-induced coronary dysfunction and was associated with increased ROS generation and reduced nitric oxide production in the endothelium. The activation of TRPV1 by capsaicin upregulated UCP2 expression via protein kinase A phosphorylation, thereby alleviating endothelial mitochondrial dysfunction and inhibiting mitochondrial ROS generation. In vivo, dietary capsaicin supplementation enhanced coronary relaxation and prolonged the survival duration of HFD-fed ApoE(-/-) mice. These effects were not observed in ApoE(-/-) mice lacking the TRPV1 or UCP2 gene. The upregulation of protein kinase A /UCP2 via TRPV1 activation ameliorates coronary dysfunction and prolongs the lifespan of atherosclerotic mice by ameliorating endothelial mitochondrial dysfunction. Dietary capsaicin supplementation may represent a promising intervention for the primary prevention of coronary heart disease. © 2015 American Heart Association, Inc.

Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection—The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress

PubMed Central

Quryshi, Nabeel; Norwood Toro, Laura E.; Ait-Aissa, Karima; Kong, Amanda; Beyer, Andreas M.

2018-01-01

Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage (mtDNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects. Telomerase, originally discovered to promote cellular proliferation, has recently emerged as a potential mechanism to counteract mitochondrial defects and restore healthy mitochondrial vascular phenotypes. This review details mechanisms currently used to assess cardiovascular damage, such as C-reactive protein (CRP) and troponin levels, while also unearthing recently researched biomarkers, including circulating mtDNA, telomere length and telomerase activity. Further, we explore a potential role of telomerase in the mitigation of mitochondrial reactive oxygen species and maintenance of mtDNA integrity. Telomerase activity presents a promising indicator for the early detection and treatment of chemotherapy-derived cardiac damage. PMID:29534446

Mitochondrial tRNA cleavage by tRNA-targeting ribonuclease causes mitochondrial dysfunction observed in mitochondrial disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogawa, Tetsuhiro, E-mail: atetsu@mail.ecc.u-tokyo.ac.jp; Shimizu, Ayano; Takahashi, Kazutoshi

2014-08-15

Highlights: • MTS-tagged ribonuclease was translocated successfully to the mitochondrial matrix. • MTS-tagged ribonuclease cleaved mt tRNA and reduced COX activity. • Easy and reproducible method of inducing mt tRNA dysfunction. - Abstract: Mitochondrial DNA (mtDNA) is a genome possessed by mitochondria. Since reactive oxygen species (ROS) are generated during aerobic respiration in mitochondria, mtDNA is commonly exposed to the risk of DNA damage. Mitochondrial disease is caused by mitochondrial dysfunction, and mutations or deletions on mitochondrial tRNA (mt tRNA) genes are often observed in mtDNA of patients with the disease. Hence, the correlation between mt tRNA activity and mitochondrialmore » dysfunction has been assessed. Then, cybrid cells, which are constructed by the fusion of an enucleated cell harboring altered mtDNA with a ρ{sup 0} cell, have long been used for the analysis due to difficulty in mtDNA manipulation. Here, we propose a new method that involves mt tRNA cleavage by a bacterial tRNA-specific ribonuclease. The ribonuclease tagged with a mitochondrial-targeting sequence (MTS) was successfully translocated to the mitochondrial matrix. Additionally, mt tRNA cleavage, which resulted in the decrease of cytochrome c oxidase (COX) activity, was observed.« less

Cellular determinants involving mitochondrial dysfunction, oxidative stress and apoptosis correlate with the synergic cytotoxicity of epigallocatechin-3-gallate and menadione in human leukemia Jurkat T cells.

PubMed

Tofolean, Ioana Teodora; Ganea, Constanta; Ionescu, Diana; Filippi, Alexandru; Garaiman, Alexandru; Goicea, Alexandru; Gaman, Mihnea-Alexandru; Dimancea, Alexandru; Baran, Irina

2016-01-01

We have investigated the growth-suppressive action of epigallocatechin-3-gallate (EGCG) on human leukemia Jurkat T cells. Results show a strong correlation between the dose-dependent reduction of clonogenic survival following acute EGCG treatments and the EGCG-induced decline of the mitochondrial level of Ca(2+). The cell killing ability of EGCG was synergistically enhanced by menadione. In addition, the cytotoxic effect of EGCG applied alone or in combination with menadione was accompanied by apoptosis induction. We also observed that in acute treatments EGCG displays strong antioxidant properties in the intracellular milieu, but concurrently triggers some oxidative stress generating mechanisms that can fully develop on a longer timescale. In parallel, EGCG dose-dependently induced mitochondrial depolarization during exposure, but this condition was subsequently reversed to a persistent hyperpolarized mitochondrial state that was dependent on the activity of respiratory Complex I. Fluorimetric measurements suggest that EGCG is a mitochondrial Complex III inhibitor and indicate that EGCG evokes a specific cellular fluorescence with emission at 400nm and two main excitation bands (at 330nm and 350nm) that may originate from a mitochondrial supercomplex containing dimeric Complex III and dimeric ATP-synthase, and therefore could provide a valuable means to characterize the functional properties of the respiratory chain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension.

PubMed

Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S; Grant, Maria B; Mocco, J; Raizada, Mohan K

2012-11-01

Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O(2)(-·), intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Binukumar, BK; Gupta, Nidhi; Bal, Amanjit

Numerous epidemiological studies have shown an association between pesticide exposure and increased risk of developing Parkinson's diseases. Oxidative stress generated as a result of mitochondrial dysfunction has been implicated as an important factor in the etiology of Parkinson's disease. Previously, we reported that chronic dichlorvos exposure causes mitochondrial impairments and nigrostriatal neuronal death in rats. The present study was designed to test whether Coenzyme Q{sub 10} (CoQ{sub 10}) administration has any neuroprotective effect against dichlorvos mediated nigrostriatal neuronal death, {alpha}-synuclein aggregation, and motor dysfunction. Male albino rats were administered dichlorvos by subcutaneous injection at a dose of 2.5 mg/kg bodymore » weight over a period of 12 weeks. Results obtained there after showed that dichlorvos exposure leads to enhanced mitochondrial ROS production, {alpha}-synuclein aggregation, decreased dopamine and its metabolite levels resulting in nigrostriatal neurodegeneration. Pretreatment by Coenzyme Q{sub 10} (4.5 mg/kg ip for 12 weeks) to dichlorvos treated animals significantly attenuated the extent of nigrostriatal neuronal damage, in terms of decreased ROS production, increased dopamine and its metabolite levels, and restoration of motor dysfunction when compared to dichlorvos treated animals. Thus, the present study shows that Coenzyme Q{sub 10} administration may attenuate dichlorvos induced nigrostriatal neurodegeneration, {alpha}-synuclein aggregation and motor dysfunction by virtue of its antioxidant action. - Highlights: > CoQ{sub 10} administration attenuates dichlorvos induced nigrostriatal neurodegenaration. > CoQ{sub 10} pre treatment leads to preservation of TH-IR neurons. > CoQ{sub 10} may decrease oxidative damage and {alpha}-synuclin aggregation. > CoQ{sub 10} treatment enhances motor function and protects rats from catalepsy.« less

Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milatovic, Dejan; Zaja-Milatovic, Snjezana; Gupta, Ramesh C.

2009-10-15

Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterationsmore » in biomarkers of oxidative damage, F{sub 2}-isoprostanes (F{sub 2}-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 {mu}M Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E{sub 2} (PGE{sub 2}). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F{sub 2}-IsoPs and PGE{sub 2} in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.« less

Transcranial near-infrared photobiomodulation attenuates memory impairment and hippocampal oxidative stress in sleep-deprived mice.

PubMed

Salehpour, Farzad; Farajdokht, Fereshteh; Erfani, Marjan; Sadigh-Eteghad, Saeed; Shotorbani, Siamak Sandoghchian; Hamblin, Michael R; Karimi, Pouran; Rasta, Seyed Hossein; Mahmoudi, Javad

2018-03-01

Sleep deprivation (SD) causes oxidative stress in the hippocampus and subsequent memory impairment. In this study, the effect of near-infrared (NIR) photobiomodulation (PBM) on learning and memory impairment induced by acute SD was investigated. The mice were subjected to an acute SD protocol for 72 h. Simultaneously, NIR PBM using a laser at 810 nm was delivered (once a day for 3 days) transcranially to the head to affect the entire brain of mice. The Barnes maze and the What-Where-Which task were used to assess spatial and episodic-like memories. The hippocampal levels of antioxidant enzymes and oxidative stress biomarkers were evaluated. The results showed that NIR PBM prevented cognitive impairment induced by SD. Moreover, NIR PBM therapy enhanced the antioxidant status and increased mitochondrial activity in the hippocampus of SD mice. Our findings revealed that hippocampus-related mitochondrial damage and extensive oxidative stress contribute to the occurrence of memory impairment. In contrast, NIR PBM reduced hippocampal oxidative damage, supporting the ability of 810 nm laser light to improve the antioxidant defense system and maintain mitochondrial survival. This confirms that non-invasive transcranial NIR PBM therapy ameliorates hippocampal dysfunction, which is reflected in enhanced memory function. Copyright © 2018 Elsevier B.V. All rights reserved.

Resveratrol Induces Cancer Cell Apoptosis through MiR-326/PKM2-Mediated ER Stress and Mitochondrial Fission.

PubMed

Wu, Haili; Wang, Yingying; Wu, Changxin; Yang, Peng; Li, Hanqing; Li, Zhuoyu

2016-12-14

Resveratrol (Res), a natural phytoalexin found in a variety of plants, has significant antitumor activity. Pyruvate kinase M2 (PKM2) has abnormally high expression in various tumor cells, and it has been implicated in the survival of tumors. However, whether and how Res inhibits PKM2 expression is poorly understood. In the present study, we found that treatment with Res inhibited cell proliferation and induced cell apoptosis. The IC 50 values of Res against DLD1, HeLa, and MCF-7 cells were 75 ± 4.54, 50 ± 3.65, and 50 ± 3.32 μM, respectively. To elucidate mechanisms underlying its antitumor activities, serial experiments were performed. Results showed that reduction of PKM2 expression in tumor cells by Res treatment increased the expression of ER stress and mitochondrial fission proteins but reduced cell viability and the levels of fusion proteins. These phenomena were reversed by artificial overexpression of PKM2. Quantitative analyses showed that the expression of microRNA-326 (miR-326) was increased upon Res treatment. Treatment with the miR-326 mimic reduced PKM2 expression, promoting recovery from ER stress and mitochondrial fission. Overall, these results demonstrate that miR-326/PKM2-mediated ER stress and mitochondrial dysfunction participate in apoptosis induced by Res. These results provide novel insight into the molecular mechanisms by which Res suppresses tumors and further support for the use of Res as an antitumor drug.

Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin

PubMed Central

do Carmo, Jussara M.; Hosler, Jonathan P.; Hall, John E.

2015-01-01

We investigated obesity-induced changes in kidney lipid accumulation, mitochondrial function, and endoplasmic reticulum (ER) stress in the absence of hypertension, and the potential role of leptin in modulating these changes. We compared two normotensive genetic mouse models of obesity, leptin-deficient ob/ob mice and hyperleptinemic melanocortin-4 receptor-deficient mice (LoxTB MC4R−/−), with their respective lean controls. Compared with controls, ob/ob and LoxTB MC4R−/− mice exhibit significant albuminuria, increased creatinine clearance, and high renal triglyceride content. Renal ATP levels were decreased in both obesity models, and mitochondria isolated from both models showed alterations that would lower mitochondrial ATP production. Mitochondria from hyperleptinemic LoxTB MC4R−/− mice kidneys respired NADH-generating substrates (including palmitate) at lower rates due to an apparent decrease in complex I activity, and these mitochondria showed oxidative damage. Kidney mitochondria of leptin-deficient ob/ob mice showed normal rates of respiration with no evidence of oxidative damage, but electron transfer was partially uncoupled from ATP synthesis. A fourfold induction of C/EBP homologous protein (CHOP) expression indicated induction of ER stress in kidneys of hyperleptinemic LoxTB MC4R−/− mice. In contrast, ER stress was not induced in kidneys of leptin-deficient ob/ob mice. Our findings show that obesity, in the absence of hypertension, is associated with renal dysfunction in mice but not with major renal injury. Alterations to mitochondria that lower cellular ATP levels may be involved in obesity-induced renal injury. The type and severity of mitochondrial and ER dysfunction differs depending upon the presence or absence of leptin. PMID:26290368

MitoQ--a mitochondria-targeted antioxidant.

PubMed

Tauskela, Joseph S

2007-06-01

MitoQ is an orally active antioxidant that has the ability to target mitochondrial dysfunction. The agent is currently under development by Antipodean Pharmaceuticals Inc in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection. MitoQ has demonstrated encouraging preclinical results in numerous studies in isolated mitochondria, cells and tissues undergoing oxidative stress and apoptotic death. MitoQ aims to not only mimic the role of the endogenous mitochondrial antioxidant coenzyme Q10 (CoQ10), but also to augment substantially the antioxidant capacity of CoQ to supraphysiological levels in a mitochondrial membrane potential-dependent manner. MitoQ represents the first foray into the clinic in an attempt to deliver an antioxidant to an intracellular region that is responsible for the formation of increased levels of potentially deleterious reactive oxygen species. Results from the clinical trials with MitoQ will have important repercussions on the relevance of a mitochondrial-targeted approach.

Isocitrate protects DJ-1 null dopaminergic cells from oxidative stress through NADP+-dependent isocitrate dehydrogenase (IDH)

PubMed Central

Kim, Eun Young; Kim, Hyunjin; Lee, Yoonjeong; Min, Boram; Son, Jin H.; Park, Hwan Tae; Chung, Jongkyeong

2017-01-01

DJ-1 is one of the causative genes for early onset familiar Parkinson’s disease (PD) and is also considered to influence the pathogenesis of sporadic PD. DJ-1 has various physiological functions which converge on controlling intracellular reactive oxygen species (ROS) levels. In RNA-sequencing analyses searching for novel anti-oxidant genes downstream of DJ-1, a gene encoding NADP+-dependent isocitrate dehydrogenase (IDH), which converts isocitrate into α-ketoglutarate, was detected. Loss of IDH induced hyper-sensitivity to oxidative stress accompanying age-dependent mitochondrial defects and dopaminergic (DA) neuron degeneration in Drosophila, indicating its critical roles in maintaining mitochondrial integrity and DA neuron survival. Further genetic analysis suggested that DJ-1 controls IDH gene expression through nuclear factor-E2-related factor2 (Nrf2). Using Drosophila and mammalian DA models, we found that IDH suppresses intracellular and mitochondrial ROS level and subsequent DA neuron loss downstream of DJ-1. Consistently, trimethyl isocitrate (TIC), a cell permeable isocitrate, protected mammalian DJ-1 null DA cells from oxidative stress in an IDH-dependent manner. These results suggest that isocitrate and its derivatives are novel treatments for PD associated with DJ-1 dysfunction. PMID:28827794

Effect of quercetin on apoptosis of PANC-1 cells

PubMed Central

Lee, Joo Hyun; Lee, Han-Beom; Jung, Gum O; Oh, Jung Taek; Park, Dong Eun

2013-01-01

Purpose To investigate the chemotherapeutic effect of quercetin against cancer cells, signaling pathway of apoptosis was explored in human pancreatic cells. Methods Various anticancer drugs including adriamycin, cisplatin, 5-fluorouracil (5-FU) and gemcitabine were used. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphe-nyltetra zolium bromide assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole nuclei staining and flow cytometry in PANC-1 cells treated with 50 µg/mL quercetin for 24 hours. Expression of endoplas mic reticulum (ER) stress mediators including, Grp78/Bip, p-PERK, PERK, ATF4, ATF6 and GADD153/CHOP proteins were measured by Western blot analysis. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123. Quercetin induced the apoptosis of PANC-1, which was characterized as nucleic acid and genomic DNA fragmentation, chromatin condensation, and sub-G0/G1 fraction of cell cycle increase. But not adriamycin, cisplatin, gemcitabine, and 5-FU. PANC-1 cells were markedly sensitive to quercetin. Results Treatment with quercetin resulted in the increased accumulation of intracellular Ca2+ ion. Treatment with quercetin also increased the expression of Grp78/Bip and GADD153/CHOP protein and induced mitochondrial dysfunction. Quercetin exerted cytotoxicity against human pancreatic cancer cells via ER stress-mediated apoptotic signaling including reactive oxygen species production and mitochondrial dysfunction. Conclusion These data suggest that quercetin may be an important modulator of chemosensitivity of cancer cells against anticancer chemotherapeutic agents. PMID:24368982

Effect of quercetin on apoptosis of PANC-1 cells.

PubMed

Lee, Joo Hyun; Lee, Han-Beom; Jung, Gum O; Oh, Jung Taek; Park, Dong Eun; Chae, Kwon Mook

2013-12-01

To investigate the chemotherapeutic effect of quercetin against cancer cells, signaling pathway of apoptosis was explored in human pancreatic cells. Various anticancer drugs including adriamycin, cisplatin, 5-fluorouracil (5-FU) and gemcitabine were used. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphe-nyltetra zolium bromide assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole nuclei staining and flow cytometry in PANC-1 cells treated with 50 µg/mL quercetin for 24 hours. Expression of endoplas mic reticulum (ER) stress mediators including, Grp78/Bip, p-PERK, PERK, ATF4, ATF6 and GADD153/CHOP proteins were measured by Western blot analysis. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123. Quercetin induced the apoptosis of PANC-1, which was characterized as nucleic acid and genomic DNA fragmentation, chromatin condensation, and sub-G0/G1 fraction of cell cycle increase. But not adriamycin, cisplatin, gemcitabine, and 5-FU. PANC-1 cells were markedly sensitive to quercetin. Treatment with quercetin resulted in the increased accumulation of intracellular Ca(2+) ion. Treatment with quercetin also increased the expression of Grp78/Bip and GADD153/CHOP protein and induced mitochondrial dysfunction. Quercetin exerted cytotoxicity against human pancreatic cancer cells via ER stress-mediated apoptotic signaling including reactive oxygen species production and mitochondrial dysfunction. These data suggest that quercetin may be an important modulator of chemosensitivity of cancer cells against anticancer chemotherapeutic agents.

Atorvastatin and Fluoxetine Prevent Oxidative Stress and Mitochondrial Dysfunction Evoked by Glutamate Toxicity in Hippocampal Slices.

PubMed

Ludka, Fabiana K; Dal-Cim, Tharine; Binder, Luisa Bandeira; Constantino, Leandra Celso; Massari, Caio; Tasca, Carla I

2017-07-01

Atorvastatin has been shown to exert a neuroprotective action by counteracting glutamatergic toxicity. Recently, we have shown atorvastatin also exerts an antidepressant-like effect that depends on both glutamatergic and serotonergic systems modulation. Excitotoxicity is involved in several brain disorders including depression; thus, it is suggested that antidepressants may target glutamatergic system as a final common pathway. In this study, a comparison of the mechanisms involved in the putative neuroprotective effect of a repetitive atorvastatin or fluoxetine treatment against glutamate toxicity in hippocampal slices was performed. Adult Swiss mice were treated with atorvastatin (10 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.), once a day during seven consecutive days. On the eighth day, animals were killed and hippocampal slices were obtained and subjected to an in vitro protocol of glutamate toxicity. An acute treatment of atorvastatin or fluoxetine was not neuroprotective; however, the repeated atorvastatin or fluoxetine treatment prevented the decrease in cellular viability induced by glutamate in hippocampal slices. The loss of cellular viability induced by glutamate was accompanied by increased D-aspartate release, increased reactive oxygen species (ROS) and nitric oxide (NO) production, and impaired mitochondrial membrane potential. Atorvastatin or fluoxetine repeated treatment also presented an antidepressant-like effect in the tail suspension test. Atorvastatin or fluoxetine treatment was effective in protecting mice hippocampal slices from glutamate toxicity by preventing the oxidative stress and mitochondrial dysfunction.

Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload.

PubMed

Hong, Quan; Qi, Ka; Feng, Zhe; Huang, Zhiyong; Cui, Shaoyuan; Wang, Liyuan; Fu, Bo; Ding, Rui; Yang, Jurong; Chen, Xiangmei; Wu, Di

2012-05-01

Uric acid (UA) has proven to be a causal agent in endothelial dysfunction in which ROS production plays an important role. Calcium overload in mitochondria can promote the mitochondrial production of ROS. We hypothesize that calcium transduction in mitochondria contributes to UA-induced endothelial dysfunction. We first demonstrated that high concentrations of UA cause endothelial dysfunction, marked by a reduction in eNOS protein expression and NO release in vitro. We further found that a high concentration of UA increased levels of [Ca2+]mito, total intracellular ROS, H2O2, and mitochondrial O2·-, and Δψmito but not the [Ca2+]cyt level. When the mitochondrial calcium channels NCXmito and MCU were blocked by CGP-37157 and Ru360, respectively, the UA-induced increases in the levels of [Ca2+]mito and total intracellular ROS were significantly reduced. Mitochondrial levels of O2·- and Δψmito were reduced by inhibition of NCXmito but not of MCU. Moreover, inhibition of NCXmito, but not of MCU, blocked the UA-induced reductions in eNOS protein expression and NO release. The increased generation of mitochondrial O2·- induced by a high concentration of UA is triggered by mitochondrial calcium overload and ultimately leads to endothelial dysfunction. In this process, the activation of NCXmito is the major cause of the influx of calcium into mitochondria. Our results provide a new pathophysiological mechanism for UA-induced endothelial dysfunction and may offer a new therapeutic target for clinicians. Copyright © 2012 Elsevier Ltd. All rights reserved.

Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases.

PubMed

Connolly, Niamh M C; Theurey, Pierre; Adam-Vizi, Vera; Bazan, Nicolas G; Bernardi, Paolo; Bolaños, Juan P; Culmsee, Carsten; Dawson, Valina L; Deshmukh, Mohanish; Duchen, Michael R; Düssmann, Heiko; Fiskum, Gary; Galindo, Maria F; Hardingham, Giles E; Hardwick, J Marie; Jekabsons, Mika B; Jonas, Elizabeth A; Jordán, Joaquin; Lipton, Stuart A; Manfredi, Giovanni; Mattson, Mark P; McLaughlin, BethAnn; Methner, Axel; Murphy, Anne N; Murphy, Michael P; Nicholls, David G; Polster, Brian M; Pozzan, Tullio; Rizzuto, Rosario; Satrústegui, Jorgina; Slack, Ruth S; Swanson, Raymond A; Swerdlow, Russell H; Will, Yvonne; Ying, Zheng; Joselin, Alvin; Gioran, Anna; Moreira Pinho, Catarina; Watters, Orla; Salvucci, Manuela; Llorente-Folch, Irene; Park, David S; Bano, Daniele; Ankarcrona, Maria; Pizzo, Paola; Prehn, Jochen H M

2018-03-01

Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium ( www.cebiond.org ), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer's, Parkinson's, and Huntington's diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field.

Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease.

PubMed

Galloway, Chad A; Lee, Hakjoo; Brookes, Paul S; Yoon, Yisang

2014-09-15

Mitochondria produce the majority of cellular ATP through oxidative phosphorylation, and their capacity to do so is influenced by many factors. Mitochondrial morphology is recently suggested as an important contributor in controlling mitochondrial bioenergetics. Mitochondria divide and fuse continuously, which is affected by environmental factors, including metabolic alterations. Underscoring its bioenergetic influence, altered mitochondrial morphology is reported in tissues of patients and in animal models of metabolic dysfunction. In this study, we found that mitochondrial fission plays a vital role in the progression of nonalcoholic fatty liver disease (NAFLD). The development of hepatic steatosis, oxidative/nitrative stress, and hepatic tissue damage, induced by a high-fat diet, were alleviated in genetically manipulated mice suppressing mitochondrial fission. The alleviation of steatosis was recapitulated in primary hepatocytes with the inhibition of mitochondrial fission. Mechanistically, our study indicates that fission inhibition enhances proton leak under conditions of free fatty acid incubation, implicating bioenergetic change through manipulating mitochondrial fission. Taken together, our results suggest a mechanistic role for mitochondrial fission in the etiology of NAFLD. The efficacy of decreasing mitochondrial fission in the suppression of NAFLD suggests that mitochondrial fission represents a novel target for therapeutic treatment of NAFLD. Copyright © 2014 the American Physiological Society.

A biophysical approach to menadione membrane interactions: relevance for menadione-induced mitochondria dysfunction and related deleterious/therapeutic effects.

PubMed

Monteiro, João P; Martins, André F; Nunes, Cláudia; Morais, Catarina M; Lúcio, Marlene; Reis, Salette; Pinheiro, Teresa J T; Geraldes, Carlos F G C; Oliveira, Paulo J; Jurado, Amália S

2013-08-01

Menadione (MEN), a polycyclic aromatic ketone, was shown to promote cell injury by imposing massive oxidative stress and has been proposed as a promising chemotherapeutic agent for the treatment of cancer diseases. The mechanisms underlying MEN-induced mitochondrial dysfunction and cell death are not yet fully understood. In this work, a systematic study was performed to unveil the effects of MEN on membrane lipid organization, using models mimicking mitochondrial membranes and native mitochondrial membranes. MEN was found to readily incorporate in membrane systems composed of a single phospholipid (phosphatidylcholine) or the lipids dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine and tetraoleoylcardiolipin at 1:1:1 molar ratio, as well as in mitochondrial membranes. Increased permeability in both membrane models, monitored by calcein release, seemed to correlate with the extent of MEN incorporation into membranes. MEN perturbed the physical properties of vesicles composed of dipalmitoylphosphatidylcholine or dipalmitoylphosphatidylethanolamine plus tetraoleoylcardiolipin (at 7:3 molar ratio), as reflected by the downshift of the lipid phase transition temperature and the emergence of a new transition peak in the mixed lipid system, detected by DSC. (31)P NMR studies revealed that MEN favored the formation of non-lamellar structures. Also, quenching studies with the fluorescent probes DPH and TMA-DPH showed that MEN distributed across the bilayer thickness in both model and native mitochondrial membranes. MEN's ability to promote alterations of membrane lipid organization was related with its reported mitochondrial toxicity and promotion of apoptosis, predictably involved in its anti-carcinogenic activity. Copyright © 2013 Elsevier B.V. All rights reserved.

Protective effect of mitochondrial-targeted antioxidant MitoQ against iron ion 56Fe radiation induced brain injury in mice.

PubMed

Gan, Lu; Wang, Zhenhua; Si, Jing; Zhou, Rong; Sun, Chao; Liu, Yang; Ye, Yancheng; Zhang, Yanshan; Liu, Zhiyuan; Zhang, Hong

2018-02-15

Exposure to iron ion 56 Fe radiation (IR) during space missions poses a significant risk to the central nervous system and radiation exposure is intimately linked to the production of reactive oxygen species (ROS). MitoQ is a mitochondria-targeted antioxidant that has been shown to decrease oxidative damage and lower mitochondrial ROS in a number of animal models. Therefore, the present study aimed to investigate role of the mitochondrial targeted antioxidant MitoQ against 56 Fe particle irradiation-induced oxidative damage and mitochondria dysfunction in the mouse brains. Increased ROS levels were observed in mouse brains after IR compared with the control group. Enhanced ROS production leads to disruption of cellular antioxidant defense systems, mitochondrial respiration dysfunction, altered mitochondria dynamics and increased release of cytochrome c (cyto c) from mitochondria into cytosol resulting in apoptotic cell death. MitoQ reduced IR-induced oxidative stress (decreased ROS production and increased SOD, CAT activities) with decreased lipid peroxidation as well as reduced protein and DNA oxidation. MitoQ also protected mitochondrial respiration after IR. In addition, MitoQ increased the expression of mitofusin2 (Mfn2) and optic atrophy gene1 (OPA1), and decreased the expression of dynamic-like protein (Drp1). MitoQ also suppressed mitochondrial DNA damage, cyto c release, and caspase-3 activity in IR-treated mice compared to the control group. These results demonstrate that MitoQ may protect against IR-induced brain injury. Copyright © 2018 Elsevier Inc. All rights reserved.

Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway.

PubMed

Cheng, Xinghua; Siow, Richard C M; Mann, Giovanni E

2011-02-01

Type 2 diabetes is an age-related disease associated with vascular pathologies, including severe blindness, renal failure, atherosclerosis, and stroke. Reactive oxygen species (ROS), especially mitochondrial ROS, play a key role in regulating the cellular redox status, and an overproduction of ROS may in part underlie the pathogenesis of diabetes and other age-related diseases. Cells have evolved endogenous defense mechanisms against sustained oxidative stress such as the redox-sensitive transcription factor nuclear factor E2-related factor 2 (Nrf2), which regulates antioxidant response element (ARE/electrophile response element)-mediated expression of detoxifying and antioxidant enzymes and the cystine/glutamate transporter involved in glutathione biosynthesis. We hypothesize that diminished Nrf2/ARE activity contributes to increased oxidative stress and mitochondrial dysfunction in the vasculature leading to endothelial dysfunction, insulin resistance, and abnormal angiogenesis observed in diabetes. Sustained hyperglycemia further exacerbates redox dysregulation, thereby providing a positive feedback loop for severe diabetic complications. This review focuses on the role that Nrf2/ARE-linked gene expression plays in regulating endothelial redox homeostasis in health and type 2 diabetes, highlighting recent evidence that Nrf2 may provide a therapeutic target for countering oxidative stress associated with vascular disease and aging.

Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.

PubMed

Zhang, Donghui; Li, Yifei; Heims-Waldron, Danielle; Bezzerides, Vassilios; Guatimosim, Silvia; Guo, Yuxuan; Gu, Fei; Zhou, Pingzhu; Lin, Zhiqiang; Ma, Qing; Liu, Jianming; Wang, Da-Zhi; Pu, William T

2018-01-05

Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Tfam inactivation by Nkx2.5 Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction. © 2017 American Heart Association, Inc.

Penehyclidine hydrochloride regulates mitochondrial dynamics and apoptosis through p38MAPK and JNK signal pathways and provides cardioprotection in rats with myocardial ischemia-reperfusion injury.

PubMed

Feng, Min; Wang, Lirui; Chang, Siyuan; Yuan, Pu

2018-05-31

The potential mechanism of penehyclidine hydrochloride (PHC) against myocardial ischemia-reperfusion (I/R) injury has not been fully elucidated. The aim of the present study was to reveal whether mitochondrial dynamics, apoptosis, and MAPKs were involved in the cardioprotective effect of this drug on myocardial I/R injury. Ninety healthy adult male Wistar rats were separately pretreated with normal saline (0.9%); PHC; and signal pathway blockers of MAPKs, Drp1, and Bcl-2. Coronary artery ligation and subsequent reperfusion were performed to induce myocardial I/R injury. Echocardiography was performed. Myocardial enzymes and oxidative stress markers were detected. Myocardial cell apoptotic rates and infarct sizes were measured. Mitochondrial function was evaluated. Expression levels of MAPKs, mitochondria regulatory proteins (Drp1, Mfn1/2), and apoptosis-related proteins (Bcl-2, Bax) were determined. PHC pretreatment improved myocardial abnormalities (dysfunction, injury, infarct size, and apoptotic rate), mitochondrial abnormalities (dysfunction and fission), and excessive oxidative stress and inhibited the activities of p38MAPK and JNK signal pathways in rats with myocardial I/R injury (P < 0.05). Additionally, p38MAPK and JNK blockers (SB239063 and SP600125, respectively) had an effect on rats same as that of PHC. Although Drp1 blocker (Mdivi-1) showed a similar cardioprotective effect (P < 0.05), it did not affect the expression of MAPKs and apoptosis-related proteins (P > 0.05). In addition, Bcl-2 blocker (ABT-737) caused a high expression of Drp1 and a low expression of Mfn1/2 (P < 0.05). PHC regulated mitochondrial dynamics and apoptosis through p38MAPK and JNK signal pathways and provided cardioprotection in rats with myocardial I/R injury. Copyright © 2018 Elsevier B.V. All rights reserved.

The interactive roles of zinc and calcium in mitochondrial dysfunction and neurodegeneration.

PubMed

Pivovarova, Natalia B; Stanika, Ruslan I; Kazanina, Galina; Villanueva, Idalis; Andrews, S Brian

2014-02-01

Zinc has been implicated in neurodegeneration following ischemia. In analogy with calcium, zinc has been proposed to induce toxicity via mitochondrial dysfunction, but the relative role of each cation in mitochondrial damage remains unclear. Here, we report that under conditions mimicking ischemia in hippocampal neurons - normal (2 mM) calcium plus elevated (> 100 μM) exogenous zinc - mitochondrial dysfunction evoked by glutamate, kainate or direct depolarization is, despite significant zinc uptake, primarily governed by calcium. Thus, robust mitochondrial ion accumulation, swelling, depolarization, and reactive oxygen species generation were only observed after toxic stimulation in calcium-containing media. This contrasts with the lack of any mitochondrial response in zinc-containing but calcium-free medium, even though zinc uptake and toxicity were strong under these conditions. Indeed, abnormally high, ionophore-induced zinc uptake was necessary to elicit any mitochondrial depolarization. In calcium- and zinc-containing media, depolarization-induced zinc uptake facilitated cell death and enhanced accumulation of mitochondrial calcium, which localized to characteristic matrix precipitates. Some of these contained detectable amounts of zinc. Together these data indicate that zinc uptake is generally insufficient to trigger mitochondrial dysfunction, so that mechanism(s) of zinc toxicity must be different from that of calcium. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

PubMed Central

Song, Young Mi; Lee, Woo Kyung; Lee, Yong-ho; Kang, Eun Seok; Cha, Bong-Soo; Lee, Byung-Wan

2016-01-01

Metformin is known to alleviate hepatosteatosis by inducing 5’ adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our ob/ob mice were divided into three groups: (1) ad libitum feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR). HepG2 cells were treated with palmitate (PA) plus high glucose in the absence or presence of metformin. We detected enhanced mitophagy in ob/ob mice treated with metformin or CR, whereas mitochondrial spheroids were observed in mice fed ad libitum. Metabolically stressed ob/ob mice and PA-treated HepG2 cells showed an increase in expression of endoplasmic reticulum (ER) stress markers and cytosolic p53. Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation. However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins. PMID:26784190

Telomeres and Mitochondria in the Aging Heart

PubMed Central

Moslehi, Javid; DePinho, Ronald A.; Sahin, Ergün

2013-01-01

Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and PGC-1β in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging. PMID:22539756

Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress.

PubMed

Koncsos, Gábor; Varga, Zoltán V; Baranyai, Tamás; Boengler, Kerstin; Rohrbach, Susanne; Li, Ling; Schlüter, Klaus-Dieter; Schreckenberg, Rolf; Radovits, Tamás; Oláh, Attila; Mátyás, Csaba; Lux, Árpád; Al-Khrasani, Mahmoud; Komlódi, Tímea; Bukosza, Nóra; Máthé, Domokos; Deres, László; Barteková, Monika; Rajtík, Tomáš; Adameová, Adriana; Szigeti, Krisztián; Hamar, Péter; Helyes, Zsuzsanna; Tretter, László; Pacher, Pál; Merkely, Béla; Giricz, Zoltán; Schulz, Rainer; Ferdinandy, Péter

2016-10-01

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca 2+ /calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria. Copyright © 2016 the American Physiological Society.

Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain.

PubMed

Hosamani, Ravikumar; Krishna, Gokul; Muralidhara

2016-12-01

Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.

Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice

PubMed Central

Guachalla, Luis Miguel; Ju, Zhenyu; Koziel, Rafal; von Figura, Guido; Song, Zhangfa; Fusser, Markus; Epe, Bernd; Jansen-Dűrr, Pidder; Rudolph, K. Lenhard

2009-01-01

Telomere shortening represents a causal factor of cellular senescence. At the same time, several lines of evidence indicate a pivotal role of oxidative DNA damage for the aging process in vivo. A causal connection between the two observations was suggested by experiments showing accelerated telomere shorting under conditions of oxidative stress in cultured cells, but has never been studied in vivo. We therefore have analysed whether an increase in mitochondrial derived oxidative stress in response to heterozygous deletion of superoxide dismutase (Sod2+/-) would exacerbate aging phenotypes in telomere dysfunctional (mTerc-/-) mice. Heterozygous deletion of Sod2 resulted in reduced SOD2 protein levels and increased oxidative stress in aging telomere dysfunctional mice, but this did not lead to an increase in basal levels of oxidative nuclear DNA damage, an accumulation of nuclear DNA breaks, or an increased rate of telomere shortening in the mice. Moreover, heterozygous deletion of Sod2 did not accelerate the depletion of stem cells and the impairment in organ maintenance in aging mTerc-/- mice. In agreement with these observations, Sod2 haploinsufficiency did not lead to a further reduction in lifespan of mTerc-/- mice. Together, these results indicate that a decrease in SOD2-dependent antioxidant defence does not exacerbate aging in the context of telomere dysfunction. PMID:20195488

Role of ROS and RNS Sources in Physiological and Pathological Conditions

PubMed Central

Victor, Victor Manuel

2016-01-01

There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis. PMID:27478531

β-Lapachone attenuates mitochondrial dysfunction in MELAS cybrid cells.

PubMed

Jeong, Moon Hee; Kim, Jin Hwan; Seo, Kang-Sik; Kwak, Tae Hwan; Park, Woo Jin

2014-11-21

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease caused by mutations in the mitochondrial genome. This study investigated the efficacy of β-lapachone (β-lap), a natural quinone compound, in rescuing mitochondrial dysfunction in MELAS cybrid cells. β-Lap significantly restored energy production and mitochondrial membrane potential as well as normalized the elevated ROS level in MELAS cybrid cells. Additionally, β-lap reduced lactic acidosis and restored glucose uptake in the MELAS cybrid cells. Finally, β-lap activated Sirt1 by increasing the intracellular NAD(+)/NADH ratio, which was accompanied by increased mtDNA content. Two other quinone compounds (idebenone and CoQ10) that have rescued mitochondrial dysfunction in previous studies of MELAS cybrid cells had a minimal effect in the current study. Taken together, these results demonstrated that β-lap may provide a novel therapeutic modality for the treatment of MELAS. Copyright © 2014 Elsevier Inc. All rights reserved.

Mitochondrial disorders: Challenges in diagnosis & treatment

PubMed Central

Khan, Nahid Akhtar; Govindaraj, Periyasamy; Meena, Angamuthu Kannan; Thangaraj, Kumarasamy

2015-01-01

Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment. PMID:25857492

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

PubMed Central

DeBalsi, Karen L.; Hoff, Kirsten E.; Copeland, William C.

2016-01-01

As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined. PMID:27143693

Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue

PubMed Central

Boengler, Kerstin; Kosiol, Maik; Mayr, Manuel; Schulz, Rainer

2017-01-01

Abstract Age is the most important risk factor for most diseases. Mitochondria play a central role in bioenergetics and metabolism. In addition, several lines of evidence indicate the impact of mitochondria in lifespan determination and ageing. The best‐known hypothesis to explain ageing is the free radical theory, which proposes that cells, organs, and organisms age because they accumulate reactive oxygen species (ROS) damage over time. Mitochondria play a central role as the principle source of intracellular ROS, which are mainly formed at the level of complex I and III of the respiratory chain. Dysfunctional mitochondria generating less ATP have been observed in various aged organs. Mitochondrial dysfunction comprises different features including reduced mitochondrial content, altered mitochondrial morphology, reduced activity of the complexes of the electron transport chain, opening of the mitochondrial permeability transition pore, and increased ROS formation. Furthermore, abnormalities in mitochondrial quality control or defects in mitochondrial dynamics have also been linked to senescence. Among the tissues affected by mitochondrial dysfunction are those with a high‐energy demand and thus high mitochondrial content. Therefore, the present review focuses on the impact of mitochondria in the ageing process of heart and skeletal muscle. In this article, we review different aspects of mitochondrial dysfunction and discuss potential therapeutic strategies to improve mitochondrial function. Finally, novel aspects of adipose tissue biology and their involvement in the ageing process are discussed. PMID:28432755

Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function

PubMed Central

Qi, Jia; Duan, Suyan; Huang, Zhimin; Zhang, Chengning; Wu, Lin; Zeng, Ming; Zhang, Bo; Wang, Ningning; Mao, Huijuan; Zhang, Aihua; Xing, Changying; Yuan, Yanggang

2017-01-01

Cisplatin chemotherapy often causes acute kidney injury (AKI) in cancer patients. There is increasing evidence that mitochondrial dysfunction plays an important role in cisplatin-induced nephrotoxicity. Degradation of damaged mitochondria is carried out by mitophagy. Although mitophagy is considered of particular importance in protecting against AKI, little is known of the precise role of mitophagy and its molecular mechanisms during cisplatin-induced nephrotoxicity. Also, evidence that activation of mitophagy improved mitochondrial function is lacking. Furthermore, several evidences have shown that mitochondrial fission coordinates with mitophagy. The aim of this study was to investigate whether activation of mitophagy protects against mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. The effect of mitochondrial fission on mitophagy was also investigated. In cultured human renal proximal tubular cells, we observed that 3-methyladenine, a pharmacological inhibitor of autophagy, blocked mitophagy and exacerbated cisplatin-induced mitochondrial dysfunction and cells injury. In contrast, autophagy activator rapamycin enhanced mitophagy and protected against the harmful effects of cisplatin on mitochondrial function and cells viability. Suppression of mitochondrial fission by knockdown of its main regulator dynamin-related protein-1 (Drp1) decreased cisplatin-induced mitophagy. Meanwhile, Drp1 suppression protected against cisplatin-induced cells injury by inhibiting mitochondrial dysfunction. Our results provide evidence that Drp1-depedent mitophagy has potential as renoprotective targets for the treatment of cisplatin-induced AKI. PMID:28423497

Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart

PubMed Central

Raza, Haider; John, Annie; Howarth, Frank C.

2012-01-01

The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) male animals develop obesity and type 2 diabetes. Morbidity and mortality from cardiovascular complications, due to increased oxidative stress and inflammatory signals, are the hallmarks of type 2 diabetes. The precise molecular mechanism of contractile dysfunction and disease progression remains to be clarified. Therefore, we have investigated molecular and metabolic targets in male ZDF (30–34 weeks old) rat heart compared to age matched Zucker lean (ZL) controls. Hyperglycemia was confirmed by a 4-fold elevation in non-fasting blood glucose (478.43 ± 29.22 mg/dL in ZDF vs. 108.22 ± 2.52 mg/dL in ZL rats). An increase in reactive oxygen species production, lipid peroxidation and oxidative protein carbonylation was observed in ZDF rats. A significant increase in CYP4502E1 activity accompanied by increased protein expression was also observed in diabetic rat heart. Increased expression of other oxidative stress marker proteins, HO-1 and iNOS was also observed. GSH concentration and activities of GSH-dependent enzymes, glutathione S-transferase and GSH reductase, were, however, significantly increased in ZDF heart tissue suggesting a compensatory defense mechanism. The activities of mitochondrial respiratory enzymes, Complex I and Complex IV were significantly reduced in the heart ventricle of ZDF rats in comparison to ZL rats. Western blot analysis has also suggested a decreased expression of IκB-α and phosphorylated-JNK in diabetic heart tissue. Our results have suggested that mitochondrial dysfunction and increased oxidative stress in ZDF rats might be associated, at least in part, with altered NF-κB/JNK dependent redox cell signaling. These results might have implications in the elucidation of the mechanism of disease progression and designing strategies for diabetes prevention. PMID:23203193

Selenium suppresses glutamate-induced cell death and prevents mitochondrial morphological dynamic alterations in hippocampal HT22 neuronal cells.

PubMed

Ma, Yan-Mei; Ibeanu, Gordon; Wang, Li-Yao; Zhang, Jian-Zhong; Chang, Yue; Dong, Jian-Da; Li, P Andy; Jing, Li

2017-01-19

Previous studies have indicated that selenium supplementation may be beneficial in neuroprotection against glutamate-induced cell damage, in which mitochondrial dysfunction is considered a major pathogenic feature. However, the exact mechanisms by which selenium protects against glutamate-provoked mitochondrial perturbation remain ambiguous. In this study glutamate exposed murine hippocampal neuronal HT22 cell was used as a model to investigate the underlying mechanisms of selenium-dependent protection against mitochondria damage. We find that glutamate-induced cytotoxicity was associated with enhancement of superoxide production, activation of caspase-9 and -3, increases of mitochondrial fission marker and mitochondrial morphological changes. Selenium significantly resolved the glutamate-induced mitochondria structural damage, alleviated oxidative stress, decreased Apaf-1, caspases-9 and -3 contents, and altered the autophagy process as observed by a decline in the ratio of the autophagy markers LC3-I and LC3-II. These findings suggest that the protection of selenium against glutamate stimulated cell damage of HT22 cells is associated with amelioration of mitochondrial dynamic imbalance.

Small Interfering RNA Targeting Mitochondrial Calcium Uniporter Improves Cardiomyocyte Cell Viability in Hypoxia/Reoxygenation Injury by Reducing Calcium Overload.

PubMed

Oropeza-Almazán, Yuriana; Vázquez-Garza, Eduardo; Chapoy-Villanueva, Héctor; Torre-Amione, Guillermo; García-Rivas, Gerardo

2017-01-01

Intracellular Ca 2+ mishandling is an underlying mechanism in hypoxia/reoxygenation (H/R) injury that results in mitochondrial dysfunction and cardiomyocytes death. These events are mediated by mitochondrial Ca 2+ ( m Ca 2+ ) overload that is facilitated by the mitochondrial calcium uniporter (MCU) channel. Along this line, we evaluated the effect of siRNA-targeting MCU in cardiomyocytes subjected to H/R injury. First, cardiomyocytes treated with siRNA demonstrated a reduction of MCU expression by 67%, which resulted in significant decrease in mitochondrial Ca 2+ transport. siRNA treated cardiomyocytes showed decreased mitochondrial permeability pore opening and oxidative stress trigger by Ca 2+ overload. Furthermore, after H/R injury MCU silencing decreased necrosis and apoptosis levels by 30% and 50%, respectively, and resulted in reduction in caspases 3/7, 9, and 8 activity. Our findings are consistent with previous conclusions that demonstrate that MCU activity is partly responsible for cellular injury induced by H/R and support the concept of utilizing siRNA-targeting MCU as a potential therapeutic strategy.