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Sample records for exercise-induced mitochondrial biogenesis

  1. Potential role of lipin-1 in exercise-induced mitochondrial biogenesis.

    PubMed

    Higashida, Kazuhiko; Higuchi, Mitsuru; Terada, Shin

    2008-09-26

    Endurance exercise induces mitochondrial biogenesis in skeletal muscle. It has been shown that lipin-1 acts as a transcriptional coactivator in liver, and stimulates gene expression of mitochondrial enzymes. We hypothesized that lipin-1 might be involved in exercise-induced mitochondrial biogenesis in skeletal muscle. The present investigation first demonstrated that lipin-1 mRNA in rat triceps muscle was increased by approximately 2-fold after an acute bout of endurance swimming exercise. Second, ectopic expression of lipin-1 in L6 myotube increased carnitine palmitoyltransferase-1 and delta-aminolevulinate synthase gene expression. Finally, lipin-1 mRNA expression in rat triceps muscle was significantly elevated at 6h after subcutaneous injections of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) or clenbuterol, which are 5'-AMP-activated protein kinase (AMPK) and beta2-adrenergic receptor (beta2-AR) activators, respectively. These results may suggest that enhanced expression of lipin-1 is involved in exercise-induced mitochondrial enzyme adaptations, possibly through AMPK- and beta2-AR-related mechanisms. PMID:18656451

  2. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle

    PubMed Central

    Okutsu, Mitsuharu; Akhtar, Yasir N.; Lira, Vitor A.

    2011-01-01

    Skeletal muscle exhibits superb plasticity in response to changes in functional demands. Chronic increases of skeletal muscle contractile activity, such as endurance exercise, lead to a variety of physiological and biochemical adaptations in skeletal muscle, including mitochondrial biogenesis, angiogenesis, and fiber type transformation. These adaptive changes are the basis for the improvement of physical performance and other health benefits. This review focuses on recent findings in genetically engineered animal models designed to elucidate the mechanisms and functions of various signal transduction pathways and gene expression programs in exercise-induced skeletal muscle adaptations. PMID:21030673

  3. Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis.

    PubMed

    Craig, Daniel M; Ashcroft, Stephen P; Belew, Micah Y; Stocks, Ben; Currell, Kevin; Baar, Keith; Philp, Andrew

    2015-01-01

    Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans. PMID:26578969

  4. Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis

    PubMed Central

    Craig, Daniel M.; Ashcroft, Stephen P.; Belew, Micah Y.; Stocks, Ben; Currell, Kevin; Baar, Keith; Philp, Andrew

    2015-01-01

    Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans. PMID:26578969

  5. Impaired exercise-induced mitochondrial biogenesis in the obese Zucker rat, despite PGC-1? induction, is due to compromised mitochondrial translation elongation.

    PubMed

    Greene, Nicholas P; Nilsson, Mats I; Washington, Tyrone A; Lee, David E; Brown, Lemuel A; Papineau, Alyssa M; Shimkus, Kevin L; Greene, Elizabeth S; Crouse, Stephen F; Fluckey, James D

    2014-03-01

    Previously, we demonstrated that high-volume resistance exercise stimulates mitochondrial protein synthesis (a measure of mitochondrial biogenesis) in lean but not obese Zucker rats. Here, we examined factors involved in regulating mitochondrial biogenesis in the same animals. PGC-1? was 45% higher following exercise in obese but not lean animals compared with sedentary counterparts. Interestingly, exercised animals demonstrated greater PPAR? protein in both lean (47%) and obese (>200%) animals. AMPK phosphorylation (300%) and CPT-I protein (30%) were elevated by exercise in lean animals only, indicating improved substrate availability/flux. These findings suggest that, despite PGC-1? induction, obese animals were resistant to exercise-induced synthesis of new mitochondrial and oxidative protein. Previously, we reported that most anabolic processes are upregulated in these same obese animals regardless of exercise, so the purpose of this study was to assess specific factors associated with the mitochondrial genome as possible culprits for impaired mitochondrial biogenesis. Exercise resulted in higher mRNA contents of mitochondrial transcription factor A (?50% in each phenotype) and mitochondrial translation initiation factor 2 (31 and 47% in lean and obese, respectively). However, mitochondrial translation elongation factor-Tu mRNA was higher following exercise in lean animals only (40%), suggesting aberrant regulation of mitochondrial translation elongation as a possible culprit in impaired mitochondrial biogenesis following exercise with obesity. PMID:24398401

  6. Deacetylation of PGC-1α by SIRT1: importance for skeletal muscle function and exercise-induced mitochondrial biogenesis.

    PubMed

    Gurd, Brendon J

    2011-10-01

    Activation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-mediated transcription is important for both the determination of mitochondrial content and the induction of mitochondrial biogenesis in skeletal muscle. SIRT1 (silent mating type information regulator 2 homolog 1) deactetylation is proposed as a potential activator of PGC-1α transcriptional activity. The current review examines the importance of SIRT1 deacetylation of PGC-1α in skeletal muscle. Models of SIRT1 overexpression and pharmacological activation are examined, but changes in SIRT1 expression and deacetylase activity following acute and chronic contractile activity will be emphasized. In addition, potential mechanisms of SIRT1 activation in skeletal muscle will be examined. The importance of the PGC-1α acetyltransferase GCN5 will also be briefly discussed. The current evidence supports the contribution of SIRT1 deacetylation of PGC-1α to exercise-induced mitochondrial biogenesis. Further research examining exercise-mediated activation of SIRT1 and the role of GCN5 in regulating PGC-1α transcriptional activity in skeletal muscle is required. PMID:21888529

  7. Regulation of mitochondrial biogenesis

    PubMed Central

    Jornayvaz, François R.; Shulman, Gerald I.

    2013-01-01

    Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer’s disease. PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1α itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets. PMID:20533901

  8. Mitochondrial biogenesis: pharmacological approaches.

    PubMed

    Valero, Teresa

    2014-01-01

    Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an important mitochondrial component both on their onset and on their development. This is the case of type 2 diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about the origin of insulin resistance Mónica Zamora and Josep A. Villena (Department of Experimental and Health Sciences, Universitat Pompeu Fabra / Laboratory of Metabolism and Obesity, Universitat Autònoma de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired (mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or the consequence of insulin resistance, it has been widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes. Thus restoring oxidative capacity by increasing mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential pharmacological targets and opens the perspectives for the design of suitable treatments for insulin resistance. In addition some of the current used strategies could be used to treat insulin resistance such as lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions (thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK activators, ERR activators). Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and morphology [1]. Parkinson´s Disease (PD) is a very good example of this important mitochondrial component on neurodegenerative diseases. Anuradha Yadav, Swati Agrawal, Shashi Kant Tiwari, and Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with special focus on the role of oxidative stress and bioenergetic deficits. These alterations may have their origin on pathogenic gene mutations in important genes such as DJ-1, -syn, parkin, PINK1 or LRRK2. These mutations, in turn, may cause defects in mitochondrial dynamics (key events like fission/fusion, biogenesis, trafficking in retrograde and anterograde directions, and mitophagy). This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials. They highlight a dual effect of PGC-1α expression on PD prognosis. Whereas a modest expression of this transcriptional co-activator results in positive effects, a moderate to substantial overexpession may have deleterious consequences. As strategies to induce PGC-1α activation, these authors remark the possibility to activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and -lipoic acid. Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental disorders. In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello (Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development. A mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control systems and mitochondrial biogenesis. Concerning the signaling pathways leading to mitochondrial biogenesis this review highlights the implication of different regulators such as AMPK, SIRT1, PGC-1α, NRF1, NRF2, Tfam, etc. on the specific case of neuronal development, providing examples of diseases in which these pathways are altered and transgenic mouse models lacking these regulators. A common hallmark of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease) is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. Among the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK (AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). This article also presents a review of the current animal and cellular models useful to study mitochondriogenesis. Although it is known that many neurodegenerative and neurodevelopmental diseases are originated in mitochondria, the regulation of mitochondrial biogenesis has never been extensively studied. (ABSTRACT TRUNCATED) PMID:24606795

  9. MITOCHONDRIAL BIOGENESIS AND HEALTHY AGING

    PubMed Central

    Lpez-Lluch, Guillermo; Irusta, Pablo M.; Navas, Placido; de Cabo, Rafael

    2008-01-01

    Aging is associated with an overall loss of function at the level of the whole organism that has origins in cellular deterioration. Most cellular components, including mitochondria, require continuous recycling and regeneration throughout the lifespan. Mitochondria are particularly susceptive to damage over time as they are the major bioenergetic machinery and source of oxidative stress in cells. Effective control of mitochondrial biogenesis and turnover, therefore, becomes critical for the maintenance of energy production, the prevention of endogenous oxidative stress and the promotion of healthy aging. Multiple endogenous and exogenous factors regulate mitochondrial biogenesis through the peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?). Activators of PGC-1? include nitric oxide, CREB and AMPK. Calorie restriction (CR) and resveratrol, a proposed CR mimetic, also increase mitochondrial biogenesis through activation of PGC-1?. Moderate exercise also mimics CR by inducing mitochondrial biogenesis. Negative regulators of PGC-1? such as RIP140 and 160MBP suppress mitochondrial biogenesis. Another mechanism involved in mitochondrial maintenance is mitochondrial fission/fusion and this process also involves an increasing number of regulatory proteins. Dysfunction of either biogenesis or fission/fusion of mitochondria is associated with diseases of the neuromuscular system and aging, and a greater understanding of the regulation of these processes should help us to ultimately control the aging process. PMID:18662766

  10. Transcriptional integration of mitochondrial biogenesis

    PubMed Central

    Scarpulla, Richard C.; Vega, Rick B.; Kelly, Daniel P.

    2012-01-01

    Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function. Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation and other functions. Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators plays a major role in transducing and integrating physiological signals governing metabolism, differentiation and cell growth to the transcriptional machinery controlling mitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease. PMID:22817841

  11. Resveratrol induces mitochondrial biogenesis in endothelial cells.

    PubMed

    Csiszar, Anna; Labinskyy, Nazar; Pinto, John T; Ballabh, Praveen; Zhang, Hanrui; Losonczy, Gyorgy; Pearson, Kevin; de Cabo, Rafael; Pacher, Pal; Zhang, Cuihua; Ungvari, Zoltan

    2009-07-01

    Pathways that regulate mitochondrial biogenesis are potential therapeutic targets for the amelioration of endothelial dysfunction and vascular disease. Resveratrol was shown to impact mitochondrial function in skeletal muscle and the liver, but its role in mitochondrial biogenesis in endothelial cells remains poorly defined. The present study determined whether resveratrol induces mitochondrial biogenesis in cultured human coronary arterial endothelial cells (CAECs). In CAECs resveratrol increased mitochondrial mass and mitochondrial DNA content, upregulated protein expression of electron transport chain constituents, and induced mitochondrial biogenesis factors (proliferator-activated receptor-coactivator-1alpha, nuclear respiratory factor-1, mitochondrial transcription factor A). Sirtuin 1 (SIRT1) was induced, and endothelial nitric oxide (NO) synthase (eNOS) was upregulated in a SIRT1-dependent manner. Knockdown of SIRT1 (small interfering RNA) or inhibition of NO synthesis prevented resveratrol-induced mitochondrial biogenesis. In aortas of type 2 diabetic (db/db) mice impaired mitochondrial biogenesis was normalized by chronic resveratrol treatment, showing the in vivo relevance of our findings. Resveratrol increases mitochondrial content in endothelial cells via activating SIRT1. We propose that SIRT1, via a pathway that involves the upregulation of eNOS, induces mitochondrial biogenesis. Resveratrol induced mitochondrial biogenesis in the aortas of type 2 diabetic mice, suggesting the potential for new treatment approaches targeting endothelial mitochondria in metabolic diseases. PMID:19429820

  12. Adiponectin is sufficient, but not required, for exercise-induced increases in the expression of skeletal muscle mitochondrial enzymes

    PubMed Central

    Ritchie, Ian R W; MacDonald, Tara L; Wright, David C; Dyck, David J

    2014-01-01

    Adiponectin (Ad) has been proposed to be a regulator of mitochondrial biogenesis in skeletal muscle, and necessary for exercise-induced increases in mitochondrial content. We first confirmed that Ad could acutely increase the expression of mitochondrial proteins during a 10 h incubation in isolated soleus and extensor digitorum longus (EDL) muscles. Next, we further examined the role of Ad as a regulator of mitochondrial content using Ad knockout (AdKO) mice. The AdKO animals showed no differences in resting , respiratory exchange ratio, or in time to exhaustion during exercise when compared to wild-type (WT) mice. There was a reduction in resting palmitate oxidation in isolated soleus from AdKO animals (−23%, P < 0.05) but not EDL, and 5-aminoimidazole-4-carboxamide (AICAR)-stimulated palmitate oxidation was similar in both genotypes regardless of muscle. There were no differences in protein markers of mitochondrial content (COX4, CORE1, CS, PDHE1α) in red and white gastrocnemius between WT and AdKO animals. A single bout of treadmill running increased the phosphorylation of AMP-activated protein kinase (AMPK) and the mRNA expression of mitochondrial proteins in red and white gastrocnemius in both WT and AdKO animals, with no differences between genotypes. Finally, 8 weeks of chronic exercise training increased the protein content of mitochondrial markers similarly (∼25–35%) in red gastrocnemius from both WT and AdKO mice. Collectively, our results demonstrate that the absence of Ad is not accompanied by reductions in mitochondrial protein content, or a reduction in aerobic exercise capacity. We conclude that Ad is not required for the maintenance of mitochondrial content, or for exercise-induced increases in skeletal muscle mitochondrial proteins. PMID:24687585

  13. Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis

    PubMed Central

    Li, Feng; Wang, Yunyue; Zeller, Karen I.; Potter, James J.; Wonsey, Diane R.; O'Donnell, Kathryn A.; Kim, Jung-whan; Yustein, Jason T.; Lee, Linda A.; Dang, Chi V.

    2005-01-01

    Although several genes involved in mitochondrial function are direct Myc targets, the role of Myc in mitochondrial biogenesis has not been directly established. We determined the effects of ectopic Myc expression or the loss of Myc on mitochondrial biogenesis. Induction of Myc in P493-6 cells resulted in increased oxygen consumption and mitochondrial mass and function. Conversely, compared to wild-type Myc fibroblasts, Myc null rat fibroblasts have diminished mitochondrial mass and decreased number of normal mitochondria. Reconstitution of Myc expression in Myc null fibroblasts partially restored mitochondrial mass and function and normal-appearing mitochondria. Concordantly, we also observed in primary hepatocytes that acute deletion of floxed murine Myc by Cre recombinase resulted in diminished mitochondrial mass in primary hepatocytes. Our microarray analysis of genes responsive to Myc in human P493-6 B lymphocytes supports a role for Myc in mitochondrial biogenesis, since genes involved in mitochondrial structure and function are overrepresented among the Myc-induced genes. In addition to the known direct binding of Myc to many genes involved in mitochondrial structure and function, we found that Myc binds the TFAM gene, which encodes a key transcriptional regulator and mitochondrial DNA replication factor, both in P493-6 lymphocytes with high ectopic MYC expression and in serum-stimulated primary human 2091 fibroblasts with induced endogenous MYC. These observations support a pivotal role for Myc in regulating mitochondrial biogenesis. PMID:15988031

  14. Mitochondrial biogenesis in the acutely injured kidney.

    PubMed

    Tran, Mei; Parikh, Samir M

    2014-01-01

    Mitochondrial dysfunction within the tubular epithelium has been implicated in the pathogenesis of acute kidney injury. Inflammatory, ischemic, or toxic insults dysregulate mitochondrial dynamics, resulting in mitochondrial swelling, fission, and apoptosis. The coordinated processes of generating healthy mitochondria and clearing damaged organelles may contribute to the preservation and restoration of mitochondrial homeostasis. Emerging literature suggests that a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor-?-coactivator-1? (PGC-1?), is highly expressed in the tubular epithelium of the healthy kidney, and its induction during the post-injury period may contribute to functional recovery from acute kidney injury. PMID:25343819

  15. Mitochondrial nutrients stimulate performance and mitochondrial biogenesis in exhaustively exercised rats.

    PubMed

    Sun, M; Qian, F; Shen, W; Tian, C; Hao, J; Sun, L; Liu, J

    2012-12-01

    The aim of this study was to investigate the effects of a combination of nutrients on physical performance, oxidative stress and mitochondrial biogenesis in rats subjected to exhaustive exercise. Rats were divided into sedentary control (SC), exhaustive exercise (EC) and exhaustive exercise with nutrient supplementation (EN). The nutrients include (mg/kg/day): R-α-lipoic acid 50, acetyl-L-carnitine 100, biotin 0.1, nicotinamide 15, riboflavin 6, pyridoxine 6, creatine 50, CoQ10 5, resveratrol 5 and taurine 100. Examination of running distances over the 4-week period revealed that EN rats ran significantly longer throughout the entire duration of the exhaustive exercise period compared with the EC rats. Nutrient supplementation significantly inhibited the increase in activities of alanine transaminase, lactate dehydrogenase and creatine kinase, reversed increases in malondialdehyde, inhibited decreases in glutathione S-transferase and total antioxidant capacity in plasma, and suppressed the elevation of reactive oxygen species and apoptosis in splenic lymphocytes. Nutrient supplementation increased the protein expression of mitochondrial complexes I, II and III, mtDNA number and transcription factors involved in mitochondrial biogenesis and fusion in skeletal muscle. These findings suggest that mitochondrial nutrient supplementation can reduce exhaustive exercise-induced oxidative damage and mitochondrial dysfunction, thus leading to enhancement of physical performance and of fatigue recovery. PMID:21507065

  16. Mitochondrial Biogenesis and Function in Arabidopsis†

    PubMed Central

    Millar, A. Harvey; Small, Ian D.; Day, David A.; Whelan, James

    2008-01-01

    Mitochondria represent the powerhouse of cells through their synthesis of ATP. However, understanding the role of mitochondria in the growth and development of plants will rely on a much deeper appreciation of the complexity of this organelle. Arabidopsis research has provided clear identification of mitochondrial components, allowed wide-scale analysis of gene expression, and has aided reverse genetic manipulation to test the impact of mitochondrial component loss on plant function. Forward genetics in Arabidopsis has identified mitochondrial involvement in mutations with notable impacts on plant metabolism, growth and development. Here we consider the evidence for components involved in mitochondria biogenesis, metabolism and signalling to the nucleus. PMID:22303236

  17. Mitochondrial Biogenesis and Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α (PGC-1α) Deacetylation by Physical Activity

    PubMed Central

    Li, Ling; Pan, Ruping; Li, Rong; Niemann, Bernd; Aurich, Anne-Cathleen; Chen, Ying; Rohrbach, Susanne

    2011-01-01

    OBJECTIVE Transcriptional peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1α activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1α activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1α activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1α deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1α deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1α deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1α–independent mechanisms without mtDNA replication. PMID:20929977

  18. Estrogenic Control of Mitochondrial Function and Biogenesis

    PubMed Central

    Klinge, Carolyn M.

    2008-01-01

    Estrogens have cell-specific effects on a variety of physiological endpoints including regulation of mitochondrial biogenesis and activity. Estrogens regulate gene transcription by the classical genomic mechanism of binding to estrogen receptors ? and ? (ER? and ER?) as well as the more recently described nongenomic pathways involving plasma membrane-associated ERs that activate intracellular protein kinase-mediated phosphorylation signaling cascades. Here I will review the rapid and longer-term effects of estrogen on mitochondrial function. The identification of ER? and ER? within mitochondria of various cells and tissues is discussed with a model of estrogen regulation of the transcription of Nuclear Respiratory Factor-1 (NRF-1, NRF1). NRF-1 subsequently promotes transcription of mitochondrial transcription factor Tfam (mtDNA maintenance factor, also called mtTFA) and then Tfam targets mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed. Overall, we are just beginning to evaluate the many direct and indirect effects of estrogens on mitochondrial activities. PMID:18846505

  19. Mitochondrial dynamic remodeling in strenuous exercise-induced muscle and mitochondrial dysfunction: regulatory effects of hydroxytyrosol.

    PubMed

    Feng, Zhihui; Bai, Liyuan; Yan, Jiong; Li, Yuan; Shen, Weili; Wang, Ying; Wertz, Karin; Weber, Peter; Zhang, Yong; Chen, Yan; Liu, Jiankang

    2011-05-15

    Physical exercise is considered to exert a positive effect on health, whereas strenuous or excessive exercise (Exe) causes fatigue and damage to muscle and immune functions. The underlying molecular mechanisms are still unclear. We designed a protocol to mimic Exe and explore the ensuing cellular damage and involvement of mitochondrial dynamics. We found that Exe was prone to decrease endurance capacity and induce damage to renal function and the immune system. Muscle atrophy markers atrogin-1 and MuRF1 mRNA were increased by Exe, accompanied by increased autophagy and mitochondrial fission in skeletal muscle. Exe caused a decrease in PGC-1? and complex I expression; it also activated JNK and Erk1/2 pathways and consequently induced p53, p21, and MnSOD expression in skeletal muscle. The involvement of oxidant-induced autophagy and mitochondrial dysfunction was confirmed in C2C12 myoblasts. Hydroxytyrosol (HT), a natural olive polyphenol, efficiently enhanced endurance capacity and prevented Exe-induced renal and immune system damage. Also, HT treatment inhibited both the Exe-induced increase in autophagy and mitochondrial fission and the decrease in PGC-1? expression. In addition, HT enhanced mitochondrial fusion and mitochondrial complex I and II activities in muscle of Exe rats. These results demonstrate that Exe-induced fatigue and damage to muscle and immune functions may be mediated via the regulation of mitochondrial dynamic remodeling, including the downregulation of mitochondrial biogenesis and upregulation of autophagy. HT supplementation may regulate mitochondrial dynamic remodeling and enhance antioxidant defenses and thus improve exercise capacity under Exe conditions. PMID:21421045

  20. Reactive Oxygen Species-Mediated Control of Mitochondrial Biogenesis

    PubMed Central

    Yoboue, Edgar D.; Devin, Anne

    2012-01-01

    Mitochondrial biogenesis is a complex process. It necessitates the contribution of both the nuclear and the mitochondrial genomes and therefore crosstalk between the nucleus and mitochondria. It is now well established that cellular mitochondrial content can vary according to a number of stimuli and physiological states in eukaryotes. The knowledge of the actors and signals regulating the mitochondrial biogenesis is thus of high importance. The cellular redox state has been considered for a long time as a key element in the regulation of various processes. In this paper, we report the involvement of the oxidative stress in the regulation of some actors of mitochondrial biogenesis. PMID:22693510

  1. Mitochondrial biogenesis and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation by physical activity: intact adipocytokine signaling is required.

    PubMed

    Li, Ling; Pan, Ruping; Li, Rong; Niemann, Bernd; Aurich, Anne-Cathleen; Chen, Ying; Rohrbach, Susanne

    2011-01-01

    OBJECTIVE Transcriptional peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1α activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1α activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1α activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1α deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1α deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1α deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1α-independent mechanisms without mtDNA replication. PMID:20929977

  2. Regulation of Mitochondrial Biogenesis and Its Intersection with Inflammatory Responses

    PubMed Central

    Piantadosi, Claude A.

    2015-01-01

    Abstract Significance: 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. Recent Advances: 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. Critical Issues: 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. Future Directions: 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. Antioxid. Redox Signal. 22, 965–976. PMID:25556935

  3. The Protective Effects of Salidroside from Exhaustive Exercise-Induced Heart Injury by Enhancing the PGC-1 α–NRF1/NRF2 Pathway and Mitochondrial Respiratory Function in Rats

    PubMed Central

    Ping, Zheng; Zhang, Long-fei; Cui, Yu-juan; Chang, Yu-mei; Jiang, Cai-wu; Meng, Zhen-zhi; Xu, Peng; Liu, Hai-yan; Wang, Dong-ying; Cao, Xue-bin

    2015-01-01

    Objective. To test the hypothesis that salidroside (SAL) can protect heart from exhaustive exercise-induced injury by enhancing mitochondrial respiratory function and mitochondrial biogenesis key signaling pathway PGC-1α–NRF1/NRF2 in rats. Methods. Male Sprague-Dawley rats were divided into 4 groups: sedentary (C), exhaustive exercise (EE), low-dose SAL (LS), and high-dose SAL (HS). After one-time exhaustive swimming exercise, we measured the changes in cardiomyocyte ultrastructure and cardiac marker enzymes and mitochondrial electron transport system (ETS) complexes activities in situ. We also measured mitochondrial biogenesis master regulator PGC-1α and its downstream transcription factors, NRF1 and NRF2, expression at gene and protein levels. Results. Compared to C group, the EE group showed marked myocardium ultrastructure injury and decrease of mitochondrial respiratory function (P < 0.05) and protein levels of PGC-1α, NRF1, and NRF2 (P < 0.05) but a significant increase of PGC-1α, NRF1, and NRF2 genes levels (P < 0.05); compared to EE group, SAL ameliorated myocardium injury, increased mitochondrial respiratory function (P < 0.05), and elevated both gene and protein levels of PGC-1α, NRF-1, and NRF-2. Conclusion. Salidroside can protect the heart from exhaustive exercise-induced injury. It might act by improving myocardial mitochondrial respiratory function by stimulating the expression of PGC-1α–NRF1/NRF2 pathway. PMID:26167242

  4. Hyperglycemia decreases mitochondrial function: The regulatory role of mitochondrial biogenesis

    SciTech Connect

    Palmeira, Carlos M. Rolo, Anabela P.; Berthiaume, Jessica; Bjork, James A.; Wallace, Kendall B.

    2007-12-01

    Increased generation of reactive oxygen species (ROS) is implicated in 'glucose toxicity' in diabetes. However, little is known about the action of glucose on the expression of transcription factors in hepatocytes, especially those involved in mitochondrial DNA (mtDNA) replication and transcription. Since mitochondrial functional capacity is dynamically regulated, we hypothesized that stressful conditions of hyperglycemia induce adaptations in the transcriptional control of cellular energy metabolism, including inhibition of mitochondrial biogenesis and oxidative metabolism. Cell viability, mitochondrial respiration, ROS generation and oxidized proteins were determined in HepG2 cells cultured in the presence of either 5.5 mM (control) or 30 mM glucose (high glucose) for 48 h, 96 h and 7 days. Additionally, mtDNA abundance, plasminogen activator inhibitor-1 (PAI-1), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF-1) transcripts were evaluated by real time PCR. High glucose induced a progressive increase in ROS generation and accumulation of oxidized proteins, with no changes in cell viability. Increased expression of PAI-1 was observed as early as 96 h of exposure to high glucose. After 7 days in hyperglycemia, HepG2 cells exhibited inhibited uncoupled respiration and decreased MitoTracker Red fluorescence associated with a 25% decrease in mtDNA and 16% decrease in TFAM transcripts. These results indicate that glucose may regulate mtDNA copy number by modulating the transcriptional activity of TFAM in response to hyperglycemia-induced ROS production. The decrease of mtDNA content and inhibition of mitochondrial function may be pathogenic hallmarks in the altered metabolic status associated with diabetes.

  5. Molecular Genetics of Mitochondrial Biogenesis in Maize.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mitochondrial genome encodes proteins essential for mitochondrial respiration and ATP synthesis. Nuclear gene products, however, are required for the expression of mitochondrial genes and the elaboration of functional mitochondrial protein complexes. We are exploiting a unique collection of maiz...

  6. Mitochondrial biogenesis-associated factors underlie the magnitude of response to aerobic endurance training in rats.

    PubMed

    Marton, Orsolya; Koltai, Erika; Takeda, Masaki; Koch, Lauren Gerard; Britton, Steven L; Davies, Kelvin J A; Boldogh, Istvan; Radak, Zsolt

    2015-04-01

    Trainability is important in elite sport and in recreational physical activity, and the wide range for response to training is largely dependent on genotype. In this study, we compare a newly developed rat model system selectively bred for low and high gain in running distance from aerobic training to test whether genetic segregation for trainability associates with differences in factors associated with mitochondrial biogenesis. Low response trainer (LRT) and high response trainer (HRT) rats from generation 11 of artificial selection were trained five times a week, 30 min per day for 3 months at 70 % VO2max to study the mitochondrial molecular background of trainability. As expected, we found significant differential for the gain in running distance between LRT and HRT groups as a result of training. However, the changes in VO2max, COX-4, redox homeostasis associated markers (reactive oxygen species (ROS)), silent mating-type information regulation 2 homolog (SIRT1), NAD(+)/NADH ratio, proteasome (R2 subunit), and mitochondrial network related proteins such as mitochondrial fission protein 1 (Fis1) and mitochondrial fusion protein (Mfn1) suggest that these markers are not strongly involved in the differences in trainability between LRT and HRT. On the other hand, according to our results, we discovered that differences in basal activity of AMP-activated protein kinase alpha (AMPK?) and differential changes in aerobic exercise-induced responses of citrate synthase, carbonylated protein, peroxisome proliferator-activated receptor gamma coactivator-1? (PGC1-?), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and Lon protease limit trainability between these selected lines. From this, we conclude that mitochondrial biogenesis-associated factors adapt differently to aerobic exercise training in training sensitive and training resistant rats. PMID:24943897

  7. Contribution of mitochondrial function to exercise-induced attenuation of renal dysfunction in spontaneously hypertensive rats.

    PubMed

    Gu, Qi; Zhao, Li; Ma, Yan-Ping; Liu, Jian-Dong

    2015-08-01

    It is well known that exercise training exhibits renal protective effects in animal models of hypertension and chronic renal failure. However, the mechanisms regulating these effects of exercise training remain unclear. This study aimed to investigate the role of mitochondrial function in exercise-induced attenuation of renal injury in spontaneously hypertensive rats (SHR). The adult male SHR and age-matched normotensive Wistar-Kyoto rats (WKY) were given moderate-intensity exercise for 12 weeks or treated with MitoQ10 for 8 weeks. In this work, exercise training in SHR reduced blood pressure, and effectively attenuated renal dysfunction, marked by reduced creatinine excretion, albuminuria, blood urea nitrogen, and glomerular sclerosis. Exercise training in SHR reduced MDA levels in plasma and kidneys and suppressed formation of 3-nitrotyrosine in kidneys. Exercise training suppressed mitochondrial ROS and [Formula: see text] formation, enhanced ATP formation, reduced mitochondrial swelling, and restored electron transport chain enzyme activity in kidneys of SHR. Furthermore, exercise training upregulated protein expression of uncoupling protein 2 and manganese superoxide dismutase in kidneys of SHR. In addition, treatment with mitochondria-targeted antioxidant MitoQ10 exhibited similar renal protective effects in SHR. In conclusion, chronic aerobic exercise training preserved mitochondrial function and abated oxidative stress in the kidneys of SHR, which may in part explain the protective effect of exercise on renal function and structure in hypertensive individuals. PMID:25963667

  8. Mitochondrial Biogenesis as a Pharmacological Target: A New Approach to Acute and Chronic Diseases.

    PubMed

    Whitaker, Ryan M; Corum, Daniel; Beeson, Craig C; Schnellmann, Rick G

    2016-01-01

    Mitochondrial dysfunction is a key pathophysiological component of many acute and chronic diseases. Maintenance of mitochondrial homeostasis through the balance of mitochondrial turnover, fission and fusion, and generation of new mitochondria via mitochondrial biogenesis is critical for tissue health. Pharmacological activation of mitochondrial biogenesis can enhance oxidative metabolism and tissue bioenergetics, and improve organ function in conditions characterized by mitochondrial dysfunction. However, owing to the complexity of mitochondrial assembly and maintenance, identification of specific activators of mitochondrial biogenesis has been difficult. This review provides an overview of the role of mitochondrial dysfunction in acute and chronic diseases, details the current state of therapeutics for the stimulation of mitochondrial biogenesis and their effects on disease outcomes, describes new screening methodologies to identify novel stimulators and noncanonical pathways of mitochondrial biogenesis, and discusses potential hurdles of mitochondrial biogenesis as a therapeutic strategy. PMID:26566156

  9. Chronic Caloric Restriction Preserves Mitochondrial Function in Senescence Without Increasing Mitochondrial Biogenesis

    PubMed Central

    Lanza, Ian R.; Zabielski, Piotrek; Klaus, Katherine A.; Morse, Dawn M.; Heppelmann, Carrie J.; Bergen, H. Robert; Dasari, Surendra; Walrand, Stephane; Short, Kevin R.; Johnson, Matthew L.; Robinson, Matthew M.; Schimke, Jill M.; Jakaitis, Daniel R.; Asmann, Yan W.; Sun, Zhifu; Nair, K. Sreekumaran

    2012-01-01

    SUMMARY Caloric restriction (CR) mitigates many detrimental effects of aging and prolongs lifespan. CR has been suggested to increase mitochondrial biogenesis, thereby attenuating age-related declines in mitochondrial function; a concept that is challenged by recent studies. Here we show that lifelong CR in mice prevents age-related loss of mitochondrial oxidative capacity and efficiency, measured in isolated mitochondria and permeabilized muscle fibers. We find that these beneficial effects of CR occur without increasing mitochondrial abundance. Whole-genome expression profiling and large-scale proteomic surveys revealed expression patterns inconsistent with increased mitochondrial biogenesis, which is further supported by lower mitochondrial protein synthesis with CR. We find that CR decreases oxidant emission, increases antioxidant scavenging, and minimizes oxidative damage to DNA and protein. These results demonstrate that CR preserves mitochondrial function by protecting the integrity and function of existing cellular components rather than by increasing mitochondrial biogenesis. PMID:23217257

  10. Echinochrome A Increases Mitochondrial Mass and Function by Modulating Mitochondrial Biogenesis Regulatory Genes

    PubMed Central

    Jeong, Seung Hun; Kim, Hyoung Kyu; Song, In-Sung; Noh, Su Jin; Marquez, Jubert; Ko, Kyung Soo; Rhee, Byoung Doo; Kim, Nari; Mishchenko, Natalia P.; Fedoreyev, Sergey A.; Stonik, Valentin A.; Han, Jin

    2014-01-01

    Echinochrome A (Ech A) is a natural pigment from sea urchins that has been reported to have antioxidant properties and a cardio protective effect against ischemia reperfusion injury. In this study, we ascertained whether Ech A enhances the mitochondrial biogenesis and oxidative phosphorylation in rat cardio myoblast H9c2 cells. To study the effects of Ech A on mitochondrial biogenesis, we measured mitochondrial mass, level of oxidative phosphorylation, and mitochondrial biogenesis regulatory gene expression. Ech A treatment did not induce cytotoxicity. However, Ech A treatment enhanced oxygen consumption rate and mitochondrial ATP level. Likewise, Ech A treatment increased mitochondrial contents in H9c2 cells. Furthermore, Ech A treatment up-regulated biogenesis of regulatory transcription genes, including proliferator-activated receptor gamma co-activator (PGC)-1?, estrogen-related receptor (ERR)-?, peroxisome proliferator-activator receptor (PPAR)-?, and nuclear respiratory factor (NRF)-1 and such mitochondrial transcription regulatory genes as mitochondrial transcriptional factor A (TFAM), mitochondrial transcription factor B2 (TFB2M), mitochondrial DNA direct polymerase (POLMRT), single strand binding protein (SSBP) and Tu translation elongation factor (TUFM). In conclusion, these data suggest that Ech A is a potentiated marine drug which enhances mitochondrial biogenesis. PMID:25196935

  11. Stress triggers mitochondrial biogenesis to preserve steroidogenesis in Leydig cells.

    PubMed

    Gak, Igor A; Radovic, Sava M; Dukic, Aleksandra R; Janjic, Marija M; Stojkov-Mimic, Natasa J; Kostic, Tatjana S; Andric, Silvana A

    2015-10-01

    Adaptability to stress is a fundamental prerequisite for survival. Mitochondria are a key component of the stress response in all cells. For steroid-hormones-producing cells, including also Leydig cells of testes, the mitochondria are a key control point for the steroid biosynthesis and regulation. However, the mitochondrial biogenesis in steroidogenic cells has never been explored. Here we show that increased mitochondrial biogenesis is the adaptive response of testosterone-producing Leydig cells from stressed rats. All markers of mitochondrial biogenesis together with transcription factors and related kinases are up-regulated in Leydig cells from rats exposed to repeated psychophysical stress. This is followed with increased mitochondrial mass. The expression of PGC1, master regulator of mitochondrial biogenesis and integrator of environmental signals, is stimulated by cAMP-PRKA, cGMP, and ?-adrenergic receptors. Accordingly, stress-triggered mitochondrial biogenesis represents an adaptive mechanism and does not only correlate with but also is an essential for testosterone production, being both events depend on the same regulators. Here we propose that all events induced by acute stress, the most common stress in human society, provoke adaptive response of testosterone-producing Leydig cells and activate PGC1, a protein required to make new mitochondria but also protector against the oxidative damage. Given the importance of mitochondria for steroid hormones production and stress response, as well as the role of steroid hormones in stress response and metabolic syndrome, we anticipate our result to be a starting point for more investigations since stress is a constant factor in life and has become one of the most significant health problems in modern societies. PMID:26036344

  12. Mitochondrial Dysregulation in the Pathogenesis of Diabetes: Potential for Mitochondrial Biogenesis-Mediated Interventions

    PubMed Central

    Joseph, Anna-Maria; Joanisse, Denis R.; Baillot, Richard G.; Hood, David A.

    2012-01-01

    Muscle mitochondrial metabolism is a tightly controlled process that involves the coordination of signaling pathways and factors from both the nuclear and mitochondrial genomes. Perhaps the most important pathway regulating metabolism in muscle is mitochondrial biogenesis. In response to physiological stimuli such as exercise, retrograde signaling pathways are activated that allow crosstalk between the nucleus and mitochondria, upregulating hundreds of genes and leading to higher mitochondrial content and increased oxidation of substrates. With type 2 diabetes, these processes can become dysregulated and the ability of the cell to respond to nutrient and energy fluctuations is diminished. This, coupled with reduced mitochondrial content and altered mitochondrial morphology, has been directly linked to the pathogenesis of this disease. In this paper, we will discuss our current understanding of mitochondrial dysregulation in skeletal muscle as it relates to type 2 diabetes, placing particular emphasis on the pathways of mitochondrial biogenesis and mitochondrial dynamics, and the therapeutic value of exercise and other interventions. PMID:22203837

  13. Selenite Stimulates Mitochondrial Biogenesis Signaling and Enhances Mitochondrial Functional Performance in Murine Hippocampal Neuronal Cells

    PubMed Central

    Idris, Haza; Kumari, Santosh; Li, P. Andy

    2012-01-01

    Supplementation of selenium has been shown to protect cells against free radical mediated cell damage. The objectives of this study are to examine whether supplementation of selenium stimulates mitochondrial biogenesis signaling pathways and whether selenium enhances mitochondrial functional performance. Murine hippocampal neuronal HT22 cells were treated with sodium selenite for 24 hours. Mitochondrial biogenesis markers, mitochondrial respiratory rate and activities of mitochondrial electron transport chain complexes were measured and compared to non-treated cells. The results revealed that treatment of selenium to the HT22 cells elevated the levels of nuclear mitochondrial biogenesis regulators PGC-1? and NRF1, as well as mitochondrial proteins cytochrome c and cytochrome c oxidase IV (COX IV). These effects are associated with phosphorylation of Akt and cAMP response element-binding (CREB). Supplementation of selenium significantly increased mitochondrial respiration and improved the activities of mitochondrial respiratory complexes. We conclude that selenium activates mitochondrial biogenesis signaling pathway and improves mitochondrial function. These effects may be associated with modulation of AKT-CREB pathway. PMID:23110128

  14. Exercise-induced heart mitochondrial cholesterol depletion influences the inhibition of mitochondrial swelling.

    PubMed

    Ziolkowski, Wieslaw; Vadhana M S, Dhivya; Kaczor, Jan Jacek; Olek, Robert Antoni; Flis, Damian Jozef; Halon, Malgorzata; Wozniak, Michal; Fedeli, Donatella; Carloni, Manuel; Antosiewicz, Jedrzej; Gabbianelli, Rosita

    2013-10-01

    The significance of the reduction of the cholesterol pool in heart mitochondria after exercise is still unknown. Recently, published data have suggested that cholesterol may influence the components of mitochondrial contact site and affect mitochondrial swelling. Therefore, the aim of this study was to determine whether the decreased cholesterol content in heart mitochondria caused by prolonged swimming may provoke changes in their bioenergetics and result in an increased resistance to calcium chloride-induced mitochondrial swelling. Male Wistar rats were divided into a sedentary control group and an exercise group. The rats exercised for 3 h, burdened with an additional 3% of their body weight. Their hearts were removed immediately after completing the exercise. The left ventricle was divided and used for experiments. Mitochondrial cholesterol content, membrane fluidity and mitochondrial bioenergetics were measured in the control and exercised rat heart mitochondria. To assess whether mitochondrial modifications are linked to disruption of lipid microdomains, methyl-β-cyclodextrin, a well-known lipid microdomain-disrupting agent and cholesterol chelator, was applied to the mitochondria of the control group. Cholesterol depletion, increased membrane fluidity and increased resistance to calcium chloride-induced swelling were observed in postexercise heart crude mitochondrial fraction. Similar results were achieved in control mitochondria treated with 2% methyl-β-cyclodextrin. All of the mitochondrial bioenergetics parameters were similar between the groups. Therefore, the disruption of raft-like microdomains appears to be an adaptive change in the rat heart following exercise. PMID:23733522

  15. Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

    PubMed Central

    Nisoli, Enzo; Falcone, Sestina; Tonello, Cristina; Cozzi, Valeria; Palomba, Letizia; Fiorani, Mara; Pisconti, Addolorata; Brunelli, Silvia; Cardile, Annalisa; Francolini, Maura; Cantoni, Orazio; Carruba, Michele O.; Moncada, Salvador; Clementi, Emilio

    2004-01-01

    We recently found that long-term exposure to nitric oxide (NO) triggers mitochondrial biogenesis in mammalian cells and tissues by activation of guanylate cyclase and generation of cGMP. Here, we report that the NO/cGMP-dependent mitochondrial biogenesis is associated with enhanced coupled respiration and content of ATP in U937, L6, and PC12 cells. The observed increase in ATP content depended entirely on oxidative phosphorylation, because ATP formation by glycolysis was unchanged. Brain, kidney, liver, heart, and gastrocnemius muscle from endothelial NO synthase null mutant mice displayed markedly reduced mitochondrial content associated with significantly lower oxygen consumption and ATP content. In these tissues, ultrastructural analyses revealed significantly smaller mitochondria. Furthermore, a significant reduction in the number of mitochondria was observed in the subsarcolemmal region of the gastrocnemius muscle. We conclude that NO/cGMP stimulates mitochondrial biogenesis, both in vitro and in vivo, and that this stimulation is associated with increased mitochondrial function, resulting in enhanced formation of ATP. PMID:15545607

  16. Increases in Mitochondrial Biogenesis Impair Carcinogenesis at Multiple Levels

    PubMed Central

    Wang, Xiao; Moraes, Carlos T.

    2011-01-01

    Although mitochondrial respiration is decreased in most cancer cells, the role of this decrease in carcinogenesis and cancer progression is still unclear. To better understand this phenomenon, instead of further inhibiting mitochondrial function, we induced mitochondrial biogenesis in transformed cells by activating the peroxisome proliferator-activated receptors (PPARs)/ peroxisome proliferator-activated receptor gamma co-activator 1? (PGC-1?) pathways. This was achieved by treating the cells with bezafibrate, a PPARs panagonist that also enhances PGC-1? expression. We confirmed that bezafibrate treatment led to increased mitochondrial proteins and enzyme functions. We found that cells with increased mitochondrial biogenesis had decreased growth rates in glucose-containing medium. In addition, they became less invasive, which was directly linked to the reduced lactate levels. Surprisingly, even though bezafibrate-treated cells had higher levels of mitochondrial markers, total respiration was not significantly altered. However, respiratory coupling, and ATP levels were. Our data show that by increasing the efficiency of the mitochondrial oxidative phosphorylation system, cancer progression is hampered by decreases in cell proliferation and invasiveness. PMID:21855427

  17. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance.

    PubMed

    Davis, J Mark; Murphy, E Angela; Carmichael, Martin D; Davis, Ben

    2009-04-01

    Quercetin is one of a broad group of natural polyphenolic flavonoid substances that are being investigated for their widespread health benefits. These benefits have generally been ascribed to its combination of antioxidant and anti-inflammatory activity, but recent in vitro evidence suggests that improved mitochondrial biogenesis could play an important role. In addition, the in vivo effects of quercetin on mitochondrial biogenesis exercise tolerance are unknown. We examined the effects of 7 days of quercetin feedings in mice on markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance. Mice were randomly assigned to one of the following three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin. Following 7 days of treatment, mice were killed, and soleus muscle and brain were analyzed for mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha) and sirtuin 1 (SIRT1), and mitochondrial DNA (mtDNA) and cytochrome c. Additional mice underwent a treadmill performance run to fatigue or were placed in voluntary activity wheel cages, and their voluntary activity (distance, time, and peak speed) was recorded. Quercetin increased mRNA expression of PGC-1alpha and SIRT1 (P < 0.05), mtDNA (P < 0.05) and cytochrome c concentration (P < 0.05). These changes in markers of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (P < 0.05) and voluntary wheel-running activity (P < 0.05). These benefits of querectin on fitness without exercise training may have important implications for enhancement of athletic and military performance and may also extend to prevention and/or treatment of chronic diseases. PMID:19211721

  18. A?25-35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons.

    PubMed

    Dong, Weiguo; Wang, Feng; Guo, Wanqing; Zheng, Xuehua; Chen, Yue; Zhang, Wenguang; Shi, Hong

    2016-01-01

    Mitochondrial biogenesis is involved in the regulation of mitochondrial content, morphology, and function. Impaired mitochondrial biogenesis has been observed in Alzheimer's disease. Amyloid-? (A?) has been shown to cause mitochondrial dysfunction in cultured neurons, but its role in mitochondrial biogenesis in neurons remains poorly defined. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are key energy-sensing molecules regulating mitochondrial biogenesis. In addition, peroxisome proliferator-activated receptor-? coactivator 1-alpha (PGC-1?), the master regulator of mitochondrial biogenesis, is a target for SIRT1 deacetylase activity. In this study, we investigated the effects of A?25-35 on mitochondrial biogenesis in cultured hippocampal neurons and the underlying mechanisms. In primary hippocampal neurons, we found that 24-h incubation with A?25-35 suppressed both phosphorylations of AMPK and SIRT1 expression and increased PGC-1? acetylation expression. In addition, A?25-35 also resulted in a decrease in mitochondrial DNA copy number, as well as decreases in the expression of mitochondrial biogenesis factors (PGC-1?, NRF 1, NRF 2, and Tfam). Taken together, these data show that A?25-35 suppresses mitochondrial biogenesis in hippocampal neurons. A?25-35-induced impairment of mitochondrial biogenesis may be associated with the inhibition of the AMPK-SIRT1-PGC-1? pathway. PMID:26055049

  19. Relationships between exercise, mitochondrial biogenesis and type 2 diabetes.

    PubMed

    Joseph, Anna-Maria; Hood, David A

    2014-01-01

    Skeletal muscle is the major site of insulin-stimulated glucose utilization in the body. Central to this process is oxidative metabolism, which is controlled by mitochondria. Therefore, defects in the biogenesis of this organelle can impact the ability of muscle to oxidize substrates and can have grave consequences on the action of insulin on glucose uptake. In healthy muscle, glucose and free fatty acids (FFAs) are efficiently metabolized preventing the accumulation of harmful lipid by-products. In contrast, in pre-diabetic conditions, reduced oxidative capacity, high levels of reactive oxygen species, and chronic elevations in FFAs culminate in greater intramyocellular lipids and lipid metabolites that interfere with insulin signaling pathways, and contribute to lower insulin sensitivity. While the extent of the involvement of mitochondria in insulin resistance and type 2 diabetes (T2D) is still an ongoing debate, there is compelling evidence to suggest that dysfunction in mitochondria, mediated by changes in gene expression, morphology, and mitochondrial turnover, contributes to the dysregulation of insulin signaling pathways observed with this metabolic syndrome. In the present review, we discuss our current understanding of mitochondrial biogenesis and highlight how dysfunction in key mitochondrial biogenesis pathways may play an important role in the pathogenesis of T2D. Moreover, we provide evidence supporting the therapeutic value of exercise in the prevention and treatment of metabolic syndromes such as T2D. PMID:25226800

  20. Coordination of plant mitochondrial biogenesis: keeping pace with cellular requirements

    PubMed Central

    Welchen, Elina; García, Lucila; Mansilla, Natanael; Gonzalez, Daniel H.

    2014-01-01

    Plant mitochondria are complex organelles that carry out numerous metabolic processes related with the generation of energy for cellular functions and the synthesis and degradation of several compounds. Mitochondria are semiautonomous and dynamic organelles changing in shape, number, and composition depending on tissue or developmental stage. The biogenesis of functional mitochondria requires the coordination of genes present both in the nucleus and the organelle. In addition, due to their central role, all processes held inside mitochondria must be finely coordinated with those in other organelles according to cellular demands. Coordination is achieved by transcriptional control of nuclear genes encoding mitochondrial proteins by specific transcription factors that recognize conserved elements in their promoter regions. In turn, the expression of most of these transcription factors is linked to developmental and environmental cues, according to the availability of nutrients, light–dark cycles, and warning signals generated in response to stress conditions. Among the signals impacting in the expression of nuclear genes, retrograde signals that originate inside mitochondria help to adjust mitochondrial biogenesis to organelle demands. Adding more complexity, several nuclear encoded proteins are dual localized to mitochondria and either chloroplasts or the nucleus. Dual targeting might establish a crosstalk between the nucleus and cell organelles to ensure a fine coordination of cellular activities. In this article, we discuss how the different levels of coordination of mitochondrial biogenesis interconnect to optimize the function of the organelle according to both internal and external demands. PMID:24409193

  1. Impaired Mitochondrial Biogenesis in Adipose Tissue in Acquired Obesity.

    PubMed

    Heinonen, Sini; Buzkova, Jana; Muniandy, Maheswary; Kaksonen, Risto; Ollikainen, Miina; Ismail, Khadeeja; Hakkarainen, Antti; Lundbom, Jesse; Lundbom, Nina; Vuolteenaho, Katriina; Moilanen, Eeva; Kaprio, Jaakko; Rissanen, Aila; Suomalainen, Anu; Pietilinen, Kirsi H

    2015-09-01

    Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8-36.2 years of age, who were discordant (?BMI >3 kg/m(2), mean length of discordance 6.3 0.3 years, n = 26) and concordant (?BMI <3 kg/m(2), n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage. PMID:25972572

  2. Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults

    PubMed Central

    Hasegawa, Koichi; Yasuda, Toru; Shiraishi, Chinatsu; Fujiwara, Kazushiro; Przedborski, Serge; Mochizuki, Hideki; Yoshikawa, Kazuaki

    2016-01-01

    Neurons rely heavily on mitochondria for their function and survival. Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease. PGC-1α is a master regulator of mitochondrial biogenesis and function. Here we identify necdin as a potent PGC-1α stabilizer that promotes mitochondrial biogenesis via PGC-1α in mammalian neurons. Expression of genes encoding mitochondria-specific proteins decreases significantly in necdin-null cortical neurons, where mitochondrial function and expression of the PGC-1α protein are reduced. Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. Moreover, overexpression of necdin in the substantia nigra in vivo of adult mice protects dopaminergic neurons against degeneration in experimental Parkinson's disease. These data reveal that necdin promotes mitochondrial biogenesis through stabilization of endogenous PGC-1α to exert neuroprotection against mitochondrial insults. PMID:26971449

  3. Resveratrol Regulates Mitochondrial Biogenesis and Fission/Fusion to Attenuate Rotenone-Induced Neurotoxicity

    PubMed Central

    Peng, Kaige; Tao, Yuan; Zhang, Jun; Wang, Jian; Ye, Feng; Dan, Guorong; Zhao, Yuanpeng; Cai, Ying; Zhao, Jiqing; Wu, Qiang; Zou, Zhongmin; Cao, Jia; Sai, Yan

    2016-01-01

    It has been confirmed that mitochondrial impairment may underlie both sporadic and familial Parkinson's disease (PD). Mitochondrial fission/fusion and biogenesis are key processes in regulating mitochondrial homeostasis. Therefore, we explored whether the protective effect of resveratrol in rotenone-induced neurotoxicity was associated with mitochondrial fission/fusion and biogenesis. The results showed that resveratrol could not only promote mitochondrial mass and DNA copy number but also improve mitochondrial homeostasis and neuron function in rats and PC12 cells damaged by rotenone. We also observed effects with alterations in proteins known to regulate mitochondrial fission/fusion and biogenesis in rotenone-induced neurotoxicity. Therefore, our findings suggest that resveratrol may prevent rotenone-induced neurotoxicity through regulating mitochondrial fission/fusion and biogenesis. PMID:26770656

  4. Acute Exercise-Induced Mitochondrial Stress Triggers an Inflammatory Response in the Myocardium via NLRP3 Inflammasome Activation with Mitophagy

    PubMed Central

    Li, Haiying; Miao, Weiguo; Ma, Jingfen; Xv, Zhen; Li, Jianyu; Zhang, Yong; Ji, Li Li

    2016-01-01

    Increasing evidence has indicated that acute strenuous exercise can induce a range of adverse reactions including oxidative stress and tissue inflammation. However, little is currently known regarding the mechanisms that underlie the regulation of the inflammatory response in the myocardium during acute heavy exercise. This study evaluated the mitochondrial function, NLRP3 inflammasome activation, and mitochondrial autophagy-related proteins to investigate the regulation and mechanism of mitochondrial stress regarding the inflammatory response of the rat myocardium during acute heavy exercise. The results indicated that the mitochondrial function of the myocardium was adaptively regulated to meet the challenge of stress during acute exercise. The exercise-induced mitochondrial stress also enhanced ROS generation and triggered an inflammatory reaction via the NLRP3 inflammasome activation. Moreover, the mitochondrial autophagy-related proteins including Beclin1, LC3, and Bnip3 were all significantly upregulated during acute exercise, which suggests that mitophagy was stimulated in response to the oxidative stress and inflammatory response in the myocardium. Taken together, our data suggest that, during acute exercise, mitochondrial stress triggers the rat myocardial inflammatory response via NLRP3 inflammasome activation and activates mitophagy to minimize myocardial injury. PMID:26770647

  5. Acute Exercise-Induced Mitochondrial Stress Triggers an Inflammatory Response in the Myocardium via NLRP3 Inflammasome Activation with Mitophagy.

    PubMed

    Li, Haiying; Miao, Weiguo; Ma, Jingfen; Xv, Zhen; Bo, Hai; Li, Jianyu; Zhang, Yong; Ji, Li Li

    2016-01-01

    Increasing evidence has indicated that acute strenuous exercise can induce a range of adverse reactions including oxidative stress and tissue inflammation. However, little is currently known regarding the mechanisms that underlie the regulation of the inflammatory response in the myocardium during acute heavy exercise. This study evaluated the mitochondrial function, NLRP3 inflammasome activation, and mitochondrial autophagy-related proteins to investigate the regulation and mechanism of mitochondrial stress regarding the inflammatory response of the rat myocardium during acute heavy exercise. The results indicated that the mitochondrial function of the myocardium was adaptively regulated to meet the challenge of stress during acute exercise. The exercise-induced mitochondrial stress also enhanced ROS generation and triggered an inflammatory reaction via the NLRP3 inflammasome activation. Moreover, the mitochondrial autophagy-related proteins including Beclin1, LC3, and Bnip3 were all significantly upregulated during acute exercise, which suggests that mitophagy was stimulated in response to the oxidative stress and inflammatory response in the myocardium. Taken together, our data suggest that, during acute exercise, mitochondrial stress triggers the rat myocardial inflammatory response via NLRP3 inflammasome activation and activates mitophagy to minimize myocardial injury. PMID:26770647

  6. Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery.

    PubMed

    Vanasco, Virginia; Saez, Trinidad; Magnani, Natalia D; Pereyra, Leonardo; Marchini, Timoteo; Corach, Alejandra; Vaccaro, Mara Ins; Corach, Daniel; Evelson, Pablo; Alvarez, Silvia

    2014-12-01

    Mitochondrial biogenesis emerges as a compensatory mechanism involved in the recovery process in endotoxemia and sepsis. The aim of this work was to analyze the time course of the cardiac mitochondrial biogenesis process occurring during endotoxemia, with emphasis on the quantitative analysis of mitochondrial function. Female Sprague-Dawley rats (45 days old) were ip injected with LPS (10 mg/kg). Measurements were performed at 0-24 h after LPS administration. PGC-1? and mtTFA expression for biogenesis and p62 and LC3 expression for autophagy were analyzed by Western blot; mitochondrial DNA levels by qPCR, and mitochondrial morphology by transmission electron microscopy. Mitochondrial function was evaluated as oxygen consumption and respiratory chain complex activity. PGC-1? and mtTFA expression significantly increased in every time point analyzed, and mitochondrial mass was increased by 20% (P<0.05) at 24 h. p62 expression was significantly decreased in a time-dependent manner. LC3-II expression was significantly increased at all time points analyzed. Ultrastructurally, mitochondria displayed several abnormalities (internal vesicles, cristae disruption, and swelling) at 6 and 18 h. Structures compatible with fusion/fission processes were observed at 24 h. A significant decrease in state 3 respiration was observed in every time point analyzed (LPS 6h: 20%, P<0.05). Mitochondrial complex I activity was found decreased by 30% in LPS-treated animals at 6 and 24h. Complex II and complex IV showed decreased activity only at 24 h. The present results show that partial restoration of cardiac mitochondrial architecture is not accompanied by improvement of mitochondrial function in acute endotoxemia. The key implication of our study is that cardiac failure due to bioenergetic dysfunction will be overcome by therapeutic interventions aimed to restore cardiac mitochondrial function. PMID:25224040

  7. CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins

    PubMed Central

    Gao, Jie; Schatton, Désirée; Martinelli, Paola; Hansen, Henriette; Pla-Martin, David; Barth, Esther; Becker, Christian; Altmueller, Janine; Frommolt, Peter; Sardiello, Marco

    2014-01-01

    Mitochondrial function requires coordination of two genomes for protein biogenesis, efficient quality control mechanisms, and appropriate distribution of the organelles within the cell. How these mechanisms are integrated is currently not understood. Loss of the Clu1/CluA homologue (CLUH) gene led to clustering of the mitochondrial network by an unknown mechanism. We find that CLUH is coregulated both with genes encoding mitochondrial proteins and with genes involved in ribosomal biogenesis and translation. Our functional analysis identifies CLUH as a cytosolic messenger ribonucleic acid (RNA; mRNA)–binding protein. RNA immunoprecipitation experiments followed by next-generation sequencing demonstrated that CLUH specifically binds a subset of mRNAs encoding mitochondrial proteins. CLUH depletion decreased the levels of proteins translated by target transcripts and caused mitochondrial clustering. A fraction of CLUH colocalizes with tyrosinated tubulin and can be detected close to mitochondria, suggesting a role in regulating transport or translation of target transcripts close to mitochondria. Our data unravel a novel mechanism linking mitochondrial biogenesis and distribution. PMID:25349259

  8. Mitochondrial biogenesis in the pulmonary vasculature during inhalation lung injury and fibrosis

    EPA Science Inventory

    Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammatio...

  9. Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations.

    PubMed

    Noh, Junghyun; Wende, Adam R; Olsen, Curtis D; Kim, Bumjun; Bevins, Jack; Zhu, Yi; Zhang, Quan-Jiang; Riehle, Christian; Abel, E Dale

    2015-12-01

    Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase in mitochondrial oxidative capacity following physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1(+/-)) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1(+/-) mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1(+/-) mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1(+/-) mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.20.2 vs. 7.10.2, P=0.001), but not in cPDPK1(+/-) (6.20.3 vs. 6.50.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.70.1 vs. 4.00.1mm, P=0.01) but not in cPDPK1(+/-) (3.80.1 vs. 3.70.1mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.60.6 vs.16.10.9, P=0.04; cPDPK1(+/-): 12.40.6 vs.15.91.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function. PMID:26476238

  10. Resveratrol Induces Hepatic Mitochondrial Biogenesis Through the Sequential Activation of Nitric Oxide and Carbon Monoxide Production

    PubMed Central

    Kim, Seul-Ki; Joe, Yeonsoo; Zheng, Min; Kim, Hyo Jeong; Yu, Jae-Kyoung; Cho, Gyeong Jae; Chang, Ki Churl; Kim, Hyoung Kyu; Han, Jin; Ryter, Stefan W.

    2014-01-01

    Abstract Aims: Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased guanosine 3′,5′-monophosphate (cGMP), and activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We sought to determine the role of NO, heme oxygenase-1 (HO-1), and its reaction product (carbon monoxide [CO]) in the induction of mitochondrial biogenesis by the natural antioxidant resveratrol. Results: S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced mitochondrial biogenesis in HepG2 hepatoma cells, and in vivo, through stimulation of PGC-1α. NO-induced mitochondrial biogenesis required cGMP, and was mimicked by the cGMP analogue (8-bromoguanosine 3′,5′-cyclic monophosphate [8-Br-cGMP]). Activation of mitochondrial biogenesis by SNAP required HO-1, as it could be reversed by genetic interference of HO-1; and by treatment with the HO inhibitor tin-protoporphyrin-IX (SnPP) in vitro and in vivo. Cobalt protoporphyrin (CoPP)-IX, an HO-1 inducing agent, stimulated mitochondrial biogenesis in HepG2 cells, which could be reversed by the CO scavenger hemoglobin. Application of CO, using the CO-releasing molecule-3 (CORM-3), stimulated mitochondrial biogenesis in HepG2 cells, in a cGMP-dependent manner. Both CoPP and CORM-3-induced mitochondrial biogenesis required NF-E2-related factor-2 (Nrf2) activation and phosphorylation of Akt. The natural antioxidant resveratrol induced mitochondrial biogenesis in HepG2 cells, in a manner dependent on NO biosynthesis, cGMP synthesis, Nrf2-dependent HO-1 activation, and endogenous CO production. Furthermore, resveratrol preserved mitochondrial biogenesis during lipopolysaccharides-induced hepatic inflammation in vivo. Innovation and Conclusions: The complex interplay between endogenous NO and CO production may underlie the mechanism by which natural antioxidants induce mitochondrial biogenesis. Strategies aimed at improving mitochondrial biogenesis may be used as therapeutics for the treatment of diseases involving mitochondrial dysfunction. Antioxid. Redox Signal. 20, 2589–2605. PMID:24041027

  11. ?2-adrenoceptor agonists in the regulation of mitochondrial biogenesis

    PubMed Central

    Peterson, Yuri K.; Cameron, Robert B.; Wills, Lauren P.; Trager, Richard E.; Lindsey, Chris C.; Beeson, Craig C.; Schnellmann, Rick G.

    2014-01-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of ?2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of ?2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB. PMID:23954364

  12. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

    PubMed Central

    Suliman, Hagir B.; Carraway, Martha Sue; Ali, Abdelwahid S.; Reynolds, Chrystal M.; Welty-Wolf, Karen E.; Piantadosi, Claude A.

    2007-01-01

    The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis. PMID:18037988

  13. Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer.

    PubMed

    Yu, Min; Li, Ruishu; Zhang, Juan

    2016-03-18

    Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells. PMID:26902121

  14. Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans

    PubMed Central

    Civitarese, Anthony E; Carling, Stacy; Heilbronn, Leonie K; Hulver, Mathew H; Ukropcova, Barbara; Deutsch, Walter A; Smith, Steven R; Ravussin, Eric

    2007-01-01

    Background Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. Methods and Findings The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 1.0 y), overweight (body mass index, 27.8 0.7 kg/m2) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, ?135 42 kcal/d, p = 0.002 and CREX, ?117 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% 5% in the CR group (p = 0.005) and 21% 4% in the CREX group (p < 0.004), with no change in the control group (2% 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (?0.56 0.11 arbitrary units, p = 0.003) and CREX (?0.45 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. Conclusions The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults. PMID:17341128

  15. The protease Omi regulates mitochondrial biogenesis through the GSK3β/PGC-1α pathway

    PubMed Central

    Xu, R; Hu, Q; Ma, Q; Liu, C; Wang, G

    2014-01-01

    Loss of the mitochondrial protease activity of Omi causes mitochondrial dysfunction, neurodegeneration with parkinsonian features and premature death in mnd2 (motor neuron degeneration 2) mice. However, the detailed mechanisms underlying this pathology remain largely unknown. Here, we report that Omi participates in the process of mitochondrial biogenesis, which has been linked to several neurodegenerative diseases. The mitochondrial biogenesis is deficit in mnd2 mice, evidenced by severe decreases of mitochondrial components, mitochondrial DNA and mitochondrial density. Omi cleaves glycogen synthase kinase 3β (GSK3β), a kinase promoting PPARγ coactivator-1α (PGC-1α) degradation, to regulate PGC-1α, a factor important for the mitochondrial biogenesis. In mnd2 mice, GSK3β abundance is increased and PGC-1α abundance is decreased significantly. Inhibition of GSK3β by SB216763 or overexpression of PGC-1α can restore mitochondrial biogenesis in mnd2 mice or Omi-knockdown N2a cells. Furthermore, there is a significant improvement of the movement ability of mnd2 mice after SB216763 treatment. Thus, our study identified Omi as a novel regulator of mitochondrial biogenesis, involving in Omi protease-deficient-induced neurodegeneration. PMID:25118933

  16. Alternative NF-?B Regulates RANKL-Induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms.

    PubMed

    Zeng, Rong; Faccio, Roberta; Novack, Deborah V

    2015-12-01

    Mitochondrial biogenesis, the generation of new mitochondrial DNA and proteins, has been linked to osteoclast (OC) differentiation and function. In this study we used mice with mutations in key alternative NF-?B pathway proteins, RelB and NF-?B-inducing kinase (NIK), to dissect the complex relationship between mitochondrial biogenesis and osteoclastogenesis. In OC precursors lacking either NIK or RelB, receptor activator of NF-?B ligand (RANKL) was unable to increase mitochondrial DNA or oxidative phosphorylation (OxPhos) protein expression, which was associated with lower oxygen consumption rates. Transgenic OC precursors expressing constitutively active NIK showed normal RANKL-induced mitochondrial biogenesis (OxPhos expression and mitochondria copy number) compared to controls, but larger mitochondrial dimensions and increased oxygen consumption rates, suggesting increased mitochondrial function. To deduce the mechanism for mitochondrial biogenesis defects in NIK-deficient and RelB-deficient precursors, we examined expression of genes known to control this process. PGC-1? (Ppargc1b) expression, but not PGC-1?, PPRC1, or ERR?, was significantly reduced in RelB(-/-) and NIK(-/-) OCs. Because PGC-1? has been reported to positively regulate both mitochondrial biogenesis and differentiation in OCs, we retrovirally overexpressed PGC-1? in RelB(-/-) cells, but surprisingly found that it did not affect differentiation, nor did it restore RANKL-induced mitochondrial biogenesis. To determine whether the blockade in osteoclastogenesis in RelB-deficient cells precludes mitochondrial biogenesis, we rescued RelB(-/-) differentiation via overexpression of NFATc1. Mitochondrial parameters in neither WT nor RelB-deficient cultures were affected by NFATc1 overexpression, and bone resorption in RelB(-/-) was not restored. Furthermore, NFATc1 co-overexpression with PGC-1?, although allowing OC differentiation, did not rescue mitochondrial biogenesis or bone resorption in RelB(-/-) OCs, by CTX-I levels. Thus, our results indicate that the alternative NF-?B pathway plays dual, but distinct, roles in controlling the independent processes of OC differentiation and OC mitochondrial biogenesis. Furthermore, the inability of PGC-1? to drive mitochondrial biogenesis in OCs without RelB indicates a cell-type specificity in mitochondria regulation. 2015 American Society for Bone and Mineral Research. PMID:26094846

  17. Exercise Increases Mitochondrial PGC-1α Content and Promotes Nuclear-Mitochondrial Cross-talk to Coordinate Mitochondrial Biogenesis*

    PubMed Central

    Safdar, Adeel; Little, Jonathan P.; Stokl, Andrew J.; Hettinga, Bart P.; Akhtar, Mahmood; Tarnopolsky, Mark A.

    2011-01-01

    Endurance exercise is known to induce metabolic adaptations in skeletal muscle via activation of the transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α). PGC-1α regulates mitochondrial biogenesis via regulating transcription of nuclear-encoded mitochondrial genes. Recently, PGC-1α has been shown to reside in mitochondria; however, the physiological consequences of mitochondrial PGC-1α remain unknown. We sought to delineate if an acute bout of endurance exercise can mediate an increase in mitochondrial PGC-1α content where it may co-activate mitochondrial transcription factor A to promote mtDNA transcription. C57Bl/6J mice (n = 12/group; ♀ = ♂) were randomly assigned to sedentary (SED), forced-endurance (END) exercise (15 m/min for 90 min), or forced endurance +3 h of recovery (END+3h) group. The END group was sacrificed immediately after exercise, whereas the SED and END+3h groups were euthanized 3 h after acute exercise. Acute exercise coordinately increased the mRNA expression of nuclear and mitochondrial DNA-encoded mitochondrial transcripts. Nuclear and mitochondrial abundance of PGC-1α in END and END+3h groups was significantly higher versus SED mice. In mitochondria, PGC-1α is in a complex with mitochondrial transcription factor A at mtDNA D-loop, and this interaction was positively modulated by exercise, similar to the increased binding of PGC-1α at the NRF-1 promoter. We conclude that in response to acute altered energy demands, PGC-1α re-localizes into nuclear and mitochondrial compartments where it functions as a transcriptional co-activator for both nuclear and mitochondrial DNA transcription factors. These results suggest that PGC-1α may dynamically facilitate nuclear-mitochondrial DNA cross-talk to promote net mitochondrial biogenesis. PMID:21245132

  18. Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy.

    PubMed

    Vincent, Andrea M; Edwards, James L; McLean, Lisa L; Hong, Yu; Cerri, Federica; Lopez, Ignazio; Quattrini, Angelo; Feldman, Eva L

    2010-10-01

    Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy. PMID:20473509

  19. Mild heat stress induces mitochondrial biogenesis in C2C12 myotubes.

    PubMed

    Liu, Chien-Ting; Brooks, George A

    2012-02-01

    During endurance exercise, most (≈75%) of the energy derived from the oxidation of metabolic fuels and ATP hydrolysis of muscle contraction is liberated as heat, the accumulation of which leads to an increase in body temperature. For example, the temperature of exercising muscles can rise to 40°C. Although severe heat injury can be deleterious, several beneficial effects of mild heat stress (HS), such as the improvement of insulin sensitivity in patients with type 2 diabetes, have been reported. However, among all cellular events induced by mild HS from physical activities, the direct effects and mechanisms of mild HS on mitochondrial biogenesis in skeletal muscle are least characterized. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are key energy-sensing molecules regulating mitochondrial biogenesis. In C2C12 myotubes, we found that 1 h mild HS at 40°C upregulated both AMPK activity and SIRT1 expression, as well as increased the expression of several mitochondrial biogenesis regulatory genes including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and transcription factors involved in mitochondrial biogenesis. In particular, PGC-1α expression was found to be transcriptionally regulated by mild HS. Additionally, after repeated mild HS for 5 days, protein levels of PGC-1α and several mitochondrial oxidative phosphorylation subunits were also upregulated. Repeated mild HS also significantly increased mitochondrial DNA copy number. In conclusion, these data show that mild HS is sufficient to induce mitochondrial biogenesis in C2C12 myotubes. Temperature-induced mitochondrial biogenesis correlates with activation of the AMPK-SIRT1-PGC-1α pathway. Therefore, it is possible that muscle heat production during exercise plays a role in mitochondrial biogenesis. PMID:22052865

  20. GPER mediates the effects of 17β-estradiol in cardiac mitochondrial biogenesis and function.

    PubMed

    Sbert-Roig, Miquel; Bauzá-Thorbrügge, Marco; Galmés-Pascual, Bel M; Capllonch-Amer, Gabriela; García-Palmer, Francisco J; Lladó, Isabel; Proenza, Ana M; Gianotti, Magdalena

    2016-01-15

    Considering the sexual dimorphism described in cardiac mitochondrial function and oxidative stress, we aimed to investigate the role of 17β-estradiol (E2) in these sex differences and the contribution of E2 receptors to these effects. As a model of chronic deprivation of ovarian hormones, we used ovariectomized (OVX) rats, half of which were treated with E2. Ovariectomy decreased markers of cardiac mitochondrial biogenesis and function and also increased oxidative stress, whereas E2 counteracted these effects. In H9c2 cardiomyocytes we observed that G-protein coupled estrogen receptor (GPER) agonist mimicked the effects of E2 in enhancing mitochondrial function and biogenesis, whereas GPER inhibitor neutralized them. These data suggest that E2 enhances mitochondrial function and decreases oxidative stress in cardiac muscle, thus it could be responsible for the sexual dimorphism observed in mitochondrial biogenesis and function in this tissue. These effects seem to be mediated through GPER stimulation. PMID:26628039

  1. Resveratrol protects cardiomyocytes from oxidative stress through SIRT1 and mitochondrial biogenesis signaling pathways.

    PubMed

    Li, Yong-guang; Zhu, Wei; Tao, Jian-ping; Xin, Ping; Liu, Ming-ya; Li, Jing-bo; Wei, Meng

    2013-08-23

    Reactive oxygen species (ROS) is generated by oxidative stress and plays an important role in various cardiac pathologies. The SIRT1 signaling pathway and mitochondrial biogenesis play essential roles in mediating the production of ROS. SIRT1 activated by resveratrol protects cardiomyocytes from oxidative stress, but the exact mechanisms by which SIRT1 prevents oxidative stress, and its relationship with mitochondrial biogenesis, remain unclear. In this study, it was observed that after stimulation with 50μMH2O2 for 6h, H9C2 cells produced excessive ROS and downregulated SIRT1. The mitochondrial protein NDUFA13 was also downregulated by ROS mediated by SIRT1. Resveratrol induced the expression of SIRT1 and mitochondrial genes NDUFA1, NDUFA2, NDUFA13 and Mn-SOD. However, the production of these genes was reversed by SIRT1 inhibitor nicotinamide. These results suggest that resveratrol inhibits ROS generation in cardiomyocytes via SIRT1 and mitochondrial biogenesis signaling pathways. PMID:23891692

  2. The fusogenic lipid phosphatidic acid promotes the biogenesis of mitochondrial outer membrane protein Ugo1

    PubMed Central

    Keller, Michael; Taskin, Asli A.; Horvath, Susanne E.; Guan, Xue Li; Prinz, Claudia; Opalińska, Magdalena; Zorzin, Carina; van der Laan, Martin; Wenk, Markus R.; Schubert, Rolf; Wiedemann, Nils; Holzer, Martin

    2015-01-01

    Import and assembly of mitochondrial proteins depend on a complex interplay of proteinaceous translocation machineries. The role of lipids in this process has been studied only marginally and so far no direct role for a specific lipid in mitochondrial protein biogenesis has been shown. Here we analyzed a potential role of phosphatidic acid (PA) in biogenesis of mitochondrial proteins in Saccharomyces cerevisiae. In vivo remodeling of the mitochondrial lipid composition by lithocholic acid treatment or by ablation of the lipid transport protein Ups1, both leading to an increase of mitochondrial PA levels, specifically stimulated the biogenesis of the outer membrane protein Ugo1, a component of the mitochondrial fusion machinery. We reconstituted the import and assembly pathway of Ugo1 in protein-free liposomes, mimicking the outer membrane phospholipid composition, and found a direct dependency of Ugo1 biogenesis on PA. Thus, PA represents the first lipid that is directly involved in the biogenesis pathway of a mitochondrial membrane protein. PMID:26347140

  3. The fusogenic lipid phosphatidic acid promotes the biogenesis of mitochondrial outer membrane protein Ugo1.

    PubMed

    Vgtle, F-Nora; Keller, Michael; Taskin, Asli A; Horvath, Susanne E; Guan, Xue Li; Prinz, Claudia; Opali?ska, Magdalena; Zorzin, Carina; van der Laan, Martin; Wenk, Markus R; Schubert, Rolf; Wiedemann, Nils; Holzer, Martin; Meisinger, Chris

    2015-09-14

    Import and assembly of mitochondrial proteins depend on a complex interplay of proteinaceous translocation machineries. The role of lipids in this process has been studied only marginally and so far no direct role for a specific lipid in mitochondrial protein biogenesis has been shown. Here we analyzed a potential role of phosphatidic acid (PA) in biogenesis of mitochondrial proteins in Saccharomyces cerevisiae. In vivo remodeling of the mitochondrial lipid composition by lithocholic acid treatment or by ablation of the lipid transport protein Ups1, both leading to an increase of mitochondrial PA levels, specifically stimulated the biogenesis of the outer membrane protein Ugo1, a component of the mitochondrial fusion machinery. We reconstituted the import and assembly pathway of Ugo1 in protein-free liposomes, mimicking the outer membrane phospholipid composition, and found a direct dependency of Ugo1 biogenesis on PA. Thus, PA represents the first lipid that is directly involved in the biogenesis pathway of a mitochondrial membrane protein. PMID:26347140

  4. Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis*

    PubMed Central

    Menzies, Keir J.; Singh, Kaustabh; Saleem, Ayesha; Hood, David A.

    2013-01-01

    The purpose of this study was to evaluate the role of sirtuin 1 (SirT1) in exercise- and resveratrol (RSV)-induced skeletal muscle mitochondrial biogenesis. Using muscle-specific SirT1-deficient (KO) mice and a cell culture model of differentiated myotubes, we compared the treatment of resveratrol, an activator of SirT1, with that of exercise in inducing mitochondrial biogenesis. These experiments demonstrated that SirT1 plays a modest role in maintaining basal mitochondrial content and a larger role in preserving mitochondrial function. Furthermore, voluntary exercise and RSV treatment induced mitochondrial biogenesis in a SirT1-independent manner. However, when RSV and exercise were combined, a SirT1-dependent synergistic effect was evident, leading to enhanced translocation of PGC-1α and SirT1 to the nucleus and stimulation of mitochondrial biogenesis. Thus, the magnitude of the effect of RSV on muscle mitochondrial biogenesis is reliant on SirT1, as well as the cellular environment, such as that produced by repeated bouts of exercise. PMID:23329826

  5. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis.

    PubMed

    Menzies, Keir J; Singh, Kaustabh; Saleem, Ayesha; Hood, David A

    2013-03-01

    The purpose of this study was to evaluate the role of sirtuin 1 (SirT1) in exercise- and resveratrol (RSV)-induced skeletal muscle mitochondrial biogenesis. Using muscle-specific SirT1-deficient (KO) mice and a cell culture model of differentiated myotubes, we compared the treatment of resveratrol, an activator of SirT1, with that of exercise in inducing mitochondrial biogenesis. These experiments demonstrated that SirT1 plays a modest role in maintaining basal mitochondrial content and a larger role in preserving mitochondrial function. Furthermore, voluntary exercise and RSV treatment induced mitochondrial biogenesis in a SirT1-independent manner. However, when RSV and exercise were combined, a SirT1-dependent synergistic effect was evident, leading to enhanced translocation of PGC-1α and SirT1 to the nucleus and stimulation of mitochondrial biogenesis. Thus, the magnitude of the effect of RSV on muscle mitochondrial biogenesis is reliant on SirT1, as well as the cellular environment, such as that produced by repeated bouts of exercise. PMID:23329826

  6. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy

    PubMed Central

    Yamano, Koji; Fogel, Adam I; Wang, Chunxin; van der Bliek, Alexander M; Youle, Richard J

    2014-01-01

    Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson’s disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. DOI: http://dx.doi.org/10.7554/eLife.01612.001 PMID:24569479

  7. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy.

    PubMed

    Yamano, Koji; Fogel, Adam I; Wang, Chunxin; van der Bliek, Alexander M; Youle, Richard J

    2014-01-01

    Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson's disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. DOI: http://dx.doi.org/10.7554/eLife.01612.001. PMID:24569479

  8. Stimulatory Effects of Balanced Deep Sea Water on Mitochondrial Biogenesis and Function

    PubMed Central

    Ha, Byung Geun; Park, Jung-Eun; Cho, Hyun-Jung; Shon, Yun Hee

    2015-01-01

    The worldwide prevalence of metabolic diseases, including obesity and diabetes, is increasing. Mitochondrial dysfunction is recognized as a core feature of these diseases. Emerging evidence also suggests that defects in mitochondrial biogenesis, number, morphology, fusion, and fission, contribute to the development and progression of metabolic diseases. Our previous studies revealed that balanced deep-sea water (BDSW) has potential as a treatment for diabetes and obesity. In this study, we aimed to investigate the mechanism by which BDSW regulates diabetes and obesity by studying its effects on mitochondrial metabolism. To determine whether BDSW regulates mitochondrial biogenesis and function, we investigated its effects on mitochondrial DNA (mtDNA) content, mitochondrial enzyme activity, and the expression of transcription factors and mitochondria specific genes, as well as on the phosphorylation of signaling molecules associated with mitochondria biogenesis and its function in C2C12 myotubes. BDSW increased mitochondrial biogenesis in a time and dose-dependent manner. Quantitative real-time PCR revealed that BDSW enhances gene expression of PGC-1α, NRF1, and TFAM for mitochondrial transcription; MFN1/2 and DRP1 for mitochondrial fusion; OPA1 for mitochondrial fission; TOMM40 and TIMM44 for mitochondrial protein import; CPT-1α and MCAD for fatty acid oxidation; CYTC for oxidative phosphorylation. Upregulation of these genes was validated by increased mitochondria staining, CS activity, CytC oxidase activity, NAD+ to NADH ratio, and the phosphorylation of signaling molecules such as AMPK and SIRT1. Moreover, drinking BDSW remarkably improved mtDNA content in the muscles of HFD-induced obese mice. Taken together, these results suggest that the stimulatory effect of BDSW on mitochondrial biogenesis and function may provide further insights into the regulatory mechanism of BDSW-induced anti-diabetic and anti-obesity action. PMID:26068191

  9. N-acetylcysteine inhibits the upregulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically

    PubMed Central

    Caro, Andres A.; Bell, Matthew; Ejiofor, Shannon; Zurcher, Grant; Petersen, Dennis R.; Ronis, Martin J. J.

    2014-01-01

    Background Chronic ethanol administration to experimental animals induces hepatic oxidative stress and upregulates mitochondrial biogenesis. The mechanisms by which chronic ethanol upregulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative stress is a factor that triggers mitochondrial biogenesis after chronic ethanol feeding. If our hypothesis is correct, co-administration of antioxidants should prevent upregulation of mitochondrial biogenesis genes. Methods Rats were fed an ethanol-containing diet intragastrically by total enteral nutrition for 150 days, in the absence or presence of the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/day; control rats were administered isocaloric diets where carbohydrates substituted for ethanol calories. Results Ethanol administration significantly increased hepatic oxidative stress, evidenced as decreased liver total glutathione and GSH/GSSG ratio. These effects were inhibited by co-administration of ethanol and NAC. Chronic ethanol increased the expression of mitochondrial biogenesis genes including peroxisome proliferator activated receptor gamma-coactivator-1 alpha and mitochondrial transcription factor A, and mitochondrial DNA; co-administration of ethanol and NAC prevented these effects. Chronic ethanol administration was associated with decreased mitochondrial mass, inactivation and depletion of mitochondrial complex I and complex IV, and increased hepatic mitochondrial oxidative damage, effects that were not prevented by NAC. Conclusions These results suggest that oxidative stress caused by chronic ethanol triggered the upregulation of mitochondrial biogenesis genes in rat liver, because an antioxidant such as NAC prevented both effects. Because NAC did not prevent liver mitochondrial oxidative damage, extra-mitochondrial effects of reactive oxygen species may regulate mitochondrial biogenesis. In spite of the induction of hepatic mitochondrial biogenesis genes by chronic ethanol, mitochondrial mass and function decreased probably in association with mitochondrial oxidative damage. These results also predict that the effectiveness of NAC as an antioxidant therapy for chronic alcoholism will be limited by its limited antioxidant effects in mitochondria, and its inhibitory effect on mitochondrial biogenesis. PMID:25581647

  10. Curcumin Attenuates Gentamicin-Induced Kidney Mitochondrial Alterations: Possible Role of a Mitochondrial Biogenesis Mechanism

    PubMed Central

    Negrette-Guzmán, Mario; García-Niño, Wylly Ramsés; Tapia, Edilia; Zazueta, Cecilia; Huerta-Yepez, Sara; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Aparicio-Trejo, Omar Emiliano; Madero, Magdalena; Pedraza-Chaverri, José

    2015-01-01

    It has been shown that curcumin (CUR), a polyphenol derived from Curcuma longa, exerts a protective effect against gentamicin- (GM-) induced nephrotoxicity in rats, associated with a preservation of the antioxidant status. Although mitochondrial dysfunction is a hallmark in the GM-induced renal injury, the role of CUR in mitochondrial protection has not been studied. In this work, LLC-PK1 cells were preincubated 24 h with CUR and then coincubated 48 h with CUR and 8 mM GM. Treatment with CUR attenuated GM-induced drop in cell viability and led to an increase in nuclear factor (erythroid-2)-related factor 2 (Nrf2) nuclear accumulation and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) cell expression attenuating GM-induced losses in these proteins. In vivo, Wistar rats were injected subcutaneously with GM (75 mg/Kg/12 h) during 7 days to develop kidney mitochondrial alterations. CUR (400 mg/Kg/day) was administered orally 5 days before and during the GM exposure. The GM-induced mitochondrial alterations in ultrastructure and bioenergetics as well as decrease in activities of respiratory complexes I and IV and induction of calcium-dependent permeability transition were mostly attenuated by CUR. Protection of CUR against GM-induced nephrotoxicity could be in part mediated by maintenance of mitochondrial functions and biogenesis with some participation of the nuclear factor Nrf2. PMID:26345660

  11. The effect of ethidium bromide and chloramphenicol on mitochondrial biogenesis in primary human fibroblasts

    SciTech Connect

    Kao, Li-Pin; Ovchinnikov, Dmitry; Wolvetang, Ernst

    2012-05-15

    The expression of mitochondrial components is controlled by an intricate interplay between nuclear transcription factors and retrograde signaling from mitochondria. The role of mitochondrial DNA (mtDNA) and mtDNA-encoded proteins in mitochondrial biogenesis is, however, poorly understood and thus far has mainly been studied in transformed cell lines. We treated primary human fibroblasts with ethidium bromide (EtBr) or chloramphenicol for six weeks to inhibit mtDNA replication or mitochondrial protein synthesis, respectively, and investigated how the cells recovered from these insults two weeks after removal of the drugs. Although cellular growth and mitochondrial gene expression were severely impaired after both inhibitor treatments we observed marked differences in mitochondrial structure, membrane potential, glycolysis, gene expression, and redox status between fibroblasts treated with EtBr and chloramphenicol. Following removal of the drugs we further detected clear differences in expression of both mtDNA-encoded genes and nuclear transcription factors that control mitochondrial biogenesis, suggesting that the cells possess different compensatory mechanisms to recover from drug-induced mitochondrial dysfunction. Our data reveal new aspects of the interplay between mitochondrial retrograde signaling and the expression of nuclear regulators of mitochondrial biogenesis, a process with direct relevance to mitochondrial diseases and chloramphenicol toxicity in humans. -- Highlights: ► Cells respond to certain environmental toxins by increasing mitochondrial biogenesis. ► We investigated the effect of Chloramphenicol and EtBr in primary human fibroblasts. ► Inhibiting mitochondrial protein synthesis or DNA replication elicit different effects. ► We provide novel insights into the cellular responses toxins and antibiotics.

  12. The Effects of NAD+ on Apoptotic Neuronal Death and Mitochondrial Biogenesis and Function after Glutamate Excitotoxicity

    PubMed Central

    Wang, Xiaowan; Li, Hailong; Ding, Shinghua

    2014-01-01

    NAD+ is an essential co-enzyme for cellular energy metabolism and is also involved as a substrate for many cellular enzymatic reactions. It has been shown that NAD+ has a beneficial effect on neuronal survival and brain injury in in vitro and in vivo ischemic models. However, the effect of NAD+ on mitochondrial biogenesis and function in ischemia has not been well investigated. In the present study, we used an in vitro glutamate excitotoxicity model of primary cultured cortical neurons to study the effect of NAD+ on apoptotic neuronal death and mitochondrial biogenesis and function. Our results show that supplementation of NAD+ could effectively reduce apoptotic neuronal death, and apoptotic inducing factor translocation after neurons were challenged with excitotoxic glutamate stimulation. Using different approaches including confocal imaging, mitochondrial DNA measurement and Western blot analysis of PGC-1 and NRF-1, we also found that NAD+ could significantly attenuate glutamate-induced mitochondrial fragmentation and the impairment of mitochondrial biogenesis. Furthermore, NAD+ treatment effectively inhibited mitochondrial membrane potential depolarization and NADH redistribution after excitotoxic glutamate stimulation. Taken together, our results demonstrated that NAD+ is capable of inhibiting apoptotic neuronal death after glutamate excitotoxicity via preserving mitochondrial biogenesis and integrity. Our findings provide insights into potential neuroprotective strategies in ischemic stroke. PMID:25387075

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

    SciTech Connect

    Perez-de-Arce, Karen; Foncea, Rocio . E-mail: rfoncea@med.puc.cl; Leighton, Federico

    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 mRNA 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.

  14. Nitrite Activates AMP Kinase to Stimulate Mitochondrial Biogenesis Independent of soluble Guanylate Cyclase

    PubMed Central

    Mo, Li; Wang, Yinna; Geary, Lisa; Corey, Catherine; Alef, Matthew J.; Beer-Stolz, Donna; Zuckerbraun, Brian S.; Shiva, Sruti

    2012-01-01

    Nitrite, a dietary constituent and endogenous signaling molecule, mediates a number of physiological responses including modulation of ischemia/reperfusion injury, glucose tolerance and vascular remodeling. While the exact molecular mechanisms underlying nitrites actions are unknown, current paradigm suggests that these effects depend on the hypoxic reduction of nitrite to nitric oxide (NO). Mitochondrial biogenesis is a fundamental mechanism of cellular adaptation and repair. However, the effect of nitrite on mitochondrial number has not been explored. Herein, we report that nitrite stimulates mitochondrial biogenesis through a mechanism distinct from NO. We demonstrate that nitrite significantly increases cellular mitochondrial number by augmenting the activity of adenylate kinase, resulting in AMP kinase phosphorylation, downstream activation of sirtuin-1, and de-acetylation of PGC1, the master regulator of mitochondrial biogenesis. Unlike NO, nitrite-mediated biogenesis does not require the activation of soluble guanylate cyclase and results in the synthesis of more functionally efficient mitochondria. Further, we provide evidence that nitrite mediates biogenesis in vivo. In a rat model of carotid injury, two weeks of continuous oral nitrite treatment post-injury prevents the hyperproliferative response of smooth muscle cells. This protection is accompanied by a nitrite-dependent upregulation of PGC1 and increased mitochondrial number in the injured artery. These data are the first to demonstrate that nitrite mediates differential signaling than NO. They show that nitrite is a versatile regulator of mitochondrial function and number both in vivo and in vitro, and suggest that nitrite-mediated biogenesis may play a protective role in the setting of vascular injury. PMID:22892143

  15. Artemisinin mimics calorie restriction to trigger mitochondrial biogenesis and compromise telomere shortening in mice.

    PubMed

    Wang, Da-Ting; He, Jiang; Wu, Ming; Li, Si-Ming; Gao, Qian; Zeng, Qing-Ping

    2015-01-01

    Calorie restriction is known to extend lifespan among organisms by a debating mechanism underlying nitric oxide-driven mitochondrial biogenesis. We report here that nitric oxide generators including artemisinin, sodium nitroprusside, and L-arginine mimics calorie restriction and resembles hydrogen peroxide to initiate the nitric oxide signaling cascades and elicit the global antioxidative responses in mice. The large quantities of antioxidant enzymes are correlated with the low levels of reactive oxygen species, which allow the down-regulation of tumor suppressors and accessory DNA repair partners, eventually leading to the compromise of telomere shortening. Accompanying with the up-regulation of signal transducers and respiratory chain signatures, mitochondrial biogenesis occurs with the elevation of adenosine triphosphate levels upon exposure of mouse skeletal muscles to the mimetics of calorie restriction. In conclusion, calorie restriction-triggered nitric oxide provides antioxidative protection and alleviates telomere attrition via mitochondrial biogenesis, thereby maintaining chromosomal stability and integrity, which are the hallmarks of longevity. PMID:25780774

  16. Artemisinin mimics calorie restriction to trigger mitochondrial biogenesis and compromise telomere shortening in mice

    PubMed Central

    Wu, Ming; Li, Si-Ming; Gao, Qian

    2015-01-01

    Calorie restriction is known to extend lifespan among organisms by a debating mechanism underlying nitric oxide-driven mitochondrial biogenesis. We report here that nitric oxide generators including artemisinin, sodium nitroprusside, and L-arginine mimics calorie restriction and resembles hydrogen peroxide to initiate the nitric oxide signaling cascades and elicit the global antioxidative responses in mice. The large quantities of antioxidant enzymes are correlated with the low levels of reactive oxygen species, which allow the down-regulation of tumor suppressors and accessory DNA repair partners, eventually leading to the compromise of telomere shortening. Accompanying with the up-regulation of signal transducers and respiratory chain signatures, mitochondrial biogenesis occurs with the elevation of adenosine triphosphate levels upon exposure of mouse skeletal muscles to the mimetics of calorie restriction. In conclusion, calorie restriction-triggered nitric oxide provides antioxidative protection and alleviates telomere attrition via mitochondrial biogenesis, thereby maintaining chromosomal stability and integrity, which are the hallmarks of longevity. PMID:25780774

  17. Complementary RNA and Protein Profiling Identifies Iron as a Key Regulator of Mitochondrial Biogenesis

    PubMed Central

    Rensvold, Jarred W.; Ong, Shao-En; Jeevananthan, Athavi; Carr, Steven A.; Mootha, Vamsi K.; Pagliarini, David J.

    2013-01-01

    Summary Mitochondria are centers of metabolism and signaling whose content and function must adapt to changing cellular environments. The biological signals that initiate mitochondrial restructuring and the cellular processes that drive this adaptive response are largely obscure. To better define these systems, we performed matched quantitative genomic and proteomic analyses of mouse muscle cells as they performed mitochondrial biogenesis. We find that proteins involved in cellular iron homeostasis are highly coordinated with this process and that depletion of cellular iron results in a rapid, dose-dependent decrease of select mitochondrial protein levels and oxidative capacity. We further show that this process is universal across a broad range of cell types and fully reversed when iron is reintroduced. Collectively, our work reveals that cellular iron is a key regulator of mitochondrial biogenesis, and provides quantitative data sets that can be leveraged to explore posttranscriptional and posttranslational processes that are essential for mitochondrial adaptation. PMID:23318259

  18. N-acetylcysteine inhibits the up-regulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Chronic ethanol (EtOH) administration to experimental animals induces hepatic oxidative stress and up-regulates mitochondrial biogenesis. The mechanisms by which chronic EtOH up-regulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative ...

  19. Acute exercise induced mitochondrial H₂O₂ production in mouse skeletal muscle: association with p(66Shc) and FOXO3a signaling and antioxidant enzymes.

    PubMed

    Wang, Ping; Li, Chun Guang; Qi, Zhengtang; Cui, Di; Ding, Shuzhe

    2015-01-01

    Exercise induced skeletal muscle phenotype change involves a complex interplay between signaling pathways and downstream regulators. This study aims to investigate the effect of acute exercise on mitochondrial H2O2 production and its association with p(66Shc), FOXO3a, and antioxidant enzymes. Male ICR/CD-1 mice were subjected to an acute exercise. Muscle tissues (gastrocnemius and quadriceps femoris) were taken after exercise to measure mitochondrial H2O2 content, expression of p(66Shc) and FOXO3a, and the activity of antioxidant enzymes. The results showed that acute exercise significantly increased mitochondrial H2O2 content and expressions of p(66Shc) and FOXO3a in a time-dependent manner, with a linear correlation between the increase in H2O2 content and p(66Shc) or FOXO3a expression. The activity of mitochondrial catalase was slightly reduced in the 90 min exercise group, but it was significantly higher in groups with 120 and 150 min exercise compared to that of 90 min exercise group. The activity of SOD was not significantly affected. The results indicate that acute exercise increases mitochondrial H2O2 production in the skeletal muscle, which is associated with the upregulation of p(66Shc) and FOXO3a. The association of p(66Shc) and FOXO3a signaling with exercise induced H2O2 generation may play a role in regulating cellular oxidative stress during acute exercise. PMID:25874020

  20. Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance

    PubMed Central

    Salem, Ahmed F.; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.

    2012-01-01

    Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would fuel enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1? and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1? and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to ~3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1? and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial power in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1?, PGC-1?, mitoNEET and POLRMT should all be considered as tumor promoters or metabolic oncogenes. Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial poison) prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells. PMID:23070475

  1. Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance.

    PubMed

    Salem, Ahmed F; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-15

    Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would "fuel" enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1α and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1α and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to ~3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1β and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial "power" in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1α, PGC-1β, mitoNEET and POLRMT should all be considered as tumor promoters or "metabolic oncogenes." Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial "poison") prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells. PMID:23070475

  2. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training.

    PubMed

    Derbré, Frederic; Gomez-Cabrera, Mari Carmen; Nascimento, Ana Lucia; Sanchis-Gomar, Fabian; Martinez-Bello, Vladimir Essau; Tresguerres, Jesus A F; Fuentes, Teresa; Gratas-Delamarche, Arlette; Monsalve, Maria; Viña, Jose

    2012-06-01

    Low mitochondriogenesis is critical to explain loss of muscle function in aging and in the development of frailty. The aim of this work was to explain the mechanism by which mitochondriogenesis is decreased in aging and to determine to which extent it may be prevented by exercise training. We used aged rats and compared them with peroxisome proliferator-activated receptor-γ coactivator-1α deleted mice (PGC-1α KO). PGC-1α KO mice showed a significant decrease in the mitochondriogenic pathway in muscle. In aged rats, we found a loss of exercise-induced expression of PGC-1α, nuclear respiratory factor-1 (NRF-1), and of cytochrome C. Thus muscle mitochondriogenesis, which is activated by exercise training in young animals, is not in aged or PGC-1α KO ones. Other stimuli to increase PGC-1α synthesis apart from exercise training, namely cold induction or thyroid hormone treatment, were effective in young rats but not in aged ones. To sum up, the low mitochondrial biogenesis associated with aging may be due to the lack of response of PGC-1α to different stimuli. Aged rats behave as PGC-1α KO mice. Results reported here highlight the role of PGC-1α in the loss of mitochondriogenesis associated with aging and point to this important transcriptional coactivator as a target for pharmacological interventions to prevent age-associated sarcopenia. PMID:21590341

  3. Exercise-Induced Bronchoconstriction

    MedlinePLUS

    ... Conditions & Treatments ▸ Conditions Dictionary ▸ Exercise-Induced Bronchoconstriction Share | Exercise-Induced Bronchoconstriction (EIB) « Back to A to Z Listing Exercise-Induced Bronchoconstriction, (EIB), often known as exercise-induced ...

  4. A new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology.

    PubMed

    Hodneland Nilsson, Linn Iren; Nitschke Pettersen, Ina Katrine; Nikolaisen, Julie; Micklem, David; Avsnes Dale, Hege; Vatne Rsland, Gro; Lorens, James; Tronstad, Karl Johan

    2015-01-01

    Changes in mitochondrial amount and shape are intimately linked to maintenance of cell homeostasis via adaptation of vital functions. Here, we developed a new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology. This was achieved by making a genetic reporter construct where a master regulator of mitochondrial biogenesis, nuclear respiratory factor 1 (NRF-1), controls expression of mitochondria targeted green fluorescent protein (mitoGFP). HeLa cells with the reporter construct demonstrated inducible expression of mitoGFP upon activation of AMP-dependent protein kinase (AMPK) with AICAR. We established stable reporter cells where the mitoGFP reporter activity corresponded with mitochondrial biogenesis both in magnitude and kinetics, as confirmed by biochemical markers and confocal microscopy. Quantitative 3D image analysis confirmed accordant increase in mitochondrial biomass, in addition to filament/network promoting and protecting effects on mitochondrial morphology, after treatment with AICAR. The level of mitoGFP reversed upon removal of AICAR, in parallel with decrease in mtDNA. In summary, we here present a new GFP-based genetic reporter strategy to study mitochondrial regulation and dynamics in living cells. This combinatorial reporter concept can readily be transferred to other cell models and contexts to address specific physiological mechanisms. PMID:26596249

  5. A new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology

    PubMed Central

    Hodneland Nilsson, Linn Iren; Nitschke Pettersen, Ina Katrine; Nikolaisen, Julie; Micklem, David; Avsnes Dale, Hege; Vatne Rsland, Gro; Lorens, James; Tronstad, Karl Johan

    2015-01-01

    Changes in mitochondrial amount and shape are intimately linked to maintenance of cell homeostasis via adaptation of vital functions. Here, we developed a new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology. This was achieved by making a genetic reporter construct where a master regulator of mitochondrial biogenesis, nuclear respiratory factor 1 (NRF-1), controls expression of mitochondria targeted green fluorescent protein (mitoGFP). HeLa cells with the reporter construct demonstrated inducible expression of mitoGFP upon activation of AMP-dependent protein kinase (AMPK) with AICAR. We established stable reporter cells where the mitoGFP reporter activity corresponded with mitochondrial biogenesis both in magnitude and kinetics, as confirmed by biochemical markers and confocal microscopy. Quantitative 3D image analysis confirmed accordant increase in mitochondrial biomass, in addition to filament/network promoting and protecting effects on mitochondrial morphology, after treatment with AICAR. The level of mitoGFP reversed upon removal of AICAR, in parallel with decrease in mtDNA. In summary, we here present a new GFP-based genetic reporter strategy to study mitochondrial regulation and dynamics in living cells. This combinatorial reporter concept can readily be transferred to other cell models and contexts to address specific physiological mechanisms. PMID:26596249

  6. Transcriptional Control of Mitochondrial Biogenesis and Its Interface with Inflammatory Processes

    PubMed Central

    Piantadosi, Claude A.; Suliman, Hagir B.

    2012-01-01

    Background Cells avoid major mitochondrial damage and energy failure during systemic inflammatory states, such as severe acute infections, by specific targeting of the inflammatory response and by inducing anti-inflammatory and anti-oxidant defenses. Recent evidence indicates that these cell defenses also include mitochondrial biogenesis and the clearance of damaged mitochondria through autophagy. Scope of Review This review addresses a group of transcriptional signaling mechanisms that engage mitochondrial biogenesis, including energy-sensing and redox-regulated transcription factors and co-activators, after major inflammatory events. Major Conclusions Stimulation of the innate immune system by activation of toll-like receptors (TLR) generates pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1β, (IL-1β), necessary for optimal host defense, but which also contribute to mitochondrial damage through oxidative stress and other mechanisms. To protect its energy supply, host cells sense mitochondrial damage and initiate mitochondrial biogenesis under the control of an inducible transcriptional program that also activates anti-oxidant and anti-inflammatory gene expression. This multifunctional network not only increases cellular resistance to metabolic failure, oxidative stress, and cell death, but promotes immune tolerance as shown in the graphical abstract. General Significance The post-inflammatory induction of mitochondrial biogenesis supports metabolic function and cell viability while helping to control inflammation. In clinical settings, patients recovering from severe systemic infections may develop transient immune suppression, placing them at risk for recurrent infection, but there may be therapeutic opportunities to enhance mitochondrial quality control that would improve the resolution of life-threatening host responses to such infections. PMID:22265687

  7. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma

    PubMed Central

    Trian, Thomas; Benard, Giovanni; Begueret, Hugues; Rossignol, Rodrigue; Girodet, Pierre-Olivier; Ghosh, Debajyoti; Ousova, Olga; Vernejoux, Jean-Marc; Marthan, Roger; Tunon-de-Lara, Jos-Manuel; Berger, Patrick

    2007-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are characterized by different patterns of airway remodeling, which all include an increased mass of bronchial smooth muscle (BSM). A remaining major question concerns the mechanisms underlying such a remodeling of BSM. Because mitochondria play a major role in both cell proliferation and apoptosis, we hypothesized that mitochondrial activation in BSM could play a role in this remodeling. We describe that both the mitochondrial mass and oxygen consumption were higher in the BSM from asthmatic subjects than in that from both COPD and controls. This feature, which is specific to asthma, was related to an enhanced mitochondrial biogenesis through up-regulation of peroxisome proliferator-activated receptor ? coactivator (PGC)1?, nuclear respiratory factor-1, and mitochondrial transcription factor A. The priming event of such activation was an alteration in BSM calcium homeostasis. BSM cell apoptosis was not different in the three groups of subjects. Asthmatic BSM was, however, characterized by increased cell growth and proliferation. Both characteristics were completely abrogated in mitochondria-deficient asthmatic BSM cells. Conversely, in both COPD and control BSM cells, induction of mitochondrial biogenesis reproduced these characteristics. Thus, BSM in asthmatic patients is characterized by an altered calcium homeostasis that increases mitochondrial biogenesis, which, in turn, enhances cell proliferation, leading to airway remodeling. PMID:18056286

  8. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy.

    PubMed

    Giordano, Carla; Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross-Cisneros, Fred N; D'Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu-Wai-Man, Patrick; Chinnery, Patrick F; Zeviani, Massimo; Salomao, Solange R; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Milton; Moraes Filho, Milton; Barboni, Piero; Sadun, Federico; De Negri, Annamaria; Sadun, Alfredo A; Tancredi, Andrea; Mancini, Massimiliano; d'Amati, Giulia; Loguercio Polosa, Paola; Cantatore, Palmiro; Carelli, Valerio

    2014-02-01

    Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies. PMID:24369379

  9. Nebivolol stimulates mitochondrial biogenesis in 3T3-L1 adipocytes

    SciTech Connect

    Huang, Chenglin; Chen, Dongrui; Xie, Qihai; Yang, Ying; Shen, Weili

    2013-08-16

    Highlights: •Nebivolol may act as a partial agonist of β3-adrenergic receptor (AR). •Nebivolol stimulates mitochondrial DNA replication and protein expression. •Nebivolol promotes mitochondrial synthesis via activation of eNOS by β3-AR. -- Abstract: Nebivolol is a third-generation β-adrenergic receptor (β-AR) blocker with additional beneficial effects, including the improvement of lipid and glucose metabolism in obese individuals. However, the underlying mechanism of nebivolol’s role in regulating the lipid profile remains largely unknown. In this study, we investigated the role of nebivolol in mitochondrial biogenesis in 3T3-L1 adipocytes. Exposure of 3T3-L1 cells to nebivolol for 24 h increased mitochondrial DNA copy number, mitochondrial protein levels and the expression of transcription factors involved in mitochondrial biogenesis, including PPAR-γ coactivator-1α (PGC-1α), Sirtuin 3 (Sirt3), mitochondrial transcription factor A (Tfam) and nuclear related factor 1 (Nrf1). These changes were accompanied by an increase in oxygen consumption and in the expression of genes involved in fatty acid oxidation and antioxidant enzymes in 3T3-L1 adipocytes, including nebivolol-induced endothelial nitric oxide synthase (eNOS), as well as an increase in the formation of cyclic guanosine monophosphate (cGMP). Pretreatment with NG-nitro-L-arginine methyl ester (l-NAME) attenuated nebivolol-induced mitochondrial biogenesis, as did the soluble guanylate cyclase inhibitor, ODQ. Treatment with nebivolol and β3-AR blocker SR59230A markedly attenuated PGC-1α, Sirt3 and manganese superoxide dismutase (MnSOD) protein levels in comparison to treatment with nebivolol alone. These data indicate that the mitochondrial synthesis and metabolism in adipocytes that is promoted by nebivolol is primarily mediated through the eNOS/cGMP-dependent pathway and is initiated by the activation of β3-AR receptors.

  10. Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes

    PubMed Central

    Liang, Chunzi; Curry, Benjamin J.; Brown, Patricia L.; Zemel, Michael B.

    2014-01-01

    Previous studies from this laboratory demonstrate that dietary leucine protects against high fat diet-induced mitochondrial impairments and stimulates mitochondrial biogenesis and energy partitioning from adipocytes to muscle cells through SIRT1-mediated mechanisms. Moreover, β-hydroxy-β-methyl butyrate (HMB), a metabolite of leucine, has been reported to activate AMPK synergistically with resveratrol in C2C12 myotubes. Therefore, we hypothesize that leucine-induced activation of SIRT1 and AMPK is the central event that links the upregulated mitochondrial biogenesis and fatty acid oxidation in skeletal muscle. Thus, C2C12 myotubes were treated with leucine (0.5 mM), alanine (0.5 mM), valine (0.5 mM), EX527 (SIRT1 inhibitor, 25 μM), and Compound C (AMPK inhibitor, 25 μM) alone or in combination to determine the roles of AMPK and SIRT1 in leucine-modulation of energy metabolism. Leucine significantly increased mitochondrial content, mitochondrial biogenesis-related genes expression, fatty acid oxidation, SIRT1 activity and gene expression, and AMPK phosphorylation in C2C12 myotubes compared to the controls, while EX527 and Compound C markedly attenuated these effects. Furthermore, leucine treatment for 24 hours resulted in time-dependent increases in cellular NAD+, SIRT1 activity, and p-AMPK level, with SIRT1 activation preceding that of AMPK, indicating that leucine activation of SIRT1, rather than AMPK, is the primary event. PMID:25400942

  11. Altered skeletal muscle mitochondrial biogenesis but improved endurance capacity in trained OPA1-deficient mice

    PubMed Central

    Caffin, F; Prola, A; Piquereau, J; Novotova, M; David, DJ; Garnier, A; Fortin, D; Alavi, MV; Veksler, V; Ventura-Clapier, R; Joubert, F

    2013-01-01

    The role of OPA1, a GTPase dynamin protein mainly involved in the fusion of inner mitochondrial membranes, has been studied in many cell types, but only a few studies have been conducted on adult differentiated tissues such as cardiac or skeletal muscle cells. Yet OPA1 is highly expressed in these cells, and could play different roles, especially in response to an environmental stress like exercise. Endurance exercise increases energy demand in skeletal muscle and repeated activity induces mitochondrial biogenesis and activation of fusionfission cycles for the synthesis of new mitochondria. But currently no study has clearly shown a link between mitochondrial dynamics and biogenesis. Using a mouse model of haploinsufficiency for the Opa1 gene (Opa1+/?), we therefore studied the impact of OPA1 deficiency on the adaptation ability of fast skeletal muscles to endurance exercise training. Our results show that, surprisingly, Opa1+/? mice were able to perform the same physical activity as control mice. However, the adaptation strategies of both strains after training differed: while in control mice mitochondrial biogenesis was increased as expected, in Opa1+/? mice this process was blunted. Instead, training in Opa1+/? mice led to an increase in endurance capacity, and a specific adaptive response involving a metabolic remodelling towards enhanced fatty acid utilization. In conclusion, OPA1 appears necessary for the normal adaptive response and mitochondrial biogenesis of skeletal muscle to training. This work opens new perspectives on the role of mitochondrial dynamics in skeletal muscle cells and during adaptation to stress. PMID:24042504

  12. Cilostazol promotes mitochondrial biogenesis in human umbilical vein endothelial cells through activating the expression of PGC-1α

    SciTech Connect

    Zuo, Luning; Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001 ; Li, Qiang; Sun, Bei; Xu, Zhiying; Ge, Zhiming

    2013-03-29

    Highlights: ► First time to show that cilostazol promotes the expressions of PGC-1α. ► First time to show that cilostazol stimulates mitochondrial biogenesis in HUVECs. ► PKA/CREB pathway mediates the effect of cilostazol on PGC-1α expression. ► Suggesting the roles of cilostazol in mitochondrial dysfunction related disease. -- Abstract: Mitochondrial dysfunction is frequently observed in vascular diseases. Cilostazol is a drug approved by the US Food and Drug Administration for the treatment of intermittent claudication. Cilostazol increases intracellular cyclic adenosine monophosphate (cAMP) levels through inhibition of type III phosphodiesterase. The effects of cilostazol in mitochondrial biogenesis in human umbilical vein endothelial cells (HUVECs) were investigated in this study. Cilostazol treated HUVECs displayed increased levels of ATP, mitochondrial DNA/nuclear DNA ratio, expressions of cytochrome B, and mitochondrial mass, suggesting an enhanced mitochondrial biogenesis induced by cilostazol. The promoted mitochondrial biogenesis could be abolished by Protein kinase A (PKA) specific inhibitor H-89, implying that PKA pathway played a critical role in increased mitochondrial biogenesis after cilostazol treatment. Indeed, expression levels of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), NRF 1 and mitochondrial transcription factor A (TFAM) were significantly increased in HUVECs after incubation with cilostazol at both mRNA levels and protein levels. Importantly, knockdown of PGC-1α could abolish cilostazol-induced mitochondrial biogenesis. Enhanced expression of p-CREB and PGC-1α induced by cilostazol could be inhibited by H-89. Moreover, the increased expression of PGC-1α induced by cilostazol could be inhibited by downregulation of CREB using CREB siRNA at both mRNA and protein levels. All the results indicated that cilostazol promoted mitochondrial biogenesis through activating the expression of PGC-1α in HUVECs, which was mediated by PKA/CREB pathway.

  13. Mitochondrial Biogenesis: Regulation By Endogenous Gases during Inflammation and Organ Stress

    PubMed Central

    Suliman, Hagir B.; Piantadosi, Claude A.

    2014-01-01

    The influence of mitochondrial dysfunction on pathological states involving inflammatory and/or oxidative stress in tissues that do not show frank cellular apoptosis or necrosis has been rather difficult to unravel, and the literature is replete with contradictory information. Although such discrepancies have many potential causes related to the type of injurious agent, the severity and duration of the injury, and the particular cells and tissues and the functions involved, it is the successful induction of cellular adaptive responses that ultimately governs the resolution of mitochondrial dysfunction and survival of the cell. Much recent attention has been devoted to unraveling the signaling pathways that activate mitochondrial biogenesis and other processes involved in mitochondrial quality control (QC) during inflammatory and oxidative stress with an eye towards the development of novel targets for therapeutic mitigation of the resultant tissue damage. This review provides a brief overview of this emerging field with an emphasis on the role of signaling through the endogenous gases (NO, CO and H2S) and a redox-based approach that brings transparency to key factors that contribute to the resolution of mitochondrial dysfunction and the maintenance of cell vitality. We make the case that targeted stimulation of mitochondrial biogenesis could be a potentially valuable approach for the development of new therapies for the treatment of diseases for which mitochondrial damage is a major consideration. PMID:24606800

  14. GABP Transcription Factor (Nuclear Respiratory Factor 2) Is Required for Mitochondrial Biogenesis

    PubMed Central

    Yang, Zhong-Fa; Drumea, Karen; Mott, Stephanie; Wang, Junling

    2014-01-01

    Mitochondria are membrane-bound cytoplasmic organelles that serve as the major source of ATP production in eukaryotic cells. GABP (also known as nuclear respiratory factor 2) is a nuclear E26 transformation-specific transcription factor (ETS) that binds and activates mitochondrial genes that are required for electron transport and oxidative phosphorylation. We conditionally deleted Gabpa, the DNA-binding component of this transcription factor complex, from mouse embryonic fibroblasts (MEFs) to examine the role of Gabp in mitochondrial biogenesis, function, and gene expression. Gabp? loss modestly reduced mitochondrial mass, ATP production, oxygen consumption, and mitochondrial protein synthesis but did not alter mitochondrial morphology, membrane potential, apoptosis, or the expression of several genes that were previously reported to be GABP targets. However, the expression of Tfb1m, a methyltransferase that modifies ribosomal rRNA and is required for mitochondrial protein translation, was markedly reduced in Gabp?-null MEFs. We conclude that Gabp regulates Tfb1m expression and plays an essential, nonredundant role in mitochondrial biogenesis. PMID:24958105

  15. Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride

    SciTech Connect

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2012-11-01

    High altitude/hypoxia training is known to improve physical performance in athletes. Hypoxia induces hypoxia inducible factor-1 (HIF-1) and its downstream genes that facilitate hypoxia adaptation in muscle to increase physical performance. Cobalt chloride (CoCl{sub 2}), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl{sub 2} supplementation on physical performance, glucose metabolism, and mitochondrial biogenesis using rodent model. The results showed significant increase in physical performance in cobalt supplemented rats without (two times) or with training (3.3 times) as compared to control animals. CoCl{sub 2} supplementation in rats augmented the biological activities of enzymes of TCA cycle, glycolysis and cytochrome c oxidase (COX); and increased the expression of glucose transporter-1 (Glut-1) in muscle showing increased glucose metabolism by aerobic respiration. There was also an increase in mitochondrial biogenesis in skeletal muscle observed by increased mRNA expressions of mitochondrial biogenesis markers which was further confirmed by electron microscopy. Moreover, nitric oxide production increased in skeletal muscle in cobalt supplemented rats, which seems to be the major reason for peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) induction and mitochondrial biogenesis. Thus, in conclusion, we state that hypoxia preconditioning by CoCl{sub 2} supplementation in rats increases mitochondrial biogenesis, glucose uptake and metabolism by aerobic respiration in skeletal muscle, which leads to increased physical performance. The significance of this study lies in understanding the molecular mechanism of hypoxia adaptation and improvement of work performance in normal as well as extreme conditions like hypoxia via hypoxia preconditioning. -- Highlights: ► We supplemented rats with CoCl{sub 2} for 15 days along with training. ► CoCl{sub 2} supplementation augmented endurance performance and aerobic respiration. ► It increased glucose uptake and metabolism in muscle. ► It enhanced mitochondrial biogenesis in red gastrocnemius muscle.

  16. Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1? Expression*

    PubMed Central

    Chowanadisai, Winyoo; Bauerly, Kathryn A.; Tchaparian, Eskouhie; Wong, Alice; Cortopassi, Gino A.; Rucker, Robert B.

    2010-01-01

    Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa16 cells to 1030 ?m PQQ for 2448 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1?, and increased PGC-1? mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1? or CREB expression. Consistent with activation of the PGC-1? pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction. PMID:19861415

  17. Apolipoprotein a1 increases mitochondrial biogenesis through AMP-activated protein kinase.

    PubMed

    Song, Parkyong; Kwon, Yonghoon; Yea, Kyungmoo; Moon, Hyo-Youl; Yoon, Jong Hyuk; Ghim, Jaewang; Hyun, Hyunjung; Kim, Dayea; Koh, Ara; Berggren, Per-Olof; Suh, Pann-Ghill; Ryu, Sung Ho

    2015-09-01

    Apolipoprotein a1, which is a major lipoprotein component of high-density lipoprotein (HDL), was reported to decrease plasma glucose in type 2 diabetes. Although recent studies also have shown that apolipoprotein a1 is involved in triglyceride (TG) metabolism, the mechanisms by which apolipoprotein a1 modulates TG levels remain largely unexplored. Here we demonstrated that apolipoprotein a1 increased mitochondrial DNA and mitochondria contents through sustained AMPK activation in myotubes. This resulted in enhanced fatty acid oxidation and attenuation of free fatty acid-induced insulin resistance features in skeletal muscle. The increment of mitochondria was mediated through induction of transcription factors, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?) and nuclear transcription factor 1 (NRF-1). The inhibition of AMPK by a pharmacological agent inhibited the induction of mitochondrial biogenesis. Increase of AMPK phosphorylation by apolipoprotein a1 occurs through activation of upstream kinase LKB1. Finally, we confirmed that scavenger receptor Class B, type 1 (SR-B1) is an important receptor for apolipoprotein a1 in stimulating AMPK pathway and mitochondrial biogenesis. Our study suggests that apolipoprotein a1 can alleviate obesity related metabolic disease by inducing AMPK dependent mitochondrial biogenesis. PMID:25982508

  18. Exercise-Induced Asthma

    MedlinePLUS

    ... Allergy Emergency Cerebral Palsy: Caring for Your Child Exercise-Induced Asthma KidsHealth > For Parents > Exercise-Induced Asthma ... they choose. previous continue Tips for Kids With Exercise-Induced Asthma For the most part, kids with ...

  19. Exercise-Induced Urticaria

    MedlinePLUS

    MENU Return to Web version Exercise-induced Urticaria Overview What is exercise-induced urticaria? Exercise-induced urticaria is a condition that causes hives and other allergic symptoms. It can occur during ...

  20. Thyroid Hormone Stimulation of Autophagy Is Essential for Mitochondrial Biogenesis and Activity in Skeletal Muscle.

    PubMed

    Lesmana, Ronny; Sinha, Rohit A; Singh, Brijesh K; Zhou, Jin; Ohba, Kenji; Wu, Yajun; Yau, Winifred Wy; Bay, Boon-Huat; Yen, Paul M

    2016-01-01

    Thyroid hormone (TH) and autophagy share similar functions in regulating skeletal muscle growth, regeneration, and differentiation. Although TH recently has been shown to increase autophagy in liver, the regulation and role of autophagy by this hormone in skeletal muscle is not known. Here, using both in vitro and in vivo models, we demonstrated that TH induces autophagy in a dose- and time-dependent manner in skeletal muscle. TH induction of autophagy involved reactive oxygen species (ROS) stimulation of 5'adenosine monophosphate-activated protein kinase (AMPK)-Mammalian target of rapamycin (mTOR)- Unc-51-like kinase 1 (Ulk1) signaling. TH also increased mRNA and protein expression of key autophagy genes, microtubule-associated protein light chain 3 (LC3), Sequestosome 1 (p62), and Ulk1, as well as genes that modulated autophagy and Forkhead box O (FOXO) 1/3a. TH increased mitochondrial protein synthesis and number as well as basal mitochondrial O2 consumption, ATP turnover, and maximal respiratory capacity. Surprisingly, mitochondrial activity and biogenesis were blunted when autophagy was blocked in muscle cells by Autophagy-related gene (Atg)5 short hairpin RNA (shRNA). Induction of ROS and 5'adenosine monophosphate-activated protein kinase (AMPK) by TH played a significant role in the up-regulation of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), the key regulator of mitochondrial synthesis. In summary, our findings showed that TH-mediated autophagy was essential for stimulation of mitochondrial biogenesis and activity in skeletal muscle. Moreover, autophagy and mitochondrial biogenesis were coupled in skeletal muscle via TH induction of mitochondrial activity and ROS generation. PMID:26562261

  1. Nebivolol stimulates mitochondrial biogenesis in 3T3-L1 adipocytes.

    PubMed

    Huang, Chenglin; Chen, Dongrui; Xie, Qihai; Yang, Ying; Shen, Weili

    2013-08-16

    Nebivolol is a third-generation ?-adrenergic receptor (?-AR) blocker with additional beneficial effects, including the improvement of lipid and glucose metabolism in obese individuals. However, the underlying mechanism of nebivolol's role in regulating the lipid profile remains largely unknown. In this study, we investigated the role of nebivolol in mitochondrial biogenesis in 3T3-L1 adipocytes. Exposure of 3T3-L1 cells to nebivolol for 24h increased mitochondrial DNA copy number, mitochondrial protein levels and the expression of transcription factors involved in mitochondrial biogenesis, including PPAR-? coactivator-1? (PGC-1?), Sirtuin 3 (Sirt3), mitochondrial transcription factor A (Tfam) and nuclear related factor 1 (Nrf1). These changes were accompanied by an increase in oxygen consumption and in the expression of genes involved in fatty acid oxidation and antioxidant enzymes in 3T3-L1 adipocytes, including nebivolol-induced endothelial nitric oxide synthase (eNOS), as well as an increase in the formation of cyclic guanosine monophosphate (cGMP). Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) attenuated nebivolol-induced mitochondrial biogenesis, as did the soluble guanylate cyclase inhibitor, ODQ. Treatment with nebivolol and ?3-AR blocker SR59230A markedly attenuated PGC-1?, Sirt3 and manganese superoxide dismutase (MnSOD) protein levels in comparison to treatment with nebivolol alone. These data indicate that the mitochondrial synthesis and metabolism in adipocytes that is promoted by nebivolol is primarily mediated through the eNOS/cGMP-dependent pathway and is initiated by the activation of ?3-AR receptors. PMID:23886954

  2. Short Term Exercise Induces PGC-1α, Ameliorates Inflammation and Increases Mitochondrial Membrane Proteins but Fails to Increase Respiratory Enzymes in Aging Diabetic Hearts

    PubMed Central

    Botta, Amy; Laher, Ismail; Beam, Julianne; DeCoffe, Daniella; Brown, Kirsty; Halder, Swagata; Devlin, Angela; Gibson, Deanna L.; Ghosh, Sanjoy

    2013-01-01

    PGC-1α, a transcriptional coactivator, controls inflammation and mitochondrial gene expression in insulin-sensitive tissues following exercise intervention. However, attributing such effects to PGC-1α is counfounded by exercise-induced fluctuations in blood glucose, insulin or bodyweight in diabetic patients. The goal of this study was to investigate the role of PGC-1α on inflammation and mitochondrial protein expressions in aging db/db mice hearts, independent of changes in glycemic parameters. In 8-month-old db/db mice hearts with diabetes lasting over 22 weeks, short-term, moderate-intensity exercise upregulated PGC-1α without altering body weight or glycemic parameters. Nonetheless, such a regimen lowered both cardiac (macrophage infiltration, iNOS and TNFα) and systemic (circulating chemokines and cytokines) inflammation. Curiously, such an anti-inflammatory effect was also linked to attenuated expression of downstream transcription factors of PGC-1α such as NRF-1 and several respiratory genes. Such mismatch between PGC-1α and its downstream targets was associated with elevated mitochondrial membrane proteins like Tom70 but a concurrent reduction in oxidative phosphorylation protein expressions in exercised db/db hearts. As mitochondrial oxidative stress was predominant in these hearts, in support of our in vivo data, increasing concentrations of H2O2 dose-dependently increased PGC-1α expression while inhibiting expression of inflammatory genes and downstream transcription factors in H9c2 cardiomyocytes in vitro. We conclude that short-term exercise-induced oxidative stress may be key in attenuating cardiac inflammatory genes and impairing PGC-1α mediated gene transcription of downstream transcription factors in type 2 diabetic hearts at an advanced age. PMID:23936397

  3. Salidroside Stimulates Mitochondrial Biogenesis and Protects against H2O2-Induced Endothelial Dysfunction

    PubMed Central

    Xing, Shasha; Yang, Xiaoyan; Li, Wenjing; Bian, Fang; Wu, Dan; Chi, Jiangyang; Xu, Gao; Zhang, Yonghui; Jin, Si

    2014-01-01

    Salidroside (SAL) is an active component of Rhodiola rosea with documented antioxidative properties. The purpose of this study is to explore the mechanism of the protective effect of SAL on hydrogen peroxide- (H2O2-) induced endothelial dysfunction. Pretreatment of the human umbilical vein endothelial cells (HUVECs) with SAL significantly reduced the cytotoxicity brought by H2O2. Functional studies on the rat aortas found that SAL rescued the endothelium-dependent relaxation and reduced superoxide anion (O2??) production induced by H2O2. Meanwhile, SAL pretreatment inhibited H2O2-induced nitric oxide (NO) production. The underlying mechanisms involve the inhibition of H2O2-induced activation of endothelial nitric oxide synthase (eNOS), adenosine monophosphate-activated protein kinase (AMPK), and Akt, as well as the redox sensitive transcription factor, NF-kappa B (NF-?B). SAL also increased mitochondrial mass and upregulated the mitochondrial biogenesis factors, peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1?), and mitochondrial transcription factor A (TFAM) in the endothelial cells. H2O2-induced mitochondrial dysfunction, as demonstrated by reduced mitochondrial membrane potential (??m) and ATP production, was rescued by SAL pretreatment. Taken together, these findings implicate that SAL could protect endothelium against H2O2-induced injury via promoting mitochondrial biogenesis and function, thus preventing the overactivation of oxidative stress-related downstream signaling pathways. PMID:24868319

  4. The mitochondrial import protein Mim1 promotes biogenesis of multispanning outer membrane proteins

    PubMed Central

    Becker, Thomas; Wenz, Lena-Sophie; Krger, Vivien; Lehmann, Waltraut; Mller, Judith M.; Goroncy, Luise; Zufall, Nicole; Lithgow, Trevor; Guiard, Bernard; Chacinska, Agnieszka; Wagner, Richard; Meisinger, Chris

    2011-01-01

    The mitochondrial outer membrane contains translocase complexes for the import of precursor proteins. The translocase of the outer membrane complex functions as a general preprotein entry gate, whereas the sorting and assembly machinery complex mediates membrane insertion of ?-barrel proteins of the outer membrane. Several ?-helical outer membrane proteins are known to carry multiple transmembrane segments; however, only limited information is available on the biogenesis of these proteins. We report that mitochondria lacking the mitochondrial import protein 1 (Mim1) are impaired in the biogenesis of multispanning outer membrane proteins, whereas overexpression of Mim1 stimulates their import. The Mim1 complex cooperates with the receptor Tom70 in binding of precursor proteins and promotes their insertion and assembly into the outer membrane. We conclude that the Mim1 complex plays a central role in the import of ?-helical outer membrane proteins with multiple transmembrane segments. PMID:21825073

  5. The mitochondrial import protein Mim1 promotes biogenesis of multispanning outer membrane proteins.

    PubMed

    Becker, Thomas; Wenz, Lena-Sophie; Krger, Vivien; Lehmann, Waltraut; Mller, Judith M; Goroncy, Luise; Zufall, Nicole; Lithgow, Trevor; Guiard, Bernard; Chacinska, Agnieszka; Wagner, Richard; Meisinger, Chris; Pfanner, Nikolaus

    2011-08-01

    The mitochondrial outer membrane contains translocase complexes for the import of precursor proteins. The translocase of the outer membrane complex functions as a general preprotein entry gate, whereas the sorting and assembly machinery complex mediates membrane insertion of ?-barrel proteins of the outer membrane. Several ?-helical outer membrane proteins are known to carry multiple transmembrane segments; however, only limited information is available on the biogenesis of these proteins. We report that mitochondria lacking the mitochondrial import protein 1 (Mim1) are impaired in the biogenesis of multispanning outer membrane proteins, whereas overexpression of Mim1 stimulates their import. The Mim1 complex cooperates with the receptor Tom70 in binding of precursor proteins and promotes their insertion and assembly into the outer membrane. We conclude that the Mim1 complex plays a central role in the import of ?-helical outer membrane proteins with multiple transmembrane segments. PMID:21825073

  6. Turn up the power –pharmacological activation of mitochondrial biogenesis in mouse models

    PubMed Central

    Komen, J C; Thorburn, D R

    2014-01-01

    The oxidative phosphorylation (OXPHOS) system in mitochondria is responsible for the generation of the majority of cellular energy in the form of ATP. Patients with genetic OXPHOS disorders form the largest group of inborn errors of metabolism. Unfortunately, there is still a lack of efficient therapies for these disorders other than management of symptoms. Developing therapies has been complicated because, although the total group of OXPHOS patients is relatively large, there is enormous clinical and genetic heterogeneity within this patient population. Thus there has been a lot of interest in generating relevant mouse models for the different kinds of OXPHOS disorders. The most common treatment strategies tested in these mouse models have aimed to up-regulate mitochondrial biogenesis, in order to increase the residual OXPHOS activity present in affected animals and thereby to ameliorate the energy deficiency. Drugs such as bezafibrate, resveratrol and AICAR target the master regulator of mitochondrial biogenesis PGC-1α either directly or indirectly to manipulate mitochondrial metabolism. This review will summarize the outcome of preclinical treatment trials with these drugs in mouse models of OXPHOS disorders and discuss similar treatments in a number of mouse models of common diseases in which pathology is closely linked to mitochondrial dysfunction. In the majority of these studies the pharmacological activation of the PGC-1α axis shows true potential as therapy; however, other effects besides mitochondrial biogenesis may be contributing to this as well. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24102298

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

    PubMed Central

    Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdlyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Hask, Gyrgy; Mechoulam, Raphael; Pacher, Pl

    2015-01-01

    Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOXs 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 ? 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

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

    PubMed

    Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdlyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Hask, Gyrgy; Mechoulam, Raphael; Pacher, Pl

    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 ? 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

  9. 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-? coactivator-1? 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. PMID:26024684

  10. Optimizing Intramuscular Adaptations to Aerobic Exercise: Effects of Carbohydrate Restriction and Protein Supplementation on Mitochondrial Biogenesis12

    PubMed Central

    Margolis, Lee M.; Pasiakos, Stefan M.

    2013-01-01

    Mitochondrial biogenesis is a critical metabolic adaptation to aerobic exercise training that results in enhanced mitochondrial size, content, number, and activity. Recent evidence has shown that dietary manipulation can further enhance mitochondrial adaptations to aerobic exercise training, which may delay skeletal muscle fatigue and enhance exercise performance. Specifically, studies have demonstrated that combining carbohydrate restriction (endogenous and exogenous) with a single bout of aerobic exercise potentiates the beneficial effects of exercise on markers of mitochondrial biogenesis. Additionally, studies have demonstrated that high-quality protein supplementation enhances anabolic skeletal muscle intracellular signaling and mitochondrial protein synthesis following a single bout of aerobic exercise. Mitochondrial biogenesis is stimulated by complex intracellular signaling pathways that appear to be primarily regulated by 5′AMP-activated protein kinase and p38 mitogen-activated protein kinase mediated through proliferator-activated γ receptor co-activator 1 α activation, resulting in increased mitochondrial DNA expression and enhanced skeletal muscle oxidative capacity. However, the mechanisms by which concomitant carbohydrate restriction and dietary protein supplementation modulates mitochondrial adaptations to aerobic exercise training remains unclear. This review summarizes intracellular regulation of mitochondrial biogenesis and the effects of carbohydrate restriction and protein supplementation on mitochondrial adaptations to aerobic exercise. PMID:24228194

  11. Cannabinoid Type 1 Receptor Blockade Promotes Mitochondrial Biogenesis Through Endothelial Nitric Oxide Synthase Expression in White Adipocytes

    PubMed Central

    Tedesco, Laura; Valerio, Alessandra; Cervino, Cristina; Cardile, Annalisa; Pagano, Claudio; Vettor, Roberto; Pasquali, Renato; Carruba, Michele O.; Marsicano, Giovanni; Lutz, Beat; Pagotto, Uberto; Nisoli, Enzo

    2008-01-01

    OBJECTIVECannabinoid type 1 (CB1) receptor blockade decreases body weight and adiposity in obese subjects; however, the underlying mechanism is not yet fully understood. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) induces mitochondrial biogenesis and function in adipocytes. This study was undertaken to test whether CB1 receptor blockade increases the espression of eNOS and mitochondrial biogenesis in white adipocytes. RESEARCH DESIGN AND METHODSWe examined the effects on eNOS and mitochondrial biogenesis of selective pharmacological blockade of CB1 receptors by SR141716 (rimonabant) in mouse primary white adipocytes. We also examined eNOS expression and mitochondrial biogenesis in white adipose tissue (WAT) and isolated mature white adipocytes of CB1 receptordeficient (CB1?/?) and chronically SR141716-treated mice on either a standard or high-fat diet. RESULTSSR141716 treatment increased eNOS expression in cultured white adipocytes. Moreover, SR141716 increased mitochondrial DNA amount, mRNA levels of genes involved in mitochondrial biogenesis, and mitochondrial mass and function through eNOS induction, as demonstrated by reversal of SR141716 effects by small interfering RNAmediated decrease in eNOS. While high-fat dietfed wild-type mice showed reduced eNOS expression and mitochondrial biogenesis in WAT and isolated mature white adipocytes, genetic CB1 receptor deletion or chronic treatment with SR141716 restored these parameters to the levels observed in wild-type mice on the standard diet, an effect linked to the prevention of adiposity and body weight increase. CONCLUSIONSCB1 receptor blockade increases mitochondrial biogenesis in white adipocytes by inducing the expression of eNOS. This is linked to the prevention of high-fat dietinduced fat accumulation, without concomitant changes in food intake. PMID:18477809

  12. MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury

    PubMed Central

    Mannam, Praveen; Shinn, Amanda S.; Srivastava, Anup; Neamu, Radu F.; Walker, Wendy E.; Bohanon, Michael; Merkel, Jane; Kang, Min-Jong; Cruz, Charles S. Dela; Ahasic, Amy M.; Pisani, Margaret A.; Trentalange, Mark; West, A. Phillip; Shadel, Gerald S.; Elias, Jack A.

    2014-01-01

    Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis. PMID:24487387

  13. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

    SciTech Connect

    Wang, Lai; Chen, Man; Yuan, Lin; Xiang, Yuting; Zheng, Ruimao; Zhu, Shigong

    2014-07-18

    Highlights: • 14,15-EET inhibits OGD-induced apoptosis in cortical neurons. • Mitochondrial biogenesis of cortical neurons is promoted by 14,15-EET. • 14,15-EET preserves mitochondrial function of cortical neurons under OGD. • CREB mediates effect of 14,15-EET on mitochondrial biogenesis and function. - Abstract: 14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and function in cortical neurons under the condition of oxygen–glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1.

  14. The multifaceted role of nitric oxide synthases in mitochondrial biogenesis and cell differentiation

    PubMed Central

    Aquilano, Katia; Barbato, Daniele Lettieri; Rosa, Ciriolo Maria

    2015-01-01

    Nitric oxide (NO) is physiologically synthetized by a family of enzymes called NO synthases (NOSs). NO is a pleiotropic second messenger having a fundamental role in several cellular processes including cell differentiation. Being a high reactive molecule, NO must be synthetized in close proximity to the effector/target. For this reason, the subcellular localization of NOSs is tightly regulated by different post-translation mechanisms. Recently, in murine C2C12myoblasts, we have demonstrated that mitochondrial biogenesis, an essential event for cell differentiation, can be effective only if the site of NO production is located at nuclear level, where NO favors the CREB-dependent expression of PGC-1? gene. The increase of NO flux in nuclei is elicited by the up-regulation and redistribution of neuronal NOS (nNOS) toward nuclei. Herein we show that an upregulation of endothelial NOS (eNOS) occurs during adipocyte differentiation in 3T3-L1 cells. However, differently to differentiating myocytes, a concomitant redistribution of eNOS toward nuclei was not detected. We also observed that, upon treatment with the NO synthesis inhibitor L-NAME, mitochondrial biogenesis as well as triglyceride accumulation that normally occurs during adipogenesis were not impeded. The absence of eNOS in nuclei together with the ineffectiveness of L-NAME suggest that, at least during 3T3-L1 differentiation, NO is not fundamental for the induction of mitochondrial biogenesis and adipogenesis. PMID:26479127

  15. Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts.

    PubMed

    Sin, Jon; Andres, Allen M; Taylor, David J R; Weston, Thomas; Hiraumi, Yoshimi; Stotland, Aleksandr; Kim, Brandon J; Huang, Chengqun; Doran, Kelly S; Gottlieb, Roberta A

    2016-02-01

    Myogenesis is a crucial process governing skeletal muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNM1L/DRP1 (dynamin 1-like)-mediated fragmentation and subsequent removal of mitochondria via SQSTM1 (sequestosome 1)-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha)-mediated biogenesis. Mitochondrial fusion protein OPA1 (optic atrophy 1 [autosomal dominant]) is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that suppressing autophagy with various inhibitors during differentiation interferes with myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation. PMID:26566717

  16. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis.

    PubMed

    Gomes, Ana P; Duarte, Filipe V; Nunes, Patricia; Hubbard, Basil P; Teodoro, João S; Varela, Ana T; Jones, John G; Sinclair, David A; Palmeira, Carlos M; Rolo, Anabela P

    2012-02-01

    Berberine (BBR) has recently been shown to improve insulin sensitivity in rodent models of insulin resistance. Although this effect was explained partly through an observed activation of AMP-activated protein kinase (AMPK), the upstream and downstream mediators of this phenotype were not explored. Here, we show that BBR supplementation reverts mitochondrial dysfunction induced by High Fat Diet (HFD) and hyperglycemia in skeletal muscle, in part due to an increase in mitochondrial biogenesis. Furthermore, we observe that the prevention of mitochondrial dysfunction by BBR, the increase in mitochondrial biogenesis, as well as BBR-induced AMPK activation, are blocked in cells in which SIRT1 has been knocked-down. Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance. PMID:22027215

  17. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle.

    PubMed

    Cho, Yoshitake; Hazen, Bethany C; Gandra, Paulo G; Ward, Samuel R; Schenk, Simon; Russell, Aaron P; Kralli, Anastasia

    2016-02-01

    Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole-body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age-related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1- and ESRR-induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno-associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4-wk-old mice. Compared to control vector, AAV1-Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40-80%). Moreover, AAV1-Perm1-transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31%, respectively), without prominent changes in fiber-type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.-Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. PMID:26481306

  18. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease-like pathology.

    PubMed

    Zhang, Wei; Gu, Guo-Jun; Shen, Xing; Zhang, Qi; Wang, Gang-Min; Wang, Pei-Jun

    2015-03-01

    Mitochondrial dysfunction, especially a defect in mitochondrial biogenesis, is an early and prominent feature of Alzheimer's disease (AD). Previous studies demonstrated that the number of mitochondria is significantly reduced in susceptible hippocampal neurons from AD patients. Neural stem cell (NSC) transplantation in AD-like mice can compensate for the neuronal loss resulting from amyloid-beta protein deposition. The effects of NSC transplantation on mitochondrial biogenesis and cognitive function in AD-like mice, however, are poorly understood. In this study, we injected NSCs or vehicle into 12-month-old amyloid precursor protein (APP)/PS1 transgenic mice, a mouse model of AD-like pathology. The effects of NSC transplantation on cognitive function, the amount of mitochondrial DNA, the expression of mitochondrial biogenesis factors and mitochondria-related proteins, and mitochondrial morphology were investigated. Our results show that in NSC-injected APP/PS1 (Tg-NSC) mice, the cognitive function, number of mitochondria, and expression of mitochondria-related proteins, specifically the mitochondrial fission factors (dynamin-related protein 1 [Drp1] and fission 1 [Fis1]) and the mitochondrial fusion factor optic atrophy 1 (OPA1), were significantly increased compared with those in age-matched vehicle-injected APP/PS1 (Tg-Veh) mice, whereas the expression of mitochondrial fusion factors mitofusion 1 (Mfn1) and Mfn2 was significantly decreased. These data indicate that NSC transplantation may enhance mitochondria biogenesis and further rescue cognitive deficits in AD-like mice. PMID:25582749

  19. Mitochondrial biogenesis and energy production in differentiating murine stem cells: a functional metabolic study.

    PubMed

    Han, Sungwon; Auger, Christopher; Thomas, Sean C; Beites, Crestina L; Appanna, Vasu D

    2014-02-01

    The significance of metabolic networks in guiding the fate of the stem cell differentiation is only beginning to emerge. Oxidative metabolism has been suggested to play a major role during this process. Therefore, it is critical to understand the underlying mechanisms of metabolic alterations occurring in stem cells to manipulate the ultimate outcome of these pluripotent cells. Here, using P19 murine embryonal carcinoma cells as a model system, the role of mitochondrial biogenesis and the modulation of metabolic networks during dimethyl sulfoxide (DMSO)-induced differentiation are revealed. Blue native polyacrylamide gel electrophoresis (BN-PAGE) technology aided in profiling key enzymes, such as hexokinase (HK) [EC 2.7.1.1], glucose-6-phosphate isomerase (GPI) [EC 5.3.1.9], pyruvate kinase (PK) [EC 2.7.1.40], Complex I [EC 1.6.5.3], and Complex IV [EC 1.9.3.1], that are involved in the energy budget of the differentiated cells. Mitochondrial adenosine triphosphate (ATP) production was shown to be increased in DMSO-treated cells upon exposure to the tricarboxylic acid (TCA) cycle substrates, such as succinate and malate. The increased mitochondrial activity and biogenesis were further confirmed by immunofluorescence microscopy. Collectively, the results indicate that oxidative energy metabolism and mitochondrial biogenesis were sharply upregulated in DMSO-differentiated P19 cells. This functional metabolic and proteomic study provides further evidence that modulation of mitochondrial energy metabolism is a pivotal component of the cellular differentiation process and may dictate the final destiny of stem cells. PMID:24350892

  20. Defects in Mitochondrial Fatty Acid Synthesis Result in Failure of Multiple Aspects of Mitochondrial Biogenesis in Saccharomyces cerevisiae

    PubMed Central

    Kursu, V. A. Samuli; Pietikäinen, Laura P.; Fontanesi, Flavia; Aaltonen, Mari J.; Suomi, Fumi; Nair, Remya Raghavan; Schonauer, Melissa S.; Dieckmann, Carol L.; Barrientos, Antoni; Hiltunen, J. Kalervo; Kastaniotis, Alexander J.

    2014-01-01

    Summary Mitochondrial fatty acid synthesis (mtFAS) shares acetyl-CoA with the Krebs cycle as a common substrate and is required for the production of octanoic acid (C8) precursors of lipoic acid (LA) in mitochondria. MtFAS is a conserved pathway essential for respiration. In a genetic screen in Saccharomyces cerevisiae designed to further elucidate the physiological role of mtFAS, we isolated mutants with defects in mitochondrial post-translational gene expression processes, indicating a novel link to mitochondrial gene expression and respiratory chain biogenesis. In our ensuing analysis, we show that mtFAS, but not lipoylation per se, is required for respiratory competence. We demonstrate that mtFAS is required for mRNA splicing, mitochondrial translation and respiratory complex assembly, and provide evidence that not LA per se, but fatty acids longer than C8 play a role in these processes. We also show that mtFAS- and LA-deficient strains suffer from a mild heme deficiency that may contribute to the respiratory complex assembly defect. Based on our data and previously published information, we propose a model implicating mtFAS as a sensor for mitochondrial acetyl-CoA availability and a coordinator of nuclear and mitochondrial gene expression by adapting the mitochondrial compartment to changes in the metabolic status of the cell. PMID:24102902

  1. Defects in mitochondrial fatty acid synthesis result in failure of multiple aspects of mitochondrial biogenesis in Saccharomyces cerevisiae.

    PubMed

    Kursu, V A Samuli; Pietikinen, Laura P; Fontanesi, Flavia; Aaltonen, Mari J; Suomi, Fumi; Raghavan Nair, Remya; Schonauer, Melissa S; Dieckmann, Carol L; Barrientos, Antoni; Hiltunen, J Kalervo; Kastaniotis, Alexander J

    2013-11-01

    Mitochondrial fatty acid synthesis (mtFAS) shares acetyl-CoA with the Krebs cycle as a common substrate and is required for the production of octanoic acid (C8) precursors of lipoic acid (LA) in mitochondria. MtFAS is a conserved pathway essential for respiration. In a genetic screen in Saccharomyces cerevisiae designed to further elucidate the physiological role of mtFAS, we isolated mutants with defects in mitochondrial post-translational gene expression processes, indicating a novel link to mitochondrial gene expression and respiratory chain biogenesis. In our ensuing analysis, we show that mtFAS, but not lipoylation per se, is required for respiratory competence. We demonstrate that mtFAS is required for mRNA splicing, mitochondrial translation and respiratory complex assembly, and provide evidence that not LA?per se, but fatty acids longer than C8 play a role in these processes. We also show that mtFAS- and LA-deficient strains suffer from a mild haem deficiency that may contribute to the respiratory complex assembly defect. Based on our data and previously published information, we propose a model implicating mtFAS as a sensor for mitochondrial acetyl-CoA availability and a co-ordinator of nuclear and mitochondrial gene expression by adapting the mitochondrial compartment to changes in the metabolic status of the cell. PMID:24102902

  2. Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice

    PubMed Central

    Athale, Janhavi; Ulrich, Allison; MacGarvey, Nancy Chou; Bartz, Raquel R.; Welty-Wolf, Karen E.; Suliman, Hagir B.; Piantadosi, Claude A.

    2013-01-01

    Acute lung injury (ALI) initiates protective responses involving genes downstream of the Nrf2 (Nfe2l2) transcription factor, including heme oxygenase-1 (HO-1), which stimulates mitochondrial biogenesis and related anti-inflammatory processes. We examined mitochondrial biogenesis during Staphylococcus aureus pneumonia in mice and the effect of Nrf2 deficiency on lung mitochondrial biogenesis and resolution of lung inflammation. S. aureus pneumonia established by nasal insufflation of live bacteria was studied in mitochondrial reporter (mt-COX8-GFP) mice, wild-type (WT) mice, and Nrf2?/? mice. Bronchoalveolar lavage, wet/dry ratios, real-time RT-PCR and Western analysis, immunohistochemistry, and fluorescence microscopy were performed on the lung at 0, 6, 24, and 48 h. The mice survived S. aureus inoculations at 5 108 CFU despite diffuse lung inflammation and edema, but the Nrf2?/? lung showed increased ALI. In mt-COX8-GFP mice, mitochondrial fluorescence was enhanced in bronchial and alveolar type II (AT2) epithelial cells. WT mice displayed rapid HO-1 upregulation and lower proinflammatory TNF-?, IL-1?, and CCL2 and, especially in AT2 cells, higher anti-inflammatory IL-10 and suppressor of cytokine signaling-3 than Nrf2?/? mice. In the alveolar region, WT but not Nrf2?/? mice showed strongly induced nuclear respiratory factor-1, PGC-1?, mitochondrial transcription factor-A, SOD2, Bnip3, mtDNA copy number, and citrate synthase. These findings indicate that S. aureus pneumonia induces Nrf2-dependent mitochondrial biogenesis in the alveolar region, mainly in AT2 cells. Absence of Nrf2 suppresses the alveolar transcriptional network for mitochondrial biogenesis and anti-inflammation, which worsens ALI. The findings link redox activation of mitochondrial biogenesis to ALI resolution. PMID:22940620

  3. Cyclovirobuxine D Attenuates Doxorubicin-Induced Cardiomyopathy by Suppression of Oxidative Damage and Mitochondrial Biogenesis Impairment

    PubMed Central

    Guo, Qian; Guo, Jiabin; Yang, Rong; Peng, Hui; Zhao, Jun; Li, Li; Peng, Shuangqing

    2015-01-01

    The clinical application of doxorubicin (DOX) is compromised by its cardiac toxic effect. Cyclovirobuxine D (CVB-D) is a steroid alkaloid extracted from a traditional Chinese medicine, Buxus microphylla. Our results showed that CVB-D pretreatment markedly attenuated DOX-induced cardiac contractile dysfunction and histological alterations. By using TUNEL assay and western blot analysis, we found that CVB-D pretreatment reduced DOX-induced apoptosis of myocardial cells and mitochondrial cytochrome c release to cytosol. CVB-D pretreatment ameliorated DOX-induced cardiac oxidative damage including lipid peroxidation and protein carbonylation and a decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Moreover, CVB-D was found to prevent DOX-induced mitochondrial biogenesis impairment as evidenced by preservation of peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) and nuclear respiratory factor 1 (NRF1), as well as mitochondrial DNA copy number. These findings demonstrate that CVB-D protects against DOX-induced cardiomyopathy, at least in part, by suppression of oxidative damage and mitochondrial biogenesis impairment. PMID:26075032

  4. β-Hydroxy-β-methylbutyrate, mitochondrial biogenesis, and skeletal muscle health.

    PubMed

    He, Xi; Duan, Yehui; Yao, Kang; Li, Fengna; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2016-03-01

    The metabolic roles of mitochondria go far beyond serving exclusively as the major producer of ATP in tissues and cells. Evidence has shown that mitochondria may function as a key regulator of skeletal muscle fiber types and overall well-being. Maintaining skeletal muscle mitochondrial content and function is important for sustaining health throughout the lifespan. Of great importance, β-hydroxy-β-methylbutyrate (HMB, a metabolite of L-leucine) has been proposed to enhance the protein deposition and efficiency of mitochondrial biogenesis in skeletal muscle, as well as muscle strength in both exercise and clinical settings. Specifically, dietary supplementation with HMB increases the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), which represents an upstream inducer of genes of mitochondrial metabolism, coordinates the expression of both nuclear- and mitochondrion-encoded genes in mitochondrial biogenesis. Additionally, PGC-1α plays a key role in the transformation of skeletal muscle fiber type, leading to a shift toward type I muscle fibers that are rich in mitochondria and have a high capacity for oxidative metabolism. As a nitrogen-free metabolite, HMB holds great promise to improve skeletal muscle mass and function, as well as whole-body health and well-being of animals and humans. PMID:26573541

  5. The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise.

    PubMed

    Marcinko, Katarina; Steinberg, Gregory R

    2014-12-01

    Insulin resistance is associated with defects in skeletal muscle fatty acid (FA) metabolism that contribute to the development of type2 diabetes. Endurance exercise increases FA and glucose metabolism, muscle mitochondrial content and insulin sensitivity. In skeletal muscle, basal rates of FA oxidation are dependent on AMP-activated protein kinase (AMPK) phosphorylation of acetyl-CoA carboxylase2, the rate-limiting enzyme controlling the production of the metabolic intermediate malonyl-CoA. Likewise, AMPK is essential for maintaining muscle mitochondrial content in untrained mice; effects that may be mediated through regulation of the peroxisome proliferator-activated receptor? co-activator-1?. However, the importance of AMPK in regulating glucose and FA uptake, FA oxidation and mitochondrial biogenesis during and following endurance exercise training is not fully understood. A better understanding of the mechanisms by which endurance exercise regulates substrate utilization and mitochondrial biogenesis may lead to improved therapeutic and preventative strategies for the treatment of insulin resistance and type2 diabetes. PMID:25261498

  6. Developmental regulation of mitochondrial biogenesis and function in the mouse mammary gland during a prolonged lactation cycle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The regulation of mitochondrial biogenesis and function in the lactating mammary cell is poorly understood. The goal of this study was to use proteomics to relate temporal changes in mammary cell mitochondrial function during lactation to changes in the proteins that make up this organelle. The hypo...

  7. Melatonin promotes adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes.

    PubMed

    Kato, Hisashi; Tanaka, Goki; Masuda, Shinya; Ogasawara, Junetsu; Sakurai, Takuya; Kizaki, Takako; Ohno, Hideki; Izawa, Tetsuya

    2015-09-01

    Melatonin is synthesized in the pineal gland, but elicits a wide range of physiological responses in peripheral target tissues. Recent advances suggest that melatonin controls adiposity, resulting in changes in body weight. The aim of this study was to investigate the effect of melatonin on adipogenesis and mitochondrial biogenesis in 3T3-L1 mouse embryo fibroblasts. Melatonin significantly increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipogenesis, and promoted differentiation into adipocytes. Melatonin-treated cells also formed smaller lipid droplets and abundantly expressed several molecules associated with lipolysis, including adipose triglyceride lipase, perilipin, and comparative gene identification-58. Moreover, the hormone promoted biogenesis of mitochondria, as indicated by fluorescent staining, elevated the citrate synthase activity, and upregulated the expression of PPAR-γ coactivator 1 α, nuclear respiratory factor-1, and transcription factor A. The expression of uncoupling protein 1 was also observable both at mRNA and at protein level in melatonin-treated cells. Finally, adiponectin secretion and the expression of adiponectin receptors were enhanced. These results suggest that melatonin promotes adipogenesis, lipolysis, mitochondrial biogenesis, and adiponectin secretion. Thus, melatonin has potential as an anti-obesity agent that may reverse obesity-related disorders. PMID:26123001

  8. High-fat diet-induced mitochondrial biogenesis is regulated by mitochondrial-derived reactive oxygen species activation of CaMKII.

    PubMed

    Jain, Swati S; Paglialunga, Sabina; Vigna, Chris; Ludzki, Alison; Herbst, Eric A; Lally, James S; Schrauwen, Patrick; Hoeks, Joris; Tupling, A Russ; Bonen, Arend; Holloway, Graham P

    2014-06-01

    Calcium/calmodulin-dependent protein kinase (CaMK) activation induces mitochondrial biogenesis in response to increasing cytosolic calcium concentrations. Calcium leak from the ryanodine receptor (RyR) is regulated by reactive oxygen species (ROS), which is increased with high-fat feeding. We examined whether ROS-induced CaMKII-mediated signaling induced skeletal muscle mitochondrial biogenesis in selected models of lipid oversupply. In obese Zucker rats and high-fat-fed rodents, in which muscle mitochondrial content was upregulated, CaMKII phosphorylation was increased independent of changes in calcium uptake because sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) protein expression or activity was not altered, implicating altered sarcoplasmic reticulum (SR) calcium leak in the activation of CaMKII. In support of this, we found that high-fat feeding increased mitochondrial ROS emission and S-nitrosylation of the RyR, whereas hydrogen peroxide induced SR calcium leak from the RyR and activation of CaMKII. Moreover, administration of a mitochondrial-specific antioxidant, SkQ, prevented high-fat diet-induced phosphorylation of CaMKII and the induction of mitochondrial biogenesis. Altogether, these data suggest that increased mitochondrial ROS emission is required for the induction of SR calcium leak, activation of CaMKII, and induction of mitochondrial biogenesis in response to excess lipid availability. PMID:24520120

  9. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation to promote metastasis

    PubMed Central

    LeBleu, Valerie S.; O'Connell, Joyce T.; Herrera, Karina N. Gonzalez; Wikman-Kocher, Harriet; Pantel, Klaus; Haigis, Marcia C.; de Carvalho, Fernanda Machado; Damascena, Aline; Chinen, Ludmilla Thome Domingos; Rocha, Rafael M.; Asara, John M.; Kalluri, Raghu

    2014-01-01

    Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumor growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favor mitochondrial respiration and increased ATP production. Invasive cancer cells use transcription co-activator, PGC-1α to enhance oxidative phosphorylation, mitochondrial biogenesis and oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1α expression in invasive cancer cells and formation of distant metastases. Silencing of PGC-1α in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumor growth or epithelial-to-mesenchymal (EMT) program. While inherent genetics of cancer cells determine the transcriptome framework required for invasion and metastasis, mitochondrial biogenesis and respiration induced by PGC-1α is also essential for functional motility of cancer cells and metastasis. PMID:25241037

  10. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis

    PubMed Central

    Hiramitsu, Masanori; Shimada, Yasuhito; Kuroyanagi, Junya; Inoue, Takashi; Katagiri, Takao; Zang, Liqing; Nishimura, Yuhei; Nishimura, Norihiro; Tanaka, Toshio

    2014-01-01

    Lemon (Citrus limon) contains various bioactive flavonoids, and prevents obesity and obesity-associated metabolic diseases. We focused on eriocitrin (eriodictyol 7-rutinoside), a powerful antioxidative flavonoid in lemon with lipid-lowering effects in a rat model of high-fat diet. To investigate the mechanism of action of eriocitrin, we conducted feeding experiments on zebrafish with diet-induced obesity. Oral administration of eriocitrin (32 mg/kg/day for 28 days) improved dyslipidaemia and decreased lipid droplets in the liver. DNA microarray analysis revealed that eriocitrin increased mRNA of mitochondrial biogenesis genes, such as mitochondria transcription factor, nuclear respiratory factor 1, cytochrome c oxidase subunit 4, and ATP synthase. In HepG2 cells, eriocitrin also induced the corresponding orthologues, and reduced lipid accumulation under conditions of lipid loading. Eriocitrin increased mitochondrial size and mtDNA content, which resulted in ATP production in HepG2 cells and zebrafish. In summary, dietary eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. PMID:24424211

  11. Recovery of Indicators of Mitochondrial Biogenesis, Oxidative Stress, and Aging With (-)-Epicatechin in Senile Mice.

    PubMed

    Moreno-Ulloa, Aldo; Nogueira, Leonardo; Rodriguez, Alonso; Barboza, Jonathan; Hogan, Michael C; Ceballos, Guillermo; Villarreal, Francisco; Ramirez-Sanchez, Israel

    2015-11-01

    There is evidence implicating oxidative stress (OS) as the cause of the deleterious effects of aging. In this study, we evaluated the capacity of the flavanol (-)-epicatechin (Epi) to reduce aging-induced OS and restore mitochondrial biogenesis, as well as, structural and functional endpoints in aged mice. Senile (S; 26-month-old) C57BL/6 male mice were randomly assigned to receive either water (vehicle) or 1mg/kg of Epi via oral gavage (twice daily) for 15 days. Young (Y; 6-month-old) mice were used as controls. In S brain, kidney, heart, and skeletal muscle (compared with Y animals) an increase in OS was observed as evidenced by increased protein-free carbonyls and decreased reduced glutathione levels as well as sirtuin 3, superoxide dismutase 2, catalase, thioredoxin and glutathione peroxidase protein levels. Well-recognized factors (eg, sirtuin 1) that regulate mitochondrial biogenesis and mitochondrial structure- and/or function-related endpoints (eg, mitofilin and citrate synthase) protein levels were also reduced in S organs. In contrast, the aging biomarker senescence-associated ?-galactosidase was increased in S compared with Y animals, and Epi administration reduced levels towards those observed in Y animals. Altogether, these data suggest that Epi is capable of shifting the biology of S mice towards that of Y animals. PMID:25143004

  12. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis.

    PubMed

    Hiramitsu, Masanori; Shimada, Yasuhito; Kuroyanagi, Junya; Inoue, Takashi; Katagiri, Takao; Zang, Liqing; Nishimura, Yuhei; Nishimura, Norihiro; Tanaka, Toshio

    2014-01-01

    Lemon (Citrus limon) contains various bioactive flavonoids, and prevents obesity and obesity-associated metabolic diseases. We focused on eriocitrin (eriodictyol 7-rutinoside), a powerful antioxidative flavonoid in lemon with lipid-lowering effects in a rat model of high-fat diet. To investigate the mechanism of action of eriocitrin, we conducted feeding experiments on zebrafish with diet-induced obesity. Oral administration of eriocitrin (32 mg/kg/day for 28 days) improved dyslipidaemia and decreased lipid droplets in the liver. DNA microarray analysis revealed that eriocitrin increased mRNA of mitochondrial biogenesis genes, such as mitochondria transcription factor, nuclear respiratory factor 1, cytochrome c oxidase subunit 4, and ATP synthase. In HepG2 cells, eriocitrin also induced the corresponding orthologues, and reduced lipid accumulation under conditions of lipid loading. Eriocitrin increased mitochondrial size and mtDNA content, which resulted in ATP production in HepG2 cells and zebrafish. In summary, dietary eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. PMID:24424211

  13. PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promotemetastasis.

    PubMed

    LeBleu, Valerie S; O'Connell, Joyce T; Gonzalez Herrera, Karina N; Wikman, Harriet; Pantel, Klaus; Haigis, Marcia C; de Carvalho, Fernanda Machado; Damascena, Aline; Domingos Chinen, Ludmilla Thome; Rocha, Rafael M; Asara, John M; Kalluri, Raghu

    2014-10-01

    Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A, also known as PGC-1?) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1? expression in invasive cancer cells and the formation of distant metastases. Silencing of PGC-1? in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumour growth or the epithelial-to-mesenchymal program. Inherent genetics of cancer cells can determine the transcriptome framework associated with invasion and metastasis, and mitochondrial biogenesis and respiration induced by PGC-1? are also essential for functional motility of cancer cells andmetastasis. PMID:25241037

  14. Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression

    SciTech Connect

    Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf; Sharma, Reeta Kumari; Kandimalla, Ramesh J.L.; Bal, Amanjit; Gill, Kiran Dip

    2013-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10 mg/kg b.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits–NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases. - Highlights: • Aluminium decreases the mRNA levels of mitochondrial and nuclear encoded subunits. • It decreases the mtDNA copy number and mitochondrial content in rat brain. • It down-regulates the mRNA and protein levels of PGC-1α, NRF-1, NRF-2 and Tfam. • It also disturbs the mitochondrial or nuclear architecture of neurons. • Finally it also decreases mitochondrial number in HC and CS regions of rat brain.

  15. Quercetin supplementation does not enhance cerebellar mitochondrial biogenesis and oxidative status in exercised rats.

    PubMed

    Casuso, Rafael A; Martnez-Amat, Antonio; Hita-Contreras, Fidel; Camiletti-Moirn, Daniel; Aranda, Pilar; Martnez-Lpez, Emilio

    2015-07-01

    The present study tested the hypothesis that quercetin may inhibit the mitochondrial and antioxidant adaptations induced by exercise in cerebellar tissue. Thirty-five 6-week-old Wistar rats were randomly allocated into the following groups: quercetin, exercised (Q-Ex; n = 9); quercetin, sedentary (Q-Sed; n = 9); no quercetin, exercised (NQ-Ex; n = 9); and no quercetin, sedentary (NQ-Sed; n = 8). After 6 weeks of quercetin supplementation and/or exercise training, cerebellums were collected. Protein carbonyl content (PCC), sirtuin 1, peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?), messenger RNA levels, citrate synthase (CS), and mitochondrial DNA were measured. When Q-Sed was compared with NQ-Sed, PCC (P < .005) showed decreased levels, whereas PGC-1?, sirtuin 1 (both, P < .01), mitochondrial DNA (P < .001), and CS (P < .01) increased. However, when Q-Ex was compared with Q-Sed, PCC showed increased levels (P < .001), whereas CS decreased (P < .01). Furthermore, the NQ-Ex group experienced an increase in PGC-1? messenger RNA levels in comparison with NQ-Sed (P > .01). This effect, however, did not appear in Q-Ex (P < .05). Therefore, we must hypothesize that either the dose (25 mg/kg) or the length of the quercetin supplementation period that was used in the present study (or perhaps both) may impair exercise-induced adaptations in cerebellar tissue. PMID:26032482

  16. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis1234

    PubMed Central

    Fernandez-Marcos, Pablo J; Auwerx, Johan

    2011-01-01

    Mechanisms responsible for energy management in the cell and in the whole organism require a complex network of transcription factors and cofactors. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a master regulator of mitochondrial biogenesis and function, thus becoming a crucial metabolic node. We present an overview of the mechanisms by which PGC-1α is regulated, including the transcriptional regulation of PGC-1α expression and the fine-tuning of its final activity via posttranslational modifications. PMID:21289221

  17. Mitochondrial Biogenesis Drives a Vicious Cycle of Metabolic Insufficiency and Mitochondrial DNA Deletion Mutation Accumulation in Aged Rat Skeletal Muscle Fibers

    PubMed Central

    Herbst, Allen; Johnson, Chad J.; Hynes, Kayla; McKenzie, Debbie; Aiken, Judd M.

    2013-01-01

    Aged muscles possess dysfunctional fibers that contain intracellular expansions of somatically derived mitochondrial DNA deletion mutations. At high abundance, these mutations disrupt the expression of mitochondrially-encoded protein subunits of the electron transport chain resulting in aerobic respiration deficient muscle fiber segments. These fiber segments atrophy and break contributing to the loss of muscle mass and function that occurs with age. By combining micro-dissection of individual muscle fibers with microarray analysis, we observed the response induced within these abnormal muscle fibers and detected an increase in many genes affecting metabolism and metabolic regulation. The transcriptional profile and subsequent protein validation suggested that a non-compensatory program of mitochondrial biogenesis was initiated. We hypothesized that this non-adaptive program of mitochondrial biogenesis was driving mtDNA deletion mutation accumulation. We tested this hypothesis by treating aged rats with ?-Guanidinopropionic acid, a compound that stimulates mitochondrial biogenesis. ?-Guanidinopropionic acid treatment increased muscle mitochondrial genome copy number and resulted in a 3.7 fold increase in the abundance of electron transport chain negative muscle fiber segments. We conclude that in electron transport system abnormal muscle fiber segments, a vicious cycle of metabolic insufficiency and non-compensatory mitochondrial biogenesis drive mtDNA deletion mutation accumulation. PMID:23516592

  18. N-Acetyl-L-cysteine prevents exercise-induced intestinal lymphocyte apoptosis by maintaining intracellular glutathione levels and reducing mitochondrial membrane depolarization.

    PubMed

    Quadrilatero, J; Hoffman-Goetz, L

    2004-07-01

    Intense exercise leads to post-exercise lymphocytopenia and immunosuppression, possibly by triggering lymphocyte apoptosis. To test the role of oxidative stress on exercise-induced lymphocyte apoptosis, we administered the antioxidant N-acetyl--cysteine (NAC) and measured apoptosis in intestinal lymphocytes (IL) from exhaustively exercised animals. Eighty-seven female C57BL/6 mice were randomly assigned to receive NAC (1 g/kg) or saline 30 min prior to treadmill exercise for 90 min at 2degrees slope (30 min at 22 m min(-1), 30 min at 25 m min(-1), and 30 min at 28 m min(-1)) and sacrificed immediately (Imm) or 24 hours (24 h) after cessation of exercise. Control mice (nonexercised) were exposed to treadmill noise and vibration without running. Exercise increased IL phosphatidylserine externalization (p<0.001), mitochondrial membrane depolarization (p<0.05), and decreased intracellular glutathione concentrations (p<0.05) immediately following exercise in saline relative to nonexercised mice. At 24 h post-exercise, saline injected mice had fewer total (p<0.001) and CD3+ (p<0.005) IL compared to nonexercised animals. NAC injection in mice maintained intracellular glutathione levels, prevented phosphatidylserine externalization, mitochondrial membrane depolarization, and loss of IL immediately and 24 h after exercise. These data suggest that lymphocyte apoptosis precedes post-exercise lymphocytopenia and may be due to oxidative stress. PMID:15184067

  19. Exercise-Induced Bronchospasm

    MedlinePLUS

    ... asthma? How does exercise-induced bronchospasm differ from asthma? Is it safe for me to exercise? What kind of exercise can I do? What other ... Recognition and Management of Exercise-Induced Bronchospasm by T Sinha, MD; ...

  20. Hypothalamic-pituitary-thyroid axis hormones stimulate mitochondrial function and biogenesis in human hair follicles.

    PubMed

    Vidali, Silvia; Knuever, Jana; Lerchner, Johannes; Giesen, Melanie; Bíró, Tamás; Klinger, Matthias; Kofler, Barbara; Funk, Wolfgang; Poeggeler, Burkhard; Paus, Ralf

    2014-01-01

    Thyroid hormones regulate mitochondrial function. As other hypothalamic-pituitary-thyroid (HPT) axis hormones, i.e., thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), are expressed in human hair follicles (HFs) and regulate mitochondrial function in human epidermis, we investigated in organ-cultured human scalp HFs whether TRH (30 nM), TSH (10 mU ml(-1)), thyroxine (T4) (100 nM), and triiodothyronine (T3) (100 pM) alter intrafollicular mitochondrial energy metabolism. All HPT-axis members increased gene and protein expression of mitochondrial-encoded subunit 1 of cytochrome c oxidase (MTCO1), a subunit of respiratory chain complex IV, mitochondrial transcription factor A (TFAM), and Porin. All hormones also stimulated intrafollicular complex I/IV activity and mitochondrial biogenesis. The TSH effects on MTCO1, TFAM, and porin could be abolished by K1-70, a TSH-receptor antagonist, suggesting a TSH receptor-mediated action. Notably, as measured by calorimetry, T3 and TSH increased follicular heat production, whereas T3/T4 and TRH stimulated ATP production in cultured HF keratinocytes. HPT-axis hormones did not increase reactive oxygen species (ROS) production. Rather, T3 and T4 reduced ROS formation, and all tested HPT-axis hormones increased the transcription of ROS scavengers (catalase, superoxide dismutase 2) in HF keratinocytes. Thus, mitochondrial biology, energy metabolism, and redox state of human HFs are subject to profound (neuro-)endocrine regulation by HPT-axis hormones. The neuroendocrine control of mitochondrial biology in a complex human mini-organ revealed here may be therapeutically exploitable. PMID:23949722

  1. Biogenesis of Mitochondria in Germinating Peanut Cotyledons II. Changes in Cytochromes and Mitochondrial DNA 1

    PubMed Central

    Breidenbach, R. W.; Castelfranco, Paul; Criddle, R. S.

    1967-01-01

    Biogenesis of mitochondria occurs in the germinating cotyledons of peanuts. This process was demonstrated by measuring both constitutive and enzymatic properties of mitochondria as a function of germination time. Direct counting by phase contrast microscopy of sucrose density gradient preparations showed that the number of mitochondria increased markedly during germination. DNA with a buoyant density distinct from the major cellular DNA was associated with these mitochondrial preparations. During germination the amount of this DNA in mitochondrial pellets increased. This increase closely paralleled the increase in number of mitochondria. Succinoxidase and succinic dehydrogenase increased during germination. Both activities were confined to the mitochondrial fraction. The rate of increase of succinoxidase activity was significantly greater than the rate of increase of succinic dehydrogenase and both increased at least initially at a greater rate than the amount of mitochondrial DNA or numbers of mitochondria. The amounts of cytochromes present in mitochondrial preparations were measured spectrophotometrically. All of the cytochromes increased in amount during germination. The rate of increase of cytochrome a — a3 very close to the rate of increase in succinoxidase activity. PMID:16656611

  2. Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations.

    PubMed

    Carelli, Valerio; Maresca, Alessandra; Caporali, Leonardo; Trifunov, Selena; Zanna, Claudia; Rugolo, Michela

    2015-06-01

    Mitochondria are cytoplasmic organelles containing their own multi-copy genome. They are organized in a highly dynamic network, resulting from balance between fission and fusion, which maintains homeostasis of mitochondrial mass through mitochondrial biogenesis and mitophagy. Mitochondrial DNA (mtDNA) mutates much faster than nuclear DNA. In particular, mtDNA point mutations and deletions may occur somatically and accumulate with aging, coexisting with the wild type, a condition known as heteroplasmy. Under specific circumstances, clonal expansion of mutant mtDNA may occur within single cells, causing a wide range of severe human diseases when mutant overcomes wild type. Furthermore, mtDNA deletions accumulate and clonally expand as a consequence of deleterious mutations in nuclear genes involved in mtDNA replication and maintenance, as well as in mitochondrial fusion genes (mitofusin-2 and OPA1), possibly implicating mtDNA nucleoids segregation. We here discuss how the intricacies of mitochondrial homeostasis impinge on the intracellular propagation of mutant mtDNA. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. PMID:25666555

  3. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.

    PubMed

    O'Neill, Hayley M; Holloway, Graham P; Steinberg, Gregory R

    2013-02-25

    Skeletal muscle plays an important role in regulating whole-body energy expenditure given it is a major site for glucose and lipid oxidation. Obesity and type 2 diabetes are causally linked through their association with skeletal muscle insulin resistance, while conversely exercise is known to improve whole body glucose homeostasis simultaneously with muscle insulin sensitivity. Exercise activates skeletal muscle AMP-activated protein kinase (AMPK). AMPK plays a role in regulating exercise capacity, skeletal muscle mitochondrial content and contraction-stimulated glucose uptake. Skeletal muscle AMPK is also thought to be important for regulating fatty acid metabolism; however, direct genetic evidence in this area is currently lacking. This review will discuss the current paradigms regarding the influence of AMPK in regulating skeletal muscle fatty acid metabolism and mitochondrial biogenesis at rest and during exercise, and highlight the potential implications in the development of insulin resistance. PMID:22750049

  4. Flavan-3-ol fraction from cocoa powder promotes mitochondrial biogenesis in skeletal muscle in mice

    PubMed Central

    2014-01-01

    Background Numerous clinical studies have reported that ingestion of chocolate has reduced risk of metabolic syndrome. In order to elucidate the mechanism, we evaluated the influence of flavan-3-ols derived from cocoa powder on energy metabolism in mice using an indirect calorimetric method. Method The mice were divided into two groups, and administered either distilled water or 50 mg/kg of flavan-3-ol fraction for 2 weeks. At the end of the experimental period, animals were sacrificed after blood pressure and the mean respiratory exchange ratio (RER) over 24 hours were measured. Results The mean respiratory exchange ratio (RER) over 24 hours was reduced significantly in the flavan-3-ols group. The mean blood pressure was significantly decreased in flavan-3-ols treatment group compared with control group. The protein level of carnitine palmitoyltransferase 2 (CPT2) was increased significantly by flavan-3-ols in skeletal muscle, but not in liver. Uncoupling protein (UCP) 1 was increased significantly in brown adipose tissue by flavan-3-ols. The mitochondria copy number in gastrocnemius and soleus muscles and brown adipose tissue were increased significantly by administration of flavan-3-ol fraction. Conclusion These results suggest that flavan-3-ols enhances lipolysis and promotes mitochondrial biogenesis. We conclude that improvement of metabolic syndrome risk factors following ingestion of chocolate may be induced, in part, by the mitochondrial biogenesis-promoting effect of flavan-3-ols. PMID:24708519

  5. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis

    PubMed Central

    Wilkins, Heather M.; Harris, Janna L.; Carl, Steven M.; E, Lezi; Lu, Jianghua; Eva Selfridge, J.; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M.; Michaelis, Mary L.; Michaelis, Elias K.; Brooks, William M.; Swerdlow, Russell H.

    2014-01-01

    Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1–2 g/kg once per day for 1–2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. 1H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. PMID:25027327

  6. Cellular and mitochondrial remodeling upon defects in iron-sulfur protein biogenesis.

    PubMed

    Hausmann, Anja; Samans, Birgit; Lill, Roland; Mhlenhoff, Ulrich

    2008-03-28

    Biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is an essential process involving the mitochondrial iron-sulfur cluster (ISC) assembly and export machineries and the cytosolic iron/sulfur protein assembly (CIA) apparatus. To define the integration of Fe/S protein biogenesis into cellular homeostasis, we compared the global transcriptional responses to defects in the three biogenesis systems in Saccharomyces cerevisiae using DNA microarrays. Depletion of a member of the CIA machinery elicited only weak (up to 2-fold) alterations in gene expression with no clear preference for any specific cellular process. In contrast, depletion of components of the mitochondrial ISC assembly and export systems induced strong and largely overlapping transcriptional responses of more than 200 genes (2-100-fold changes). These alterations were strikingly similar, yet not identical, to the transcriptional profiles developed upon iron starvation. Hence, mitochondria and their ISC systems serve as primary physiological regulators exerting a global control of numerous iron-dependent processes. First, ISC depletion activates the iron-responsive transcription factors Aft1/2p leading to increased cellular iron acquisition. Second, respiration and heme metabolism are repressed ensuring the balanced utilization of iron by the two major iron-consuming processes, iron-sulfur protein and heme biosynthesis. Third, the decreased respiratory activity is compensated by induction of genes involved in glucose acquisition. Finally, transcriptional remodeling of the citric acid cycle and the biosyntheses of ergosterol and biotin reflect the iron dependence of these pathways. Together, our data suggest a model in which mitochondria perform a global regulatory role in numerous cellular processes linked to iron homeostasis. PMID:18227070

  7. Role of human mitochondrial Nfs1 in cytosolic iron-sulfur protein biogenesis and iron regulation.

    PubMed

    Biederbick, Annette; Stehling, Oliver; Rsser, Ralf; Niggemeyer, Brigitte; Nakai, Yumi; Elssser, Hans-Peter; Lill, Roland

    2006-08-01

    The biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is a complex process involving more than 20 components. So far, functional investigations have mainly been performed in Saccharomyces cerevisiae. Here, we have analyzed the role of the human cysteine desulfurase Nfs1 (huNfs1), which serves as a sulfur donor in biogenesis. The protein is located predominantly in mitochondria, but small amounts are present in the cytosol/nucleus. huNfs1 was depleted efficiently in HeLa cells by a small interfering RNA (siRNA) approach, resulting in a drastic growth retardation and striking morphological changes of mitochondria. The activities of both mitochondrial and cytosolic Fe/S proteins were strongly impaired, demonstrating that huNfs1 performs an essential function in Fe/S protein biogenesis in human cells. Expression of murine Nfs1 (muNfs1) in huNfs1-depleted cells restored both growth and Fe/S protein activities to wild-type levels, indicating the specificity of the siRNA depletion approach. No complementation of the growth retardation was observed, when muNfs1 was synthesized without its mitochondrial presequence. This extramitochondrial muNfs1 did not support maintenance of Fe/S protein activities, neither in the cytosol nor in mitochondria. In conclusion, our study shows that the essential huNfs1 is required inside mitochondria for efficient maturation of cellular Fe/S proteins. The results have implications for the regulation of iron homeostasis by cytosolic iron regulatory protein 1. PMID:16847322

  8. Altered signaling for mitochondrial and myofibrillar biogenesis in skeletal muscles of patients with multiple sclerosis.

    PubMed

    Hansen, Dominique; Wens, Inez; Vandenabeele, Frank; Verboven, Kenneth; Eijnde, Bert O

    2015-07-01

    Patients with multiple sclerosis (pwMS) experience muscle weakness and lowered muscle oxidative capacity. To explore the etiology for the development of such muscle phenotype we studied skeletal muscle adenosine monophosphate (AMP)-activated protein kinase phosphorylation (phospho-AMPK?, governing mitochondrial biogenesis) and mammalian target of rapamycin phosphorylation (phospho-mTOR, governing myofibrillar biogenesis) in pwMS. After assessment of body composition, muscle strength, exercise tolerance, and muscle fiber type, muscle phospho-AMPK? and phospho-mTOR were assessed in 14 pwMS and 10 healthy controls (part 1). Next, an endurance exercise bout was executed by 9 pwMS and 7 healthy subjects, with assessment of changes in muscle phospho-AMPK? and phospho-mTOR (part 2). Increased basal muscle phospho-AMPK? and phospho-mTOR were present in MS (P < 0.01) and independently related to MS. Correlations between muscle phospho-AMPK? or phospho-mTOR and whole-body fat mass, peak oxygen uptake, and expanded disability status scale (P < 0.05) were found. After endurance exercise muscle phospho-AMPK? and phospho-mTOR remained increased in pwMS (P < 0.01). Muscle signaling cascades for mitochondrial and myofibrillar biogenesis are altered in MS and related to the impairment and disability level. These findings indicate a link between muscle signaling cascades and the level of disability and impairment, and thus may open a new area for the development of novel therapies for peripheral muscle impairment in MS. PMID:25666356

  9. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells.

    PubMed

    De Luca, Arianna; Fiorillo, Marco; Peiris-Pags, Maria; Ozsvari, Bela; Smith, Duncan L; Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E; Cappello, Anna Rita; Pezzi, Vincenzo; Lisanti, Michael P; Sotgia, Federica

    2015-06-20

    Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERR?-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system. Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGF?-SMAD, STAT3, and Wnt signaling. We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel. Consistent with our findings, over-expression of ERR? significantly enhances the efficiency of mammosphere formation, which can be blocked by treatment with mitochondrial inhibitors. Similarly, mammosphere formation augmented by FOXM1, a downstream target of Wnt/?-catenin signaling, can also be blocked by treatment with three different classes of mitochondrial inhibitors (XCT790, oligomycin A, or doxycycline). In this context, our unbiased proteomics analysis reveals that FOXM1 drives the expression of >90 protein targets associated with mitochondrial biogenesis, glycolysis, the EMT and protein synthesis in MCF7 cells, processes which are characteristic of an anabolic CSC phenotype. Finally, doxycycline is an FDA-approved antibiotic, which is very well-tolerated in patients. As such, doxycycline could be re-purposed clinically as a 'safe' mitochondrial inhibitor, to target FOXM1 and mitochondrial biogenesis in CSCs, to prevent tumor recurrence and distant metastasis, thereby avoiding patient relapse. PMID:26087310

  10. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells

    PubMed Central

    Peiris-Pagès, Maria; Ozsvari, Bela; Smith, Duncan L.; Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Cappello, Anna Rita; Pezzi, Vincenzo; Lisanti, Michael P.; Sotgia, Federica

    2015-01-01

    Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERRα-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system. Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFβ-SMAD, STAT3, and Wnt signaling. We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel. Consistent with our findings, over-expression of ERRα significantly enhances the efficiency of mammosphere formation, which can be blocked by treatment with mitochondrial inhibitors. Similarly, mammosphere formation augmented by FOXM1, a downstream target of Wnt/β-catenin signaling, can also be blocked by treatment with three different classes of mitochondrial inhibitors (XCT790, oligomycin A, or doxycycline). In this context, our unbiased proteomics analysis reveals that FOXM1 drives the expression of >90 protein targets associated with mitochondrial biogenesis, glycolysis, the EMT and protein synthesis in MCF7 cells, processes which are characteristic of an anabolic CSC phenotype. Finally, doxycycline is an FDA-approved antibiotic, which is very well-tolerated in patients. As such, doxycycline could be re-purposed clinically as a ‘safe’ mitochondrial inhibitor, to target FOXM1 and mitochondrial biogenesis in CSCs, to prevent tumor recurrence and distant metastasis, thereby avoiding patient relapse. PMID:26087310

  11. PGC-1? controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity

    PubMed Central

    Dabrowska, Aleksandra; Venero, Jose Luis; Iwasawa, Ryota; Hankir, Mohammed-khair; Rahman, Sunniyat; Boobis, Alan; Hajji, Nabil

    2015-01-01

    Due to its role in regulation of mitochondrial function, PGC1? is emerging as an important player in ageing and neurodegenerative disorders. PGC1? exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1? in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1? in vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1? expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1? expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1? expression is a key regulator of MD and the maintenance of tolerated PGC1? expression may offer a promising strategy for neuroprotective therapies. PMID:26363853

  12. Leptin Modulates Mitochondrial Function, Dynamics and Biogenesis in MCF-7 Cells.

    PubMed

    Blanquer-Rossell, M Mar; Santandreu, Francisca M; Oliver, Jordi; Roca, Pilar; Valle, Adamo

    2015-09-01

    The adipokine leptin, known for its key role in the control of energy metabolism, has been shown to be involved in both normal and tumoral mammary growth. One of the hallmarks of cancer is an alteration of tumor metabolism since cancerous cells must rewire metabolism to satisfy the demands of growth and proliferation. Considering the sensibility of breast cancer cells to leptin, the objective of this study was to explore the effects of this adipokine on their metabolism. To this aim, we treated the MCF-7 breast cancer cell line with 50 ng/mL leptin and analyzed several features related to cellular and mitochondrial metabolism. As a result, leptin increased cell proliferation, shifted ATP production from glycolysis to mitochondria and decreased the levels of the glycolytic end-product lactate. We observed an improvement in ADP-dependent oxygen consumption and an amelioration of oxidative stress without changes in total mitochondrial mass or specific oxidative phosphorylation (OXPHOS) complexes. Furthermore, RT-PCR and western blot showed an up-regulation for genes and proteins related to biogenesis and mitochondrial dynamics. This expression signature, together with an increased mitophagy observed by confocal microscopy suggests that leptin may improve mitochondrial quality and function. Taken together, our results propose that leptin may improve bioenergetic efficiency by avoiding the production of reactive oxygen species (ROS) and conferring benefits for growth and survival of MCF-7 breast cancer cells. PMID:25752935

  13. Expression of nuclear-encoded genes involved in mitochondrial biogenesis and dynamics in experimentally denervated muscle.

    PubMed

    Wagatsuma, Akira; Kotake, Naoki; Mabuchi, Kunihiko; Yamada, Shigeru

    2011-09-01

    The abundance, morphology, and functional properties of mitochondria become altered in response to denervation. To gain insight into the regulation of this process, mitochondrial enzyme activities and gene expression involved in mitochondrial biogenesis and dynamics in mouse gastrocnemius muscle was investigated. Sciatic nerve transactions were performed on mice, and then gastrocnemius muscles were isolated at days 5 and 30 after surgery. Muscle weight was decreased significantly by 15% and 62% at days 5 and 30 after surgery, respectively. The activity of citrate synthase, a marker of oxidative enzyme, was reduced significantly by 31% and 53% at days 5 and 30, respectively. Enzyme histochemical analysis revealed that subsarcolemmal mitochondria were largely lost than intermyofibrillar mitochondria at day 5, and this trend was further progressed at day 30 after surgery. Expression levels of peroxisome proliferator-activated receptor, γ coactivator 1 (PGC-1)α, estrogen-related receptor α (ERRα), and mitofusin 2 were down-regulated throughout the experimental period, whereas those of PGC-1β, PRC, nuclear respiratory factor (NRF)-1, NRF-2, TFAM, and Lon protease were down-regulated at day 30 after surgery. These results suggest that PGC-1α, ERRα, and mitofusin 2 may be important factors in the process of denervation-induced mitochondrial adaptation. In addition, other PGC-1 family of transcriptional coactivators and DNA binding transcription factors may also contribute to mitochondrial adaptation after early response to denervation. PMID:21394548

  14. PGC-1? controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity.

    PubMed

    Dabrowska, Aleksandra; Venero, Jose Luis; Iwasawa, Ryota; Hankir, Mohammed-Khair; Rahman, Sunniyat; Boobis, Alan; Hajji, Nabil

    2015-09-01

    Due to its role in regulation of mitochondrial function, PGC1? is emerging as an important player in ageing and neurodegenerative disorders. PGC1? exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1? in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1?in vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1? expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1? expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1? expression is a key regulator of MD and the maintenance of tolerated PGC1? expression may offer a promising strategy for neuroprotective therapies. PMID:26363853

  15. Role of Tob55 on mitochondrial protein biogenesis in Trypanosoma brucei

    PubMed Central

    Sharma, Shvetank; Singha, Ujjal K; Chaudhuri, Minu

    2010-01-01

    Mitochondrial outer membrane (MOM) proteins in parasitic protozoa like Trypanosoma brucei are poorly characterized. In fungi and higher eukaryotes, Tob55 is responsible for the assembly of ?-barrel proteins in the MOM. Here we show that T. brucei Tob55 (TbTob55) has considerable similarity in its primary and secondary structure to Tob55 from other species. TbTob55 is localized in T. brucei MOM and is essential for procyclic cell survival. Induction of Tob55 RNAi decreased the level of the voltage-dependent anion channel (VDAC) within 48 h. Although the primary effect is on VDAC, induction of TbTob55 RNAi for a longer time period also decreased the levels of other nucleus encoded mitochondrial proteins. In addition, the mitochondrial membrane potential was reduced at this later time point possibly due to a reduction in the level of the proteins involved in oxidative phosphorylation. However, mitochondrial structure was not altered due to depletion of Tob55. In vitro protein import of VDAC into mitochondria with a 50-60% reduction of TbTob55 was reduced about 40% in comparison to uninduced control. In addition, the import of presequence-containing proteins such as, cytochrome oxidase subunit 4 (COIV) and trypanosome alternative oxidase (TAO) was affected by about 20 % under this condition. Depletion of VDAC levels by RNAi did not affect the import of either COIV or TAO. Furthermore, TbTob55 over expression increased the steady state level of VDAC as well as the level of the assembled protein complex of VDAC, suggesting that similar to other eukaryotes TbTob55 is involved in assembly of MOM ?-barrel proteins and plays an indirect role in the biogenesis of mitochondrial preproteins destined for the mitochondrial inner membrane. PMID:20659504

  16. Regular postexercise cooling enhances mitochondrial biogenesis through AMPK and p38 MAPK in human skeletal muscle.

    PubMed

    Ihsan, Mohammed; Markworth, James F; Watson, Greig; Choo, Hui Cheng; Govus, Andrew; Pham, Toan; Hickey, Anthony; Cameron-Smith, David; Abbiss, Chris R

    2015-08-01

    This study investigated the effect of regular postexercise cold water immersion (CWI) on muscle aerobic adaptations to endurance training. Eight males performed 3 sessions/wk of endurance training for 4 wk. Following each session, subjects immersed one leg in a cold water bath (10C; COLD) for 15 min, while the contralateral leg served as a control (CON). Muscle biopsies were obtained from vastus lateralis of both CON and COLD legs prior to training and 48 h following the last training session. Samples were analyzed for signaling kinases: p38 MAPK and AMPK, peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?), enzyme activities indicative of mitochondrial biogenesis, and protein subunits representative of respiratory chain complexes I-V. Following training, subjects' peak oxygen uptake and running velocity were improved by 5.9% and 6.2%, respectively (P < 0.05). Repeated CWI resulted in higher total AMPK, phosphorylated AMPK, phosphorylated acetyl-CoA carboxylase, ?-3-hydroxyacyl-CoA-dehydrogenase and the protein subunits representative of complex I and III (P < 0.05). Moreover, large effect sizes (Cohen's d > 0.8) were noted with changes in protein content of p38 (d = 1.02, P = 0.064), PGC-1? (d = 0.99, P = 0.079), and peroxisome proliferator-activated receptor ? (d = 0.93, P = 0.10) in COLD compared with CON. No differences between conditions were observed in the representative protein subunits of respiratory complexes II, IV, and V and in the activities of several mitochondrial enzymes (P > 0.05). These findings indicate that regular CWI enhances p38, AMPK, and possibly mitochondrial biogenesis. PMID:26041108

  17. Gene expression of key regulators of mitochondrial biogenesis is sex dependent in mice with growth hormone receptor deletion in liver.

    PubMed

    Zawada, Ilona; Masternak, Michal M; List, Edward O; Stout, Michael B; Berryman, Darlene E; Lewinski, Andrzej; Kopchick, John J; Bartke, Andrzej; Karbownik-Lewinska, Malgorzata; Gesing, Adam

    2015-03-01

    Mitochondrial biogenesis is an essential process for cell viability. Mice with disruption of the growth hormone receptor (GHR) gene (Ghr gene) in the liver (LiGHRKO), in contrast to long-lived mice with global deletion of the Ghr gene (GHRKO), are characterized by lack of improved insulin sensitivity and severe hepatic steatosis. Tissue-specific disruption of the GHR in liver results in a mouse model with dramatically altered GH/IGF1 axis. We have previously shown increased levels of key regulators of mitochondrial biogenesis in insulin-sensitive GHRKO mice. The aim of the present study is to assess, using real-time PCR, the gene expression of key regulators of mitochondrial biogenesis (Pgc1?, Ampk, Sirt1, Nrf2 and Mfn2) and a marker of mitochondrial activity (CoxIV) in brains, kidneys and livers of male and female LiGHRKO and wild-type (WT) mice. There were significant differences between males and females. In the brain, expression of Pgc1?, Ampk, Sirt1, Nrf2 and Mfn2 was lower in pooled females compared to pooled males. In the kidneys, expression of Ampk and Sirt1 was also lower in female mice. In the liver, no differences between males and females were observed. Sexual dimorphism may play an important role in regulating the biogenesis of mitochondria. PMID:25855408

  18. Nuclear Recruitment of Neuronal Nitric-oxide Synthase by ?-Syntrophin Is Crucial for the Induction of Mitochondrial Biogenesis*

    PubMed Central

    Aquilano, Katia; Baldelli, Sara; Ciriolo, Maria R.

    2014-01-01

    Neuronal nitric-oxide synthase (nNOS) has various splicing variants and different subcellular localizations. nNOS can be found also in the nucleus; however, its exact role in this compartment is still not completely defined. In this report, we demonstrate that the PDZ domain allows the recruitment of nNOS to nuclei, thus favoring local NO production, nuclear protein S-nitrosylation, and induction of mitochondrial biogenesis. In particular, overexpression of PDZ-containing nNOS (nNOS?) increases S-nitrosylated CREB with consequent augmented binding on cAMP response element consensus sequence on peroxisome proliferator-activated receptor ? co-activator (PGC)-1? promoter. The resulting PGC-1? induction is accompanied by the expression of mitochondrial genes (e.g., TFAM, MtCO1) and increased mitochondrial mass. Importantly, full active nNOS lacking PDZ domain (nNOS?) does not localize in nuclei and fails in inducing the expression of PGC-1?. Moreover, we substantiate that the mitochondrial biogenesis normally accompanying myogenesis is associated with nuclear translocation of nNOS. We demonstrate that ?-Syntrophin, which resides in nuclei of myocytes, functions as the upstream mediator of nuclear nNOS translocation and nNOS-dependent mitochondrial biogenesis. Overall, our results indicate that altered nNOS splicing and nuclear localization could be contributing factors in human muscular diseases associated with mitochondrial impairment. PMID:24235139

  19. Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1/TFAM pathway in human umbilical vein endothelial cells (HUVECs).

    PubMed

    Yao, Kai; Zhang, Wayne W; Yao, Luyu; Yang, Shu; Nie, Wanpin; Huang, Feizhou

    2016-02-19

    Carvedilol, a third-generation and nonselective β-adrenoceptor antagonist, is a licensed drug for treating patients suffering from heart failure in clinics. It has been shown that Carvedilol protects cells against mitochondrial dysfunction. However, it's unknown whether Carvedilol affects mitochondrial biogenesis. In this study, we found that treatment with Carvedilol in HUVECs resulted in a significant increase of PGC-1α, NRF1, and TFAM. Notably, Carvedilol significantly increased mtDNA contents and the two mitochondrial proteins, cytochrome C and COX IV. In addition, MitoTracker Red staining results indicated that treatment with Carvedilol increased mitochondria mass. Mechanistically, we found that the effect of Carvedilol on the expression of PGC-1α is mediated by the PKA-CREB pathway. Importantly, our results revealed that stimulation of mitochondrial biogenesis by carvedilol resulted in functional gain of the mitochondria by showing increased oxygen consumption and mitochondrial respiratory rate. The increased expression of PGC-1α and mitochondrial biogenesis induced by Carvedilol might suggest a new mechanism of the therapeutic effects of Carvedilol in heart failure. PMID:26797282

  20. Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1?

    PubMed Central

    Bartoletti-Stella, A; Mariani, E; Kurelac, I; Maresca, A; Caratozzolo, M F; Iommarini, L; Carelli, V; Eusebi, L H; Guido, A; Cenacchi, G; Fuccio, L; Rugolo, M; Tullo, A; Porcelli, A M; Gasparre, G

    2013-01-01

    Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that ?-rays, at doses commonly used in the radiation therapy for cancer treatment, induce an increase in mitochondrial mass and function, in response to a genotoxic stress that pushes cells into senescence, in the presence of a functional p53. Although the main effector of the response to ?-rays is the p53-p21 axis, we demonstrated that mitochondrial biogenesis is only indirectly regulated by p53, whose activation triggers a murine double minute 2 (MDM2)-mediated hypoxia-inducible factor 1? (HIF1?) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1? inhibition by HIF1?, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1? stabilization, in fact, blunts the mitochondrial response to ?-rays as well as the induction of p21-mediated cell senescence, indicating prevalence of the hypoxic over the genotoxic response. Finally, we also show in vivo that post-radiotherapy mitochondrial DNA copy number increase well correlates with lack of HIF1? increase in the tissue, concluding this may be a useful molecular tool to infer the trigger of a hypoxic response during radiotherapy, which may lead to failure of activation of cell senescence. PMID:23764844

  1. Overexpression of UCP1 in tobacco induces mitochondrial biogenesis and amplifies a broad stress response

    PubMed Central

    2014-01-01

    Background Uncoupling protein one (UCP1) is a mitochondrial inner membrane protein capable of uncoupling the electrochemical gradient from adenosine-5?-triphosphate (ATP) synthesis, dissipating energy as heat. UCP1 plays a central role in nonshivering thermogenesis in the brown adipose tissue (BAT) of hibernating animals and small rodents. A UCP1 ortholog also occurs in plants, and aside from its role in uncoupling respiration from ATP synthesis, thereby wasting energy, it plays a beneficial role in the plant response to several abiotic stresses, possibly by decreasing the production of reactive oxygen species (ROS) and regulating cellular redox homeostasis. However, the molecular mechanisms by which UCP1 is associated with stress tolerance remain unknown. Results Here, we report that the overexpression of UCP1 increases mitochondrial biogenesis, increases the uncoupled respiration of isolated mitochondria, and decreases cellular ATP concentration. We observed that the overexpression of UCP1 alters mitochondrial bioenergetics and modulates mitochondrial-nuclear communication, inducing the upregulation of hundreds of nuclear- and mitochondrial-encoded mitochondrial proteins. Electron microscopy analysis showed that these metabolic changes were associated with alterations in mitochondrial number, area and morphology. Surprisingly, UCP1 overexpression also induces the upregulation of hundreds of stress-responsive genes, including some involved in the antioxidant defense system, such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione-S-transferase (GST). As a consequence of the increased UCP1 activity and increased expression of oxidative stress-responsive genes, the UCP1-overexpressing plants showed reduced ROS accumulation. These beneficial metabolic effects may be responsible for the better performance of UCP1-overexpressing lines in low pH, high salt, high osmolarity, low temperature, and oxidative stress conditions. Conclusions Overexpression of UCP1 in the mitochondrial inner membrane induced increased uncoupling respiration, decreased ROS accumulation under abiotic stresses, and diminished cellular ATP content. These events may have triggered the expression of mitochondrial and stress-responsive genes in a coordinated manner. Because these metabolic alterations did not impair plant growth and development, UCP1 overexpression can potentially be used to create crops better adapted to abiotic stress conditions. PMID:24886177

  2. Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts

    PubMed Central

    Karamanlidis, Georgios; Garcia-Menendez, Lorena; Kolwicz, Stephen C.; Lee, Chi Fung

    2014-01-01

    Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice. PMID:25172896

  3. AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1

    PubMed Central

    Corum, Daniel G.; Tsichlis, Philip N.; Muise-Helmericks, Robin C.

    2014-01-01

    Our previous work has shown that Akt3 is required for mitochondrial biogenesis in primary human endothelial cells (ECs) and in Akt3-null mice; Akt3 affects subcellular localization of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α), the master regulator of mitochondrial biogenesis. The purpose of this study is to determine the mechanism by which Akt3 controls the subcellular distribution of PGC-1α and to explore the effect on mitochondrial biogenesis and turnover during angiogenesis. Here we use standard biochemical analyses and Akt3-knockdown strategies to show that Akt3 controls the stabilization of chromosome maintenance region-1 (CRM-1), the major nuclear export receptor. Site-directed mutagenesis and association analyses show that PGC-1α nuclear export is CRM-1 dependent. Akt3 knockdown and CRM-1 overexpression cause 3-fold reductions in PGC-1α target gene expression, compared to control levels. Akt3 inhibition causes autophagy, as measured by autophagosome formation, in a CRM-1-dependent, Akt1/mTOR-independent pathway. In vivo, Akt3-null and heterozygous mice show dose-dependent decreases in angiogenesis compared to wild-type littermates (∼5- and 2.5-fold decreases, respectively), as assessed by Matrigel plug assays. This correlates with an ∼1.5-fold decrease in mitochondrial Cox IV expression. Our studies suggest that Akt3 is a regulator of mitochondrial dynamics in the vasculature via regulation of CRM-1-dependent nuclear export.—Corum, D. G., Tsichlis, P. N., Muise-Helmericks, R. C. AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1. PMID:24081905

  4. Differentiation of Human Neural Stem Cells into Motor Neurons Stimulates Mitochondrial Biogenesis and Decreases Glycolytic Flux.

    PubMed

    O'Brien, Laura C; Keeney, Paula M; Bennett, James P

    2015-09-01

    Differentiation of human pluripotent stem cells (hPSCs) in vitro offers a way to study cell types that are not accessible in living patients. Previous research suggests that hPSCs generate ATP through anaerobic glycolysis, in contrast to mitochondrial oxidative phosphorylation (OXPHOS) in somatic cells; however, specialized cell types have not been assessed. To test if mitobiogenesis is increased during motor neuron differentiation, we differentiated human embryonic stem cell (hESC)- and induced pluripotent stem cell-derived human neural stem cells (hNSCs) into motor neurons. After 21 days of motor neuron differentiation, cells increased mRNA and protein levels of genes expressed by postmitotic spinal motor neurons. Electrophysiological analysis revealed voltage-gated currents characteristic of excitable cells and action potential formation. Quantitative PCR revealed an increase in peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), an upstream regulator of transcription factors involved in mitobiogenesis, and several of its downstream targets in hESC-derived cultures. This correlated with an increase in protein expression of respiratory subunits, but no increase in protein reflecting mitochondrial mass in either cell type. Respiration analysis revealed a decrease in glycolytic flux in both cell types on day 21 (D21), suggesting a switch from glycolysis to OXPHOS. Collectively, our findings suggest that mitochondrial biogenesis, but not mitochondrial mass, is increased during differentiation of hNSCs into motor neurons. These findings help us to understand human motor neuron mitobiogenesis, a process impaired in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. PMID:25892363

  5. Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage.

    PubMed

    Crane, Justin D; Ogborn, Daniel I; Cupido, Colleen; Melov, Simon; Hubbard, Alan; Bourgeois, Jacqueline M; Tarnopolsky, Mark A

    2012-02-01

    Massage therapy is commonly used during physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. Although there is evidence that massage may relieve pain in injured muscle, how massage affects cellular function remains unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of 11 young male participants after exercise-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline, immediately after 10 min of massage treatment, and after a 2.5-hour period of recovery. We found that massage activated the mechanotransduction signaling pathways focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (ERK1/2), potentiated mitochondrial biogenesis signaling [nuclear peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?)], and mitigated the rise in nuclear factor ?B (NF?B) (p65) nuclear accumulation caused by exercise-induced muscle trauma. Moreover, despite having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6) and reduced heat shock protein 27 (HSP27) phosphorylation, thereby mitigating cellular stress resulting from myofiber injury. In summary, when administered to skeletal muscle that has been acutely damaged through exercise, massage therapy appears to be clinically beneficial by reducing inflammation and promoting mitochondrial biogenesis. PMID:22301554

  6. Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1? signaling pathway.

    PubMed

    Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf; Sharma, Reeta Kumari; Verma, Deepika; Priyanka, Kumari; Bal, Amanjit; Gill, Kiran Dip

    2015-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1? and its downstream targets, i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt./day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt./day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and citrate synthase activity in the hippocampus (HC) and corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits - ND1, ND2, ND3, Cyt b, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of electron transport chain (ETC). In quercetin treated group an increase in the mitochondrial DNA copy number and mitochondrial content in both the regions of rat brain was observed. The PGC-1? was up regulated in quercetin treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1?. Electron microscopy results revealed a significant decrease in the mitochondrial cross-section area, mitochondrial perimeter length and increase in mitochondrial number in case of quercetin treated rats as compared to aluminium treated ones. Therefore it seems quercetin increases mitochondrial biogenesis and makes it an almost ideal flavanoid to control or limit the damage that has been associated with the defective mitochondrial function seen in many neurodegenerative diseases. PMID:26493151

  7. Lipoamide or lipoic acid stimulates mitochondrial biogenesis in 3T3-L1 adipocytes via the endothelial NO synthase-cGMP-protein kinase G signalling pathway

    PubMed Central

    Shen, Weili; Hao, Jiejie; Feng, Zhihui; Tian, Chuan; Chen, Weijun; Packer, Lester; Shi, Xianglin; Zang, Weijin; Liu, Jiankang

    2011-01-01

    BACKGROUND AND PURPOSE Metabolic dysfunction due to loss of mitochondria plays an important role in diabetes, and stimulation of mitochondrial biogenesis by anti-diabetic drugs improves mitochondrial function. In a search for potent stimulators of mitochondrial biogenesis, we examined the effects and mechanisms of lipoamide and ?-lipoic acid (LA) in adipocytes. EXPERIMENTAL APPROACH Differentiated 3T3-L1 adipocytes were treated with lipoamide or LA. Mitochondrial biogenesis and possible signalling pathways were examined. KEY RESULTS Exposure of 3T3-L1 cells to lipoamide or LA for 24 h increased the number and mitochondrial mass per cell. Such treatment also increased mitochondrial DNA copy number, protein levels and expression of transcription factors involved in mitochondrial biogenesis, including PGC-1?, mitochondrial transcription factor A and nuclear respiratory factor 1. Lipoamide produced these effects at concentrations of 1 and 10 molL?1, whereas LA was most effective at 100 molL?1. At 10 molL?1, lipoamide, but not LA, stimulated mRNA expressions of PPAR-?, PPAR-? and CPT-1?. The potency of lipoamide was 10100-fold greater than that of LA. Lipoamide dose-dependently stimulated expression of endothelial nitric oxide synthase (eNOS) and formation of cGMP. Knockdown of eNOS (with small interfering RNA) prevented lipoamide-induced mitochondrial biogenesis, which was also blocked by the soluble guanylate cyclase inhibitor, ODQ and the protein kinase G (PKG) inhibitor, KT5823. Thus, stimulation of mitochondrial biogenesis by lipoamide involved signalling via the eNOS-cGMP-PKG pathway. CONCLUSIONS AND IMPLICATIONS Our data suggest that lipoamide is a potent stimulator of mitochondrial biogenesis in adipocyte, and may have potential therapeutic application in obesity and diabetes. PMID:21108628

  8. Increased mitochondrial biogenesis preserves intestinal stem cell homeostasis and contributes to longevity in Indy mutant flies

    PubMed Central

    Rogers, Ryan P.; Rogina, Blanka

    2014-01-01

    The Drosophila Indy (I'm Not Dead Yet) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR); however, little is known about the tissue specific physiological effects of INDY reduction. Here we focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity. The expression of Indy mRNA in the midgut changes in response to aging and nutrition. Genetic reduction of Indy expression increases midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. Genetic studies confirm that dPGC-1 mediates the regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. Our data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs by modulating dPGC-1 PMID:24827528

  9. Increased mitochondrial biogenesis preserves intestinal stem cell homeostasis and contributes to longevity in Indy mutant flies.

    PubMed

    Rogers, Ryan P; Rogina, Blanka

    2014-04-01

    The Drosophila Indy (I'm Not Dead Yet) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR); however, little is known about the tissue specific physiological effects of INDY reduction. Here we focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity. The expression of Indy mRNA in the midgut changes in response to aging and nutrition. Genetic reduction of Indy expression increases midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. Genetic studies confirm that dPGC-1 mediates the regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. Our data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs by modulating dPGC-1. PMID:24827528

  10. Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective

    PubMed Central

    Valerio, Alessandra; D'Antona, Giuseppe; Nisoli, Enzo

    2011-01-01

    Malnutrition is common among older persons, with important consequences increasing frailty and morbidity and reducing health expectancy. On the contrary, calorie restriction (CR, a low-calorie dietary regimen with adequate nutrition) slows the progression of age-related diseases and extends the lifespan of many species. Identification of strategies mimicking key CR mechanisms – increased mitochondrial respiration and reduced production of oxygen radicals – is a hot topic in gerontology. Dietary supplementation with essential and/or branched chain amino acids (BCAAs) exerts a variety of beneficial effects in experimental animals and humans and has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, prevent oxidative damage, and enhance physical endurance in middle-aged mice, resulting in prolonged survival. Here we review recent studies addressing the possible role of BCAAs in energy metabolism and in the longevity of species ranging from unicellular organisms to mammals. We also summarize observations from human studies supporting the exciting hypothesis that dietary BCAA enriched mixture supplementation might be a health-promoting strategy in aged patients at risk. PMID:21566257

  11. Monitoring of neuronal loss in the hippocampus of A?-injected rat: autophagy, mitophagy, and mitochondrial biogenesis stand against apoptosis.

    PubMed

    Shaerzadeh, Fatemeh; Motamedi, Fereshteh; Minai-Tehrani, Dariush; Khodagholi, Fariba

    2014-03-01

    In the present study, we tried to answer the following questions: which kind of defense pathways are activated after A? insult? How defense systems react against noxious effects of A? and whether they are able to deal against apoptosis or not? So, we traced some molecular pathways including autophagy, mitophagy, and mitochondrial biogenesis before reaching to the endpoint of apoptosis. Besides, we measured the function of mitochondria after injection of A? (1-42) in CA1 area of hippocampus as a model of Alzheimer's disease (AD). Based on our data, autophagy markers reached to their maximum level and returned to the control level as apoptotic markers started to increase. As a specialized form of autophagy, mitophagy markers followed the trend of autophagy markers. Whereas mitochondrial dynamic processes shifted toward fission, mitochondrial biogenesis was severely affected by A? and significantly decreased. Alongside suppression of mitochondrial biogenesis, activity of specific enzymes involved in antioxidant defense system, electron transport chain, and tricarboxylic acid cycle (TCA) decreased in response to the A?. Activity of antioxidant enzymes increased at first and then decreased significantly compared to the control. TCA enzymes aconitase and malate dehydrogenase activities reduced immediately while citrate synthase and fumarase activities did not change. Based on our finding, monitoring of the master molecules of intracellular cascades and determining their trends before the destructive function of A? could be the target of therapeutic issues for AD. PMID:24203394

  12. MITOPLD is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline.

    PubMed

    Watanabe, Toshiaki; Chuma, Shinichiro; Yamamoto, Yasuhiro; Kuramochi-Miyagawa, Satomi; Totoki, Yasushi; Toyoda, Atsushi; Hoki, Yuko; Fujiyama, Asao; Shibata, Tatsuhiro; Sado, Takashi; Noce, Toshiaki; Nakano, Toru; Nakatsuji, Norio; Lin, Haifan; Sasaki, Hiroyuki

    2011-03-15

    MITOPLD is a member of the phospholipase D superfamily proteins conserved among diverse species. Zucchini (Zuc), the Drosophila homolog of MITOPLD, has been implicated in primary biogenesis of Piwi-interacting RNAs (piRNAs). By contrast, MITOPLD has been shown to hydrolyze cardiolipin in the outer membrane of mitochondria to generate phosphatidic acid, which is a signaling molecule. To assess whether the mammalian MITOPLD is involved in piRNA biogenesis, we generated Mitopld mutant mice. The mice display meiotic arrest during spermatogenesis, demethylation and derepression of retrotransposons, and defects in primary piRNA biogenesis. Furthermore, in mutant germ cells, mitochondria and the components of the nuage, a perinuclear structure involved in piRNA biogenesis/function, are mislocalized to regions around the centrosome, suggesting that MITOPLD may be involved in microtubule-dependent localization of mitochondria and these proteins. Our results indicate a conserved role for MITOPLD/Zuc in the piRNA pathway and link mitochondrial membrane metabolism/signaling to small RNA biogenesis. PMID:21397847

  13. Aging and Calorie Restriction Oppositely Affect Mitochondrial Biogenesis through TFAM Binding at Both Origins of Mitochondrial DNA Replication in Rat Liver

    PubMed Central

    Picca, Anna; Pesce, Vito; Fracasso, Flavio; Joseph, Anna-Maria; Leeuwenburgh, Christiaan; Lezza, Angela M. S.

    2013-01-01

    Aging affects mitochondria in a tissue-specific manner. Calorie restriction (CR) is, so far, the only intervention able to delay or prevent the onset of several age-related changes also in mitochondria. Using livers from middle age (18-month-old), 28-month-old and 32-month-old ad libitum-fed and 28-month-old calorie-restricted rats we found an age-related decrease in mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (TFAM) amount, fully prevented by CR. We revealed also an age-related decrease, completely prevented by CR, for the proteins PGC-1? NRF-1 and cytochrome c oxidase subunit IV, supporting the efficiency of CR to forestall the age-related decrease in mitochondrial biogenesis. Furthermore, CR counteracted the age-related increase in oxidative damage to proteins, represented by the increased amount of oxidized peroxiredoxins (PRX-SO3) in the ad libitum-fed animals. An unexpected age-related decrease in the mitochondrial proteins peroxiredoxin III (Prx III) and superoxide dismutase 2 (SOD2), usually induced by increased ROS and involved in mitochondrial biogenesis, suggested a prevailing relevance of the age-reduced mitochondrial biogenesis above the induction by ROS in the regulation of expression of these genes with aging. The partial prevention of the decrease in Prx III and SOD2 proteins by CR also supported the preservation of mitochondrial biogenesis in the anti-aging action of CR. To investigate further the age- and CR-related effects on mitochondrial biogenesis we analyzed the in vivo binding of TFAM to specific mtDNA regions and demonstrated a marked increase in the TFAM-bound amounts of mtDNA at both origins of replication with aging, fully prevented by CR. A novel, positive correlation between the paired amounts of TFAM-bound mtDNA at these sub-regions was found in the joined middle age ad libitum-fed and 28-month-old calorie-restricted groups, but not in the 28-month-old ad libitum-fed counterpart suggesting a quite different modulation of TFAM binding at both origins of replication in aging and CR. PMID:24058615

  14. Exercise-Induced Changes in Caveolin-1, Depletion of Mitochondrial Cholesterol, and the Inhibition of Mitochondrial Swelling in Rat Skeletal Muscle but Not in the Liver

    PubMed Central

    Flis, Damian Jozef; Olek, Robert Antoni; Kaczor, Jan Jacek; Rodziewicz, Ewa; Halon, Malgorzata; Wozniak, Michal; Gabbianelli, Rosita; Ziolkowski, Wieslaw

    2016-01-01

    The reduction in cholesterol in mitochondria, observed after exercise, is related to the inhibition of mitochondrial swelling. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and is required by various signalling pathways. Therefore, the aim of this study was to investigate the effect of prolonged swimming on the mitochondrial Cav-1 concentration; additionally, we identified the results of these changes as they relate to the induction of changes in the mitochondrial swelling and cholesterol in rat skeletal muscle and liver. Male Wistar rats were divided into a sedentary control group and an exercise group. The exercised rats swam for 3 hours and were burdened with an additional 3% of their body weight. After the cessation of exercise, their quadriceps femoris muscles and livers were immediately removed for experimentation. The exercise protocol caused an increase in the Cav-1 concentration in crude muscle mitochondria; this was related to a reduction in the cholesterol level and an inhibition of mitochondrial swelling. There were no changes in rat livers, with the exception of increased markers of oxidative stress in mitochondria. These data indicate the possible role of Cav-1 in the adaptive change in the rat muscle mitochondria following exercise. PMID:26839631

  15. Exercise-Induced Changes in Caveolin-1, Depletion of Mitochondrial Cholesterol, and the Inhibition of Mitochondrial Swelling in Rat Skeletal Muscle but Not in the Liver.

    PubMed

    Flis, Damian Jozef; Olek, Robert Antoni; Kaczor, Jan Jacek; Rodziewicz, Ewa; Halon, Malgorzata; Antosiewicz, Jedrzej; Wozniak, Michal; Gabbianelli, Rosita; Ziolkowski, Wieslaw

    2016-01-01

    The reduction in cholesterol in mitochondria, observed after exercise, is related to the inhibition of mitochondrial swelling. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and is required by various signalling pathways. Therefore, the aim of this study was to investigate the effect of prolonged swimming on the mitochondrial Cav-1 concentration; additionally, we identified the results of these changes as they relate to the induction of changes in the mitochondrial swelling and cholesterol in rat skeletal muscle and liver. Male Wistar rats were divided into a sedentary control group and an exercise group. The exercised rats swam for 3 hours and were burdened with an additional 3% of their body weight. After the cessation of exercise, their quadriceps femoris muscles and livers were immediately removed for experimentation. The exercise protocol caused an increase in the Cav-1 concentration in crude muscle mitochondria; this was related to a reduction in the cholesterol level and an inhibition of mitochondrial swelling. There were no changes in rat livers, with the exception of increased markers of oxidative stress in mitochondria. These data indicate the possible role of Cav-1 in the adaptive change in the rat muscle mitochondria following exercise. PMID:26839631

  16. The MIA pathway: a key regulator of mitochondrial oxidative protein folding and biogenesis.

    PubMed

    Mordas, Amelia; Tokatlidis, Kostas

    2015-08-18

    Mitochondria are fundamental intracellular organelles with key roles in important cellular processes like energy production, Fe/S cluster biogenesis, and homeostasis of lipids and inorganic ions. Mitochondrial dysfunction is consequently linked to many human pathologies (cancer, diabetes, neurodegeneration, stroke) and apoptosis. Mitochondrial biogenesis relies on protein import as most mitochondrial proteins (about 10-15% of the human proteome) are imported after their synthesis in the cytosol. Over the last several years many mitochondrial translocation pathways have been discovered. Among them, the import pathway that targets proteins to the intermembrane space (IMS) stands out as it is the only one that couples import to folding and oxidation and results in the covalent modification of the incoming precursor that adopt internal disulfide bonds in the process (the MIA pathway). The discovery of this pathway represented a significant paradigm shift as it challenged the prevailing dogma that the endoplasmic reticulum is the only compartment of eukaryotic cells where oxidative folding can occur. The concept of the oxidative folding pathway was first proposed on the basis of folding and import data for the small Tim proteins that have conserved cysteine motifs and must adopt intramolecular disulfides after import so that they are retained in the organelle. The introduction of disulfides in the IMS is catalyzed by Mia40 that functions as a chaperone inducing their folding. The sulfhydryl oxidase Erv1 generates the disulfide pairs de novo using either molecular oxygen or, cytochrome c and other proteins as terminal electron acceptors that eventually link this folding process to respiration. The solution NMR structure of Mia40 (and supporting biochemical experiments) showed that Mia40 is a novel type of disulfide donor whose recognition capacity for its substrates relies on a hydrophobic binding cleft found adjacent to a thiol active CPC motif. Targeting of the substrates to this pathway is guided by a novel type of IMS targeting signal called ITS or MISS. This consists of only 9 amino acids, found upstream or downstream of a unique Cys that is primed for docking to Mia40 when the substrate is accommodated in the Mia40 binding cleft. Different routes exist to complete the folding of the substrates and their final maturation in the IMS. Identification of new Mia40 substrates (some even without the requirement of their cysteines) reveals an expanded chaperone-like activity of this protein in the IMS. New evidence on the targeting of redox active proteins like thioredoxin, glutaredoxin, and peroxiredoxin into the IMS suggests the presence of redox-dependent regulatory mechanisms of the protein folding and import process in mitochondria. Maintenance of redox balance in mitochondria is crucial for normal cell physiology and depends on the cross-talk between the various redox signaling processes and the mitochondrial oxidative folding pathway. PMID:26214018

  17. Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2

    PubMed Central

    Zhu, J H; Gusdon, A M; Cimen, H; Van Houten, B; Koc, E; Chu, C T

    2012-01-01

    The regulation of mitochondrial quality has emerged as a central issue in neurodegeneration, diabetes, and cancer. We utilized repeated low-dose applications of the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+) over 2 weeks to study cellular responses to chronic mitochondrial stress. Chronic MPP+ triggered depletion of functional mitochondria resulting in diminished capacities for aerobic respiration. Inhibiting autophagy/mitophagy only partially restored mitochondrial content. In contrast, inhibiting activation of extracellular signal-regulated protein kinases conferred complete cytoprotection with full restoration of mitochondrial functional and morphological parameters, enhancing spare respiratory capacity in MPP+ co-treated cells above that of control cells. Reversal of mitochondrial injury occurred when U0126 was added 1 week after MPP+, implicating enhanced repair mechanisms. Chronic MPP+ caused a >90% decrease in complex I subunits, along with decreases in complex III and IV subunits. Decreases in respiratory complex subunits were reversed by co-treatment with U0126, ERK1/2 RNAi or transfection of dominant-negative MEK1, but only partially restored by degradation inhibitors. Chronic MPP+ also suppressed the de novo synthesis of mitochondrial DNA-encoded proteins, accompanied by decreased expression of the mitochondrial transcription factor TFAM. U0126 completely reversed each of these deficits in mitochondrial translation and protein expression. These data indicate a key, limiting role for mitochondrial biogenesis in determining the outcome of injuries associated with elevated mitophagy. PMID:22622131

  18. Testosterone Plus Low-Intensity Physical Training in Late Life Improves Functional Performance, Skeletal Muscle Mitochondrial Biogenesis, and Mitochondrial Quality Control in Male Mice

    PubMed Central

    Guo, Wen; Wong, Siu; Li, Michelle; Liang, Wentao; Liesa, Marc; Serra, Carlo; Jasuja, Ravi; Bartke, Andrzej; Kirkland, James L.; Shirihai, Orian; Bhasin, Shalender

    2012-01-01

    Testosterone supplementation increases muscle mass in older men but has not been shown to consistently improve physical function and activity. It has been hypothesized that physical exercise is required to induce the adaptations necessary for translation of testosterone-induced muscle mass gain into functional improvements. However, the effects of testosterone plus low intensity physical exercise training (T/PT) on functional performance and bioenergetics are unknown. In this pilot study, we tested the hypothesis that combined administration of T/PT would improve functional performance and bioenergetics in male mice late in life more than low-intensity physical training alone. 28-month old male mice were randomized to receive T/PT or vehicle plus physical training (V/PT) for 2 months. Compare to V/PT control, administration of T/PT was associated with improvements in muscle mass, grip strength, spontaneous physical movements, and respiratory activity. These changes were correlated with increased mitochondrial DNA copy number and expression of markers for mitochondrial biogenesis. Mice receiving T/PT also displayed increased expression of key elements for mitochondrial quality control, including markers for mitochondrial fission-and-fusion and mitophagy. Concurrently, mice receiving T/PT also displayed increased expression of markers for reduced tissue oxidative damage and improved muscle quality. Conclusion: Testosterone administered with low-intensity physical training improves grip strength, spontaneous movements, and respiratory activity. These functional improvements were associated with increased muscle mitochondrial biogenesis and improved mitochondrial quality control. PMID:23240002

  19. Genome-Wide Screens in Saccharomyces cerevisiae Highlight a Role for Cardiolipin in Biogenesis of Mitochondrial Outer Membrane Multispan Proteins

    PubMed Central

    Sauerwald, Julia; Jores, Tobias; Eisenberg-Bord, Michal; Chuartzman, Silvia Gabriela

    2015-01-01

    A special group of mitochondrial outer membrane (MOM) proteins spans the membrane several times via multiple helical segments. Such multispan proteins are synthesized on cytosolic ribosomes before their targeting to mitochondria and insertion into the MOM. Previous work recognized the import receptor Tom70 and the mitochondrial import (MIM) complex, both residents of the MOM, as required for optimal biogenesis of these proteins. However, their involvement is not sufficient to explain either the entire import pathway or its regulation. To identify additional factors that are involved in the biogenesis of MOM multispan proteins, we performed complementary high-throughput visual and growth screens in Saccharomyces cerevisiae. Cardiolipin (CL) synthase (Crd1) appeared as a candidate in both screens. Our results indeed demonstrate lower steady-state levels of the multispan proteins Ugo1, Scm4, and Om14 in mitochondria from crd1? cells. Importantly, MOM single-span proteins were not affected by this mutation. Furthermore, organelles lacking Crd1 had a lower in vitro capacity to import newly synthesized Ugo1 and Scm4 molecules. Crd1, which is located in the mitochondrial inner membrane, condenses phosphatidylglycerol together with CDP-diacylglycerol to obtain de novo synthesized CL molecules. Hence, our findings suggest that CL is an important component in the biogenesis of MOM multispan proteins. PMID:26149385

  20. COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2.

    PubMed

    Stroud, David A; Maher, Megan J; Lindau, Caroline; Vgtle, F-Nora; Frazier, Ann E; Surgenor, Elliot; Mountford, Hayley; Singh, Abeer P; Bonas, Matteo; Oeljeklaus, Silke; Warscheid, Bettina; Meisinger, Chris; Thorburn, David R; Ryan, Michael T

    2015-10-01

    Biogenesis of complex IV of the mitochondrial respiratory chain requires assembly factors for subunit maturation, co-factor attachment and stabilization of intermediate assemblies. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Here, we demonstrate that the complex IV defect correlates with a severe loss in complex IV assembly in patient heart but not fibroblasts. Complete loss of COA6 activity using gene editing in HEK293T cells resulted in a profound growth defect due to complex IV deficiency, caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates. We show that the pathogenic mutation in COA6 does not affect its import into mitochondria but impairs its maturation and stability. Furthermore, we show that COA6 has the capacity to bind copper and can associate with newly translated COX2 and the mitochondrial copper chaperone SCO1. Our data reveal that COA6 is intricately involved in the copper-dependent biogenesis of COX2. PMID:26160915

  1. Phosphatidylcholine affects the role of the sorting and assembly machinery in the biogenesis of mitochondrial ?-barrel proteins.

    PubMed

    Schuler, Max-Hinderk; Di Bartolomeo, Francesca; Bttinger, Lena; Horvath, Susanne E; Wenz, Lena-Sophie; Daum, Gnther; Becker, Thomas

    2015-10-30

    Two protein translocases drive the import of ?-barrel precursor proteins into the mitochondrial outer membrane: The translocase of the outer membrane (TOM complex) promotes transport of the precursor to the intermembrane space, whereas the sorting and assembly machinery (SAM complex) mediates subsequent folding of the ?-barrel and its integration into the target membrane. The non-bilayer-forming phospholipids phosphatidylethanolamine (PE) and cardiolipin (CL) are required for the biogenesis of ?-barrel proteins. Whether bilayer-forming phospholipids such as phosphatidylcholine (PC), the most abundant phospholipid of the mitochondrial outer membrane, play a role in the import of ?-barrel precursors is unclear. In this study, we show that PC is required for stability and function of the SAM complex during the biogenesis of ?-barrel proteins. PC further promotes the SAM-dependent assembly of the TOM complex, indicating a general role of PC for the function of the SAM complex. In contrast to PE-deficient mitochondria precursor accumulation at the TOM complex is not affected by depletion of PC. We conclude that PC and PE affect the function of distinct protein translocases in mitochondrial ?-barrel biogenesis. PMID:26385920

  2. Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells.

    PubMed

    Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Lisanti, Michael P; Sotgia, Federica

    2012-11-01

    We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer-associated fibroblasts. This appears to be mechanistically controlled by the stromal expression of caveolin-1 (Cav-1) and/or serum starvation. In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the "two-compartment tumor metabolism" model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers. PMID:23082721

  3. Mitochondrial DNA copy number and biogenesis in different tissues of early- and late-lactating dairy cows.

    PubMed

    Laubenthal, L; Hoelker, M; Frahm, J; Dnicke, S; Gerlach, K; Sdekum, K-H; Sauerwein, H; Hussler, S

    2016-02-01

    Energy balance in dairy cows changes during the course of lactation due to alterations in voluntary feed intake and energy required for milk synthesis. To adapt to the demands of lactation, energy metabolism needs to be regulated and coordinated in key organs such as adipose tissue (AT), liver, and mammary gland. Mitochondria are the main sites of energy production in mammalian cells and their number varies depending on age, organ, and physiological condition. The copy number of the mitochondrial genome, the mitochondrial DNA (mtDNA), reflects the abundance of mitochondria within a cell and is regulated by transcriptional and translational factors. Environmental, physiological, and energetic conditions change during lactation and we thus hypothesized that these changes may influence the mtDNA copy number and the abundance of genes regulating mitochondrial biogenesis. Therefore, we aimed to provide an overview of mitochondrial biogenesis in liver, subcutaneous (sc)AT, mammary gland, and peripheral blood cells during early and late lactation in dairy cows. German Holstein cows (n=21) were fed according to their requirements, and biopsies from scAT, liver, mammary gland, and blood were collected in early and late lactation and assayed for relative mtDNA copy numbers and the mRNA abundance of genes regulating mitochondrial biogenesis, such as nuclear-respiratory factor 1 and 2 (NRF-1, NRF-2), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor-gamma coactivator 1-? (PGC-1?). The number of mtDNA copies increased from early to late lactation in all tissues, whereas that in peripheral blood cells was greater in early compared with late lactation. Moreover, mitochondrial activity enzymes (i.e., citrate synthase and cytochrome c oxidase) increased from early to late lactation in scAT. Comparing the number of mtDNA copies between tissues and blood in dairy cows, the highest mtDNA content was observed in liver. The mRNA abundance of genes related to mitochondrial biogenesis changed in a tissue-specific manner when comparing early versus late lactation. The mtDNA copy number was associated with transcriptional factors only in AT, suggesting nontranscriptional regulation of mtDNA in the other tissues. We detected strong correlations between peripheral blood mtDNA and tissue mtDNA content in early lactation. Peripheral blood forms an appropriate medium to display the cellular content of mtDNA copy numbers and consequently the cellular energy status of tissues during early lactation. PMID:26686730

  4. Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications.

    PubMed

    Chen, Jin-Qiang; Cammarata, Patrick R; Baines, Christopher P; Yager, James D

    2009-10-01

    There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17beta-estradiol (E(2)) and estrogen receptors (ER) in a number of cell types and tissues that have high demands for mitochondrial energy metabolism. This novel E(2)-mediated mitochondrial pathway involves the cooperation of both nuclear and mitochondrial ERalpha and ERbeta and their co-activators on the coordinate regulation of both nuclear DNA- and mitochondrial DNA-encoded genes for MRC proteins. In this paper, we have: 1) comprehensively reviewed studies that reveal a novel role of estrogens and ERs in the regulation of MRC biogenesis; 2) discussed their physiological, pathological and pharmacological implications in the control of cell proliferation and apoptosis in relation to estrogen-mediated carcinogenesis, anti-cancer drug resistance in human breast cancer cells, neuroprotection for Alzheimer's disease and Parkinson's disease in brain, cardiovascular protection in human heart and their beneficial effects in lens physiology related to cataract in the eye; and 3) pointed out new research directions to address the key questions in this important and newly emerging area. We also suggest a novel conceptual approach that will contribute to innovative regimens for the prevention or treatment of a wide variety of medical complications based on E(2)/ER-mediated MRC biogenesis pathway. PMID:19559056

  5. Regulation of Mitochondrial Respiratory Chain Biogenesis by Estrogens/Estrogen Receptors and Physiological, Pathological and Pharmacological Implications

    PubMed Central

    Chen, Jin-Qiang; Cammarata, Patrick R.; Baines, Christopher P.; Yager, James D.

    2009-01-01

    There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17β-estradiol(E2) and estrogen receptors (ER) in a number of cell types and tissues that have high demands for mitochondrial energy metabolism. This novel E2-mediated mitochondrial pathway involves the cooperation of both nuclear and mitochondrial ERα and ERβ and their co-activators on the coordinate regulation of both nuclear DNA- and mitochondrial DNA-encoded genes for MRC proteins. In this paper, we have: 1) comprehensively reviewed studies that reveal a novel role of estrogens and ERs in the regulation of MRC biogenesis; 2) discussed their physiological, pathological and pharmacological implications in the control of cell proliferation and apoptosis in relation to estrogen-mediated carcinogenesis, anticancer drug resistance in human breast cancer cells, neuro-protection for Alzheimer’s disease and Parkinson’s disease in brain, cardiovascular protection in human heart and their beneficial effects in lens physiology related to cataract in the eye; and 3) pointed out new research directions to address the key questions in this important and newly emerging area. We also suggest a novel conceptual approach that will contribute to innovative regimines for the prevention or treatment of a wide variety of medical complications based on E2/ER-mediated MRC biogenesis pathway. PMID:19559056

  6. Rutin Increases Muscle Mitochondrial Biogenesis with AMPK Activation in High-Fat Diet-Induced Obese Rats

    PubMed Central

    Seo, Sangjin; Lee, Mak-Soon; Chang, Eugene; Shin, Yoonjin; Oh, Soojung; Kim, In-Hwan; Kim, Yangha

    2015-01-01

    Decreased mitochondrial number and dysfunction in skeletal muscle are associated with obesity and the progression of obesity-associated metabolic disorders. The specific aim of the current study was to investigate the effects of rutin on mitochondrial biogenesis in skeletal muscle of high-fat diet-induced obese rats. Supplementation with rutin reduced body weight and adipose tissue mass, despite equivalent energy intake (p < 0.05). Rutin significantly increased mitochondrial size and mitochondrial DNA (mtDNA) content as well as gene expression related to mitochondrial biogenesis, such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor-1 (NRF-1), transcription factor A (Tfam), and nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, sirtulin1 (SIRT1) in skeletal muscle (p < 0.05). Moreover, rutin consumption increased muscle adenosine monophosphate-activated protein kinase (AMPK) activity by 40% (p < 0.05). Taken together, these results suggested at least partial involvement of muscle mitochondria and AMPK activation in the rutin-mediated beneficial effect on obesity. PMID:26402699

  7. Spatio-Temporal Dynamics of Yeast Mitochondrial Biogenesis: Transcriptional and Post-Transcriptional mRNA Oscillatory Modules

    PubMed Central

    Lelandais, Gaëlle; Saint-Georges, Yann; Geneix, Colette; Al-Shikhley, Liza; Dujardin, Geneviève; Jacq, Claude

    2009-01-01

    Examples of metabolic rhythms have recently emerged from studies of budding yeast. High density microarray analyses have produced a remarkably detailed picture of cycling gene expression that could be clustered according to metabolic functions. We developed a model-based approach for the decomposition of expression to analyze these data and to identify functional modules which, expressed sequentially and periodically, contribute to the complex and intricate mitochondrial architecture. This approach revealed that mitochondrial spatio-temporal modules are expressed during periodic spikes and specific cellular localizations, which cover the entire oscillatory period. For instance, assembly factors (32 genes) and translation regulators (47 genes) are expressed earlier than the components of the amino-acid synthesis pathways (31 genes). In addition, we could correlate the expression modules identified with particular post-transcriptional properties. Thus, mRNAs of modules expressed “early” are mostly translated in the vicinity of mitochondria under the control of the Puf3p mRNA-binding protein. This last spatio-temporal module concerns mostly mRNAs coding for basic elements of mitochondrial construction: assembly and regulatory factors. Prediction that unknown genes from this module code for important elements of mitochondrial biogenesis is supported by experimental evidence. More generally, these observations underscore the importance of post-transcriptional processes in mitochondrial biogenesis, highlighting close connections between nuclear transcription and cytoplasmic site-specific translation. PMID:19521515

  8. Role of Phosphatidylethanolamine in the Biogenesis of Mitochondrial Outer Membrane Proteins*

    PubMed Central

    Becker, Thomas; Horvath, Susanne E.; Bttinger, Lena; Gebert, Natalia; Daum, Gnther; Pfanner, Nikolaus

    2013-01-01

    The mitochondrial outer membrane contains proteinaceous machineries for the import and assembly of proteins, including TOM (translocase of the outer membrane) and SAM (sorting and assembly machinery). It has been shown that the dimeric phospholipid cardiolipin is required for the stability of TOM and SAM complexes and thus for the efficient import and assembly of ?-barrel proteins and some ?-helical proteins of the outer membrane. Here, we report that mitochondria deficient in phosphatidylethanolamine (PE), the second non-bilayer-forming phospholipid, are impaired in the biogenesis of ?-barrel proteins, but not of ?-helical outer membrane proteins. The stability of TOM and SAM complexes is not disturbed by the lack of PE. By dissecting the import steps of ?-barrel proteins, we show that an early import stage involving translocation through the TOM complex is affected. In PE-depleted mitochondria, the TOM complex binds precursor proteins with reduced efficiency. We conclude that PE is required for the proper function of the TOM complex. PMID:23625917

  9. Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators.

    PubMed

    Pijuan, Jordi; Mara, Carlos; Herrero, Enrique; Bell, Gemma

    2015-12-15

    Fe-S cluster biogenesis machinery is required for multiple DNA metabolism processes. In this work, we show that, in Saccharomyces cerevisiae, defects at different stages of the mitochondrial Fe-S cluster assembly machinery (ISC) result in increased spontaneous mutation rate and hyper-recombination, accompanied by an increment in Rad52-associated DNA repair foci and a higher phosphorylated state of ?H2A histone, altogether supporting the presence of constitutive DNA lesions. Furthermore, ISC assembly machinery deficiency elicits a DNA damage response that upregulates ribonucleotide reductase activity by promoting the reduction of Sml1 levels and the cytosolic redistribution of Rnr2 and Rnr4 enzyme subunits. Depending on the impaired stage of the ISC machinery, different signaling pathway mediators contribute to such a response, converging on Dun1. Thus, cells lacking the glutaredoxin Grx5, which are compromised at the core ISC system, show Mec1- and Rad53-independent Dun1 activation, whereas both Mec1 and Chk1 are required when the non-core ISC member Iba57 is absent. Grx5-null cells exhibit a strong dependence on the error-free post-replication repair and the homologous recombination pathways, demonstrating that a DNA damage response needs to be activated upon ISC impairment to preserve cell viability. PMID:26567217

  10. Mitochondrial disease genes COA6, COX6B and SCO2 have overlapping roles in COX2 biogenesis.

    PubMed

    Ghosh, Alok; Pratt, Anthony T; Soma, Shivatheja; Theriault, Sarah G; Griffin, Aaron T; Trivedi, Prachi P; Gohil, Vishal M

    2016-02-15

    Biogenesis of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain, is a complex process facilitated by several assembly factors. Pathogenic mutations were recently reported in one such assembly factor, COA6, and our previous work linked Coa6 function to mitochondrial copper metabolism and expression of Cox2, a copper-containing subunit of CcO. However, the precise role of Coa6 in Cox2 biogenesis remained unknown. Here we show that yeast Coa6 is an orthologue of human COA6, and like Cox2, is regulated by copper availability, further implicating it in copper delivery to Cox2. In order to place Coa6 in the Cox2 copper delivery pathway, we performed a comprehensive genetic epistasis analysis in the yeast Saccharomyces cerevisiae and found that simultaneous deletion of Coa6 and Sco2, a mitochondrial copper metallochaperone, or Coa6 and Cox12/COX6B, a structural subunit of CcO, completely abrogates Cox2 biogenesis. Unlike Coa6 deficient cells, copper supplementation fails to rescue Cox2 levels of these double mutants. Overexpression of Cox12 or Sco proteins partially rescues the coa6? phenotype, suggesting their overlapping but non-redundant roles in copper delivery to Cox2. These genetic data are strongly corroborated by biochemical studies demonstrating physical interactions between Coa6, Cox2, Cox12 and Sco proteins. Furthermore, we show that patient mutations in Coa6 disrupt Coa6-Cox2 interaction, providing the biochemical basis for disease pathogenesis. Taken together, these results place COA6 in the copper delivery pathway to CcO and, surprisingly, link it to a previously unidentified function of CcO subunit Cox12 in Cox2 biogenesis. PMID:26669719

  11. Human ISCA1 interacts with IOP1/NARFL and functions in both cytosolic and mitochondrial iron-sulfur protein biogenesis.

    PubMed

    Song, Daisheng; Tu, Zheng; Lee, Frank S

    2009-12-18

    Iron-sulfur proteins play an essential role in many biologic processes. Hence, understanding their assembly is an important goal. In Escherichia coli, the protein IscA is a product of the isc (iron-sulfur cluster) operon and functions in the iron-sulfur cluster assembly pathway in this organism. IscA is conserved in evolution, but its function in mammalian cells is not known. Here, we provide evidence for a role for a human homologue of IscA, named IscA1, in iron-sulfur protein biogenesis. We observe that small interfering RNA knockdown of IscA1 in HeLa cells leads to decreased activity of two mitochondrial iron-sulfur enzymes, succinate dehydrogenase and mitochondrial aconitase, as well as a cytosolic iron-sulfur enzyme, cytosolic aconitase. IscA1 is observed both in cytosolic and mitochondrial fractions. We find that IscA1 interacts with IOP1 (iron-only hydrogenase-like protein 1)/NARFL (nuclear prelamin A recognition factor-like), a cytosolic protein that plays a role in the cytosolic iron-sulfur protein assembly pathway. We therefore propose that human IscA1 plays an important role in both mitochondrial and cytosolic iron-sulfur cluster biogenesis, and a notable component of the latter is the interaction between IscA1 and IOP1. PMID:19864422

  12. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa.

    PubMed

    Taub, Pam R; Ramirez-Sanchez, Israel; Ciaraldi, Theodore P; Perkins, Guy; Murphy, Anne N; Naviaux, Robert; Hogan, Michael; Maisel, Alan S; Henry, Robert R; Ceballos, Guillermo; Villarreal, Francisco

    2012-02-01

    (-)-Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide, cGMP, SIRT1, PGC1α, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi-rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function. PMID:22376256

  13. Enhanced oxidative stress and aberrant mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells during methamphetamine induced apoptosis

    SciTech Connect

    Wu, C.-W.; Ping, Y.-H.; Yen, J.-C.; Chang, C.-Y.; Wang, S.-F.; Yeh, C.-L.; Chi, C.-W.; Lee, H.-C. . E-mail: hclee2@ym.edu.tw

    2007-05-01

    Methamphetamine (METH) is an abused drug that may cause psychiatric and neurotoxic damage, including degeneration of monoaminergic terminals and apoptosis of non-monoaminergic cells in Brain. The cellular and molecular mechanisms underlying these METH-induced neurotoxic effects remain to be clarified. In this study, we performed a time course assessment to investigate the effects of METH on intracellular oxidative stress and mitochondrial alterations in a human dopaminergic neuroblastoma SH-SY5Y cell line. We characterized that METH induces a temporal sequence of several cellular events including, firstly, a decrease in mitochondrial membrane potential within 1 h of the METH treatment, secondly, an extensive decline in mitochondrial membrane potential and increase in the level of reactive oxygen species (ROS) after 8 h of the treatment, thirdly, an increase in mitochondrial mass after the drug treatment for 24 h, and finally, a decrease in mtDNA copy number and mitochondrial proteins per mitochondrion as well as the occurrence of apoptosis after 48 h of the treatment. Importantly, vitamin E attenuated the METH-induced increases in intracellular ROS level and mitochondrial mass, and prevented METH-induced cell death. Our observations suggest that enhanced oxidative stress and aberrant mitochondrial biogenesis may play critical roles in METH-induced neurotoxic effects.

  14. Sam37 is crucial for formation of the mitochondrial TOM-SAM supercomplex, thereby promoting ?-barrel biogenesis.

    PubMed

    Wenz, Lena-Sophie; Ellenrieder, Lars; Qiu, Jian; Bohnert, Maria; Zufall, Nicole; van der Laan, Martin; Pfanner, Nikolaus; Wiedemann, Nils; Becker, Thomas

    2015-09-28

    Biogenesis of mitochondrial ?-barrel proteins requires two preprotein translocases, the general translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM). TOM and SAM form a supercomplex that promotes transfer of ?-barrel precursors. The SAM core complex contains the channel protein Sam50, which cooperates with Sam35 in precursor recognition, and the peripheral membrane protein Sam37. The molecular function of Sam37 has been unknown. We report that Sam37 is crucial for formation of the TOM-SAM supercomplex. Sam37 interacts with the receptor domain of Tom22 on the cytosolic side of the mitochondrial outer membrane and links TOM and SAM complexes. Sam37 thus promotes efficient transfer of ?-barrel precursors to the SAM complex. We conclude that Sam37 functions as a coupling factor of the translocase supercomplex of the mitochondrial outer membrane. PMID:26416958

  15. Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure.

    PubMed

    Pisano, Annalinda; Cerbelli, Bruna; Perli, Elena; Pelullo, Maria; Bargelli, Valentina; Preziuso, Carmela; Mancini, Massimiliano; He, Langping; Bates, Matthew Gd; Lucena, Joaquin R; Della Monica, Paola Lilla; Familiari, Giuseppe; Petrozza, Vincenzo; Nediani, Chiara; Taylor, Robert W; d'Amati, Giulia; Giordano, Carla

    2016-01-01

    Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium. PMID:26764143

  16. Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure

    PubMed Central

    Pisano, Annalinda; Cerbelli, Bruna; Perli, Elena; Pelullo, Maria; Bargelli, Valentina; Preziuso, Carmela; Mancini, Massimiliano; He, Langping; Bates, Matthew GD; Lucena, Joaquin R; Della Monica, Paola Lilla; Familiari, Giuseppe; Petrozza, Vincenzo; Nediani, Chiara; Taylor, Robert W; d’Amati, Giulia; Giordano, Carla

    2016-01-01

    Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium. PMID:26764143

  17. ?-Lipoic acid treatment increases mitochondrial biogenesis and promotes beige adipose features in subcutaneous adipocytes from overweight/obese subjects.

    PubMed

    Fernndez-Galilea, Marta; Prez-Matute, Patricia; Prieto-Hontoria, Pedro L; Houssier, Marianne; Burrell, Mara A; Langin, Dominique; Martnez, J Alfredo; Moreno-Aliaga, Mara J

    2015-03-01

    ?-Lipoic acid (?-Lip) is a natural occurring antioxidant with beneficial anti-obesity properties. The aim of this study was to investigate the putative effects of ?-Lip on mitochondrial biogenesis and the acquirement of brown-like characteristics by subcutaneous adipocytes from overweight/obese subjects. Thus, fully differentiated human subcutaneous adipocytes were treated with ?-Lip (100 and 250?M) for 24h for studies on mitochondrial content and morphology, mitochondrial DNA (mtDNA) copy number, fatty acid oxidation enzymes and brown/beige characteristic genes. The involvement of the Sirtuin1/Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (SIRT1/PGC-1?) pathway was also evaluated. Our results showed that ?-Lip increased mitochondrial content in cultured human adipocytes as revealed by electron microscopy and by mitotracker green labeling. Moreover, an enhancement in mtDNA content was observed. This increase was accompanied by an up-regulation of SIRT1 protein levels, a decrease in PGC-1? acetylation and up-regulation of Nuclear respiratory factor 1 (Nrf1) and Mitochondrial transcription factor (Tfam) transcription factors. Enhanced oxygen consumption and fatty acid oxidation enzymes, Carnitine palmitoyl transferase 1 and Acyl-coenzyme A oxidase (CPT-1 and ACOX) were also observed. Mitochondria from ?-Lip-treated adipocytes exhibited some morphological characteristics of brown mitochondria, and ?-Lip also induced up-regulation of some brown/beige adipocytes markers such as cell death-inducing DFFA-like effector a (Cidea) and T-box1 (Tbx1). Moreover, ?-Lip up-regulated PR domain containing 16 (Prdm16) mRNA levels in treated adipocytes. Therefore, our study suggests the ability of ?-Lip to promote mitochondrial biogenesis and brown-like remodeling in cultured white subcutaneous adipocytes from overweight/obese donors. PMID:25542506

  18. Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM).

    PubMed

    Quiones-Lombraa, Adolfo; Blanco, Javier G

    2015-07-01

    The regulation of mitochondrial biogenesis is under the control of nuclear genes including the master Mitochondrial Transcription Factor A (TFAM). Recent evidence suggests that the expression of TFAM is regulated by microRNAs (miRNAs) in various cellular contexts. Here, we show that hsa-miR-155-5p, a prominent miRNA encoded in chromosome 21, controls the expression of TFAM at the post-transcriptional level. In human fibroblasts derived from a diploid donor, downregulation of TFAM by hsa-miR-155-5p decreased mitochondrial DNA (mtDNA) content. In contrast, downregulation of TFAM by hsa-miR-155-5p did not decrease mtDNA content in fibroblasts derived from a donor with Down syndrome (DS, trisomy 21). In line, downregulation of mitochondrial TFAM levels through hsa-miR-155-5p decreased mitochondrial mass in diploid fibroblasts but not in trisomic cells. Due to the prevalence of mitochondrial dysfunction and cardiac abnormalities in subjects with DS, we examined the presence of potential associations between hsa-miR-155-5p and TFAM expression in heart samples from donors with and without DS. There were significant negative associations between hsa-miR-155-5p and TFAM expression in heart samples from donors with and without DS. These results suggest that regulation of TFAM by hsa-miR-155-5p impacts mitochondrial biogenesis in the diploid setting but not in the DS setting. PMID:25869329

  19. Melatonin Improves mitochondrial function by promoting MT1/SIRT1/PGC-1 alpha-dependent mitochondrial biogenesis in cadmium-induced hepatotoxicity in vitro.

    PubMed

    Guo, Pan; Pi, Huifeng; Xu, Shangcheng; Zhang, Lei; Li, Yuming; Li, Min; Cao, Zhengwang; Tian, Li; Xie, Jia; Li, Renyan; He, Mindi; Lu, Yonghui; Liu, Chuan; Duan, Weixia; Yu, Zhengping; Zhou, Zhou

    2014-11-01

    Melatonin is an indolamine synthesized in the pineal gland that has a wide range of physiological functions, and it has been under clinical investigation for expanded applications. Increasing evidence demonstrates that melatonin can ameliorate cadmium-induced hepatotoxicity. However, the potentially protective effects of melatonin against cadmium-induced hepatotoxicity and the underlying mechanisms of this protection remain unclear. This study investigates the protective effects of melatonin pretreatment on cadmium-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 ?M) for 12 h. We found that Cd stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content. Consistent with this finding, Cd exposure was associated with decreased Sirtuin 1 (SIRT1) protein expression and activity, thus promoted acetylation of PGC-1 alpha, a key enzyme involved in mitochondrial biogenesis and function, although Cd did not disrupt the interaction between SIRT1 and PGC-1 alpha. However, all cadmium-induced mitochondrial oxidative injuries were efficiently attenuated by melatonin pretreatment. Moreover, Sirtinol and SIRT1 siRNA each blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT1/ PGC-1 alpha signaling. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to promote SIRT1/ PGC-1 alpha signaling. In summary, our results indicate that SIRT1 plays an essential role in the ability of moderate melatonin to stimulate PGC-1 alpha and improve mitochondrial biogenesis and function at least partially through melatonin receptors in cadmium-induced hepatotoxicity. PMID:25159133

  20. Melatonin Improves Mitochondrial Function by Promoting MT1/SIRT1/PGC-1 Alpha-Dependent Mitochondrial Biogenesis in Cadmium-Induced Hepatotoxicity In Vitro

    PubMed Central

    Guo, Pan; Pi, Huifeng; Xu, Shangcheng; Zhang, Lei; Li, Yuming; Li, Min; Cao, Zhengwang; Tian, Li; Xie, Jia; Li, Renyan; He, Mindi; Lu, Yonghui; Liu, Chuan; Duan, Weixia; Yu, Zhengping; Zhou, Zhou

    2014-01-01

    Melatonin is an indolamine synthesized in the pineal gland that has a wide range of physiological functions, and it has been under clinical investigation for expanded applications. Increasing evidence demonstrates that melatonin can ameliorate cadmium-induced hepatotoxicity. However, the potentially protective effects of melatonin against cadmium-induced hepatotoxicity and the underlying mechanisms of this protection remain unclear. This study investigates the protective effects of melatonin pretreatment on cadmium-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10μM) for 12 h. We found that Cd stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content. Consistent with this finding, Cd exposure was associated with decreased Sirtuin 1 (SIRT1) protein expression and activity, thus promoted acetylation of PGC-1 alpha, a key enzyme involved in mitochondrial biogenesis and function, although Cd did not disrupt the interaction between SIRT1 and PGC-1 alpha. However, all cadmium-induced mitochondrial oxidative injuries were efficiently attenuated by melatonin pretreatment. Moreover, Sirtinol and SIRT1 siRNA each blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT1/ PGC-1 alpha signaling. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to promote SIRT1/ PGC-1 alpha signaling. In summary, our results indicate that SIRT1 plays an essential role in the ability of moderate melatonin to stimulate PGC-1 alpha and improve mitochondrial biogenesis and function at least partially through melatonin receptors in cadmium-induced hepatotoxicity. PMID:25159133

  1. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression.

    PubMed

    Chowanadisai, Winyoo; Bauerly, Kathryn A; Tchaparian, Eskouhie; Wong, Alice; Cortopassi, Gino A; Rucker, Robert B

    2010-01-01

    Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa1-6 cells to 10-30 microm PQQ for 24-48 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1alpha, and increased PGC-1alpha mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1alpha or CREB expression. Consistent with activation of the PGC-1alpha pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction. PMID:19861415

  2. Resistance exercise enhances the molecular signaling of mitochondrial biogenesis induced by endurance exercise in human skeletal muscle.

    PubMed

    Wang, Li; Mascher, Henrik; Psilander, Niklas; Blomstrand, Eva; Sahlin, Kent

    2011-11-01

    Combining endurance and strength training (concurrent training) may change the adaptation compared with single mode training. However, the site of interaction and the mechanisms are unclear. We have investigated the hypothesis that molecular signaling of mitochondrial biogenesis after endurance exercise is impaired by resistance exercise. Ten healthy subjects performed either only endurance exercise (E; 1-h cycling at ?65% of maximal oxygen uptake), or endurance exercise followed by resistance exercise (ER; 1-h cycling + 6 sets of leg press at 70-80% of 1 repetition maximum) in a randomized cross-over design. Muscle biopsies were obtained before and after exercise (1 and 3 h postcycling). The mRNA of genes related to mitochondrial biogenesis [(peroxisome proliferator-activated receptor-? coactivator-1 (PGC-1)?, PGC-1-related coactivator (PRC)] related coactivator) and substrate regulation (pyruvate dehydrogenase kinase-4) increased after both E and ER, but the mRNA levels were about twofold higher after ER (P < 0.01). Phosphorylation of proteins involved in the signaling cascade of protein synthesis [mammalian target of rapamycin (mTOR), ribosomal S6 kinase 1, and eukaryotic elongation factor 2] was altered after ER but not after E. Moreover, ER induced a larger increase in mRNA of genes associated with positive mTOR signaling (cMyc and Rheb). Phosphorylation of AMP-activated protein kinase, acetyl-CoA carboxylase, and Akt increased similarly at 1 h postcycling (P < 0.01) after both types of exercise. Contrary to our hypothesis, the results demonstrate that ER, performed after E, amplifies the adaptive signaling response of mitochondrial biogenesis compared with single-mode endurance exercise. The mechanism may relate to a cross talk between signaling pathways mediated by mTOR. The results suggest that concurrent training may be beneficial for the adaptation of muscle oxidative capacity. PMID:21836044

  3. Time-course effect of high-glucose-induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells.

    PubMed

    Al-Kafaji, Ghada; Sabry, Mohamed Abdalla; Skrypnyk, Cristina

    2016-01-01

    The present study investigated the time-course effect of high-glucose-induced reactive oxygen species (ROS) on mitochondrial biogenesis and function in human renal mesangial cells and the effect of direct inhibition of ROS on mitochondria. The cells were cultured for 1, 4, and 7 days in normal glucose or high glucose in the presence and absence of Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) or catalase. Mitochondrial ROS production was assessed by confocal microscope. mtDNA copy number and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1?), nuclear respiratory factors 1 (NRF-1), and mitochondrial transcription factor A (TFAM) transcripts were analyzed by real-time PCR. PGC-1?, NRF-1, and TFAM proteins were analyzed by Western blotting. Mitochondrial function was determined by assessing mitochondrial membrane potential and adenosine triphosphate (ATP) levels. High glucose induced significant increases in mitochondrial superoxide and hydrogen peroxide (H2 O2 ) at day 1, which remained significantly elevated at days 4 and 7. The copy number of mtDNA and expression of PGC-1?, NRF-1, and TFAM were significantly increased at 1 day in high glucose but were significantly decreased at 4 and 7 days. A progressive decrease in mitochondrial membrane potential was observed at 1, 4, and 7 days in high glucose, and this was associated with decreased ATP levels. Treatment of cells with MnTBAP or catalase during high-glucose incubation attenuated ROS production and reversed the alterations in mitochondrial biogenesis and function. Increased mitochondrial biogenesis in human renal mesangial cells may be an early adaptive response to high-glucose-induced ROS, and prolonged ROS production induced by chronic high glucose decreased mitochondrial biogenesis and impaired mitochondrial function. Protection of mitochondria from high-glucose-induced ROS may provide a potential approach to retard the development and progression of diabetic nephropathy. PMID:26251331

  4. Roux-en-Y Gastric Bypass Acutely Decreases Protein Carbonylation and Increases Expression of Mitochondrial Biogenesis Genes in Subcutaneous Adipose Tissue

    PubMed Central

    Jahansouz, Cyrus; Serrot, Federico J.; Frohnert, Brigitte I.; Foncea, Rocio E.; Dorman, Robert B.; Slusarek, Bridget; Leslie, Daniel B.; Bernlohr, David A.; Ikramuddin, Sayeed

    2015-01-01

    Background Mitochondrial dysfunction in adipose tissue has been implicated as a pathogenic step in the development of type 2 diabetes mellitus (T2DM). In adipose tissue, chronic nutrient overload results in mitochondria driven increased reactive oxygen species (ROS) leading to carbonylation of proteins that impair mitochondrial function and downregulation of key genes linked to mitochondrial biogenesis. In patients with T2DM, Roux-en-Y gastric bypass (RYGB) surgery leads to improvements in glycemic profile prior to significant weight loss. Consequently, we hypothesized that improved glycemia early after RYGB would be paralleled by decreased protein carbonylation and increased expression of genes related to mitochondrial biogenesis in adipose tissue. Methods To evaluate this hypothesis, 16 obese individuals were studied before and 7–8 days following RYGB and adjustable gastric banding (AGB). Subcutaneous adipose tissue was obtained pre- and post-bariatric surgery as well as from eight healthy, non-obese individual controls. Results Prior to surgery, adipose tissue expression of PGC1α, NRF1, Cyt C, and eNOS (but not Tfam) showed significantly lower expression in the obese bariatric surgery group when compared to lean controls (p<0.05). Following RYGB, but not after AGB, patients showed significant decrease in HOMA-IR, reduction in adipose protein carbonylation, and increased expression of genes linked to mitochondrial biogenesis. Conclusions These results suggest that rapid reduction in protein carbonylation and increased mitochondrial biogenesis may explain postoperative metabolic improvements following RYGB. PMID:25975200

  5. Decreased Levels of Proapoptotic Factors and Increased Key Regulators of Mitochondrial Biogenesis Constitute New Potential Beneficial Features of Long-lived Growth Hormone Receptor GeneDisrupted Mice

    PubMed Central

    2013-01-01

    Decreased somatotrophic signaling is among the most important mechanisms associated with extended longevity. Mice homozygous for the targeted disruption of the growth hormone (GH) receptor gene (GH receptor knockout; GHRKO) are obese and dwarf, are characterized by a reduced weight and body size, undetectable levels of GH receptor, high concentration of serum GH, and greatly reduced plasma levels of insulin and insulin-like growth factor-I, and are remarkably long lived. Recent results suggest new features of GHRKO mice that may positively affect longevitydecreased levels of proapoptotic factors and increased levels of key regulators of mitochondrial biogenesis. The alterations in levels of the proapoptotic factors and key regulators of mitochondrial biogenesis were not further improved by two other potential life-extending interventionscalorie restriction and visceral fat removal. This may attribute the primary role to GH resistance in the regulation of apoptosis and mitochondrial biogenesis in GHRKO mice in terms of increased life span. PMID:23197187

  6. Role of PGC-1? during acute exercise-induced autophagy and mitophagy in skeletal muscle.

    PubMed

    Vainshtein, Anna; Tryon, Liam D; Pauly, Marion; Hood, David A

    2015-05-01

    Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1? plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1? knockout (KO) animals. Deletion of PGC-1? resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1?. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1? that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1?. PMID:25673772

  7. The neurogenic basic helix-loop-helix transcription factor NeuroD6 enhances mitochondrial biogenesis and bioenergetics to confer tolerance of neuronal PC12-NeuroD6 cells to the mitochondrial stressor rotenone

    SciTech Connect

    Baxter, Kristin Kathleen; Uittenbogaard, Martine; Chiaramello, Anne

    2012-10-15

    The fundamental question of how and which neuronal specific transcription factors tailor mitochondrial biogenesis and bioenergetics to the need of developing neuronal cells has remained largely unexplored. In this study, we report that the neurogenic basic helix-loop-helix transcription factor NeuroD6 possesses mitochondrial biogenic properties by amplifying the mitochondrial DNA content and TFAM expression levels, a key regulator for mitochondrial biogenesis. NeuroD6-mediated increase in mitochondrial biogenesis in the neuronal progenitor-like PC12-NEUROD6 cells is concomitant with enhanced mitochondrial bioenergetic functions, including increased expression levels of specific subunits of respiratory complexes of the electron transport chain, elevated mitochondrial membrane potential and ATP levels produced by oxidative phosphorylation. Thus, NeuroD6 augments the bioenergetic capacity of PC12-NEUROD6 cells to generate an energetic reserve, which confers tolerance to the mitochondrial stressor, rotenone. We found that NeuroD6 induces an adaptive bioenergetic response throughout rotenone treatment involving maintenance of the mitochondrial membrane potential and ATP levels in conjunction with preservation of the actin network. In conclusion, our results support the concept that NeuroD6 plays an integrative role in regulating and coordinating the onset of neuronal differentiation with acquisition of adequate mitochondrial mass and energetic capacity to ensure energy demanding events, such as cytoskeletal remodeling, plasmalemmal expansion, and growth cone formation. -- Highlights: Black-Right-Pointing-Pointer NeuroD6 induces mitochondrial biogenesis in neuroprogenitor-like cells. Black-Right-Pointing-Pointer NeuroD6 augments the bioenergetic reserve of the neuronal PC12-NeuroD6 cells. Black-Right-Pointing-Pointer NeuroD6 increases the mitochondrial membrane potential and ATP levels. Black-Right-Pointing-Pointer NeuroD6 confers tolerance to rotenone via an adaptive mitochondrial response.

  8. 4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway.

    PubMed

    Rawat, Arun Kumar; Korthikunta, Venkateswarlu; Gautam, Sudeep; Pal, Savita; Tadigoppula, Narender; Tamrakar, Akhilesh Kumar; Srivastava, Arvind Kumar

    2014-12-01

    4-Hydroxyisoleucine (4-HIL) is an unusual amino acid isolated from fenugreek seeds (Trigonella foenum graecum L). Various studies have shown that it acts as an antidiabetic agent yet its mechanism of action is not clear. We therefore investigated the effect 4-HIL on the high fructose diet fed streptozotocin induced diabetic rats and L6 myotubes. 4-HIL (50 mg/kg) has improved blood lipid profile, glucose tolerance and insulin sensitivity in a diabetic rat model. It has increased the glucose uptake in L6 myotubes in AMPK-dependent manner and upregulated the expression of genes (PGC-1?, PGC-1?, CPT 1 and CPT 2), which have role in mitochondrial biogenesis and energy metabolism in the liver, skeletal muscles as well as in L6 myotubes. Interestingly, it also increased the AMPK and Akt expression along with their phosphorylated forms in the liver and muscle tissues of treated animals. Altogether we concluded that 4-HIL acts to improve insulin resistance by promoting mitochondrial biogenesis in high fructose diet fed STZ induced diabetic rats. PMID:25454462

  9. The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis.

    PubMed

    Gurd, Brendon J; Yoshida, Yuko; Lally, James; Holloway, Graham P; Bonen, Arend

    2009-04-15

    Deacetylation of PGC-1alpha by SIRT1 is thought to be an important step in increasing PGC-1alpha transcriptional activity, since in muscle cell lines SIRT1 induces PGC-1alpha protein expression and mitochondrial biogenesis. We examined the relationship between SIRT1 protein and activity, PGC-1alpha and markers of mitochondrial density, (a) across a range of metabolically heterogeneous skeletal muscles and the heart, and when mitochondrial biogenesis was stimulated by (b) chronic muscle stimulation (7 days) and (c) AICAR administration (5 days), and finally, (d) we also examined the effects of SIRT1 overexpression on mitochondrial biogenesis and PGC-1alpha. SIRT1 protein and activity were correlated (r = 0.97). There were negative correlations between SIRT1 protein and PGC-1alpha (r = -0.95), COX IV (r = -0.94) and citrate synthase (r = -0.97). Chronic muscle stimulation and AICAR upregulated PGC-1alpha protein (22-159%) and oxidative capacity (COX IV, 20-69%); in each instance SIRT1 protein was downregulated by 20-40%, while SIRT1 intrinsic activity was increased. SIRT1 overexpression in rodent muscle increased SIRT1 protein (+240%) and doubled SIRT1 activity, but PGC-1alpha (-25%), mtTFA (-14%) and COX IV (-10%) proteins were downregulated. Taken altogether these experiments are not consistent with the notion that SIRT1 protein plays an obligatory regulatory role in the process of PGC-1alpha-mediated mitochondrial biogenesis in mammalian muscle. PMID:19237425

  10. Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

    SciTech Connect

    Hagland, Hanne R.; Nilsson, Linn I.H.; Burri, Lena; Nikolaisen, Julie; Berge, Rolf K.; Department of Heart Disease, Haukeland University Hospital ; Tronstad, Karl J.

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We investigated mechanisms of mitochondrial regulation in rat hepatocytes. Black-Right-Pointing-Pointer Tetradecylthioacetic acid (TTA) was employed to activate mitochondrial oxidation. Black-Right-Pointing-Pointer Mitochondrial biogenesis and respiration were induced. Black-Right-Pointing-Pointer It was confirmed that PPAR target genes were induced. Black-Right-Pointing-Pointer The mechanism involved activation mTOR. -- Abstract: The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPAR{alpha}-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR.

  11. Mitochondria fuel breast cancer metabolism: Fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells

    PubMed Central

    Sotgia, Federica; Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E.; Salem, Ahmed F.; Tsirigos, Aristotelis; Lamb, Rebecca; Sneddon, Sharon; Hulit, James; Howell, Anthony; Lisanti, Michael P.

    2012-01-01

    Here, we present new genetic and morphological evidence that human tumors consist of two distinct metabolic compartments. First, re-analysis of genome-wide transcriptional profiling data revealed that > 95 gene transcripts associated with mitochondrial biogenesis and/or mitochondrial translation were significantly elevated in human breast cancer cells, as compared with adjacent stromal tissue. Remarkably, nearly 40 of these upregulated gene transcripts were mitochondrial ribosomal proteins (MRPs), functionally associated with mitochondrial translation of protein components of the OXPHOS complex. Second, during validation by immunohistochemistry, we observed that antibodies directed against 15 markers of mitochondrial biogenesis and/or mitochondrial translation (AKAP1, GOLPH3, GOLPH3L, MCT1, MRPL40, MRPS7, MRPS15, MRPS22, NRF1, NRF2, PGC1-?, POLRMT, TFAM, TIMM9 and TOMM70A) selectively labeled epithelial breast cancer cells. These same mitochondrial markers were largely absent or excluded from adjacent tumor stromal cells. Finally, markers of mitochondrial lipid synthesis (GOLPH3) and mitochondrial translation (POLRMT) were associated with poor clinical outcome in human breast cancer patients. Thus, we conclude that human breast cancers contain two distinct metabolic compartmentsa glycolytic tumor stroma, which surrounds oxidative epithelial cancer cellsthat are mitochondria-rich. The co-existence of these two compartments is indicative of metabolic symbiosis between epithelial cancer cells and their surrounding stroma. As such, epithelial breast cancer cells should be viewed as predatory metabolic parasites, which undergo anabolic reprogramming to amplify their mitochondrial power. This notion is consistent with the observation that the anti-malarial agent chloroquine may be an effective anticancer agent. New anticancer therapies should be developed to target mitochondrial biogenesis and/or mitochondrial translation in human cancer cells. PMID:23172368

  12. Nicotinamide phosphoribosyltransferase is required for the calorie restriction-mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation.

    PubMed

    Song, Jie; Ke, Sen-Fang; Zhou, Can-Can; Zhang, Sai-Long; Guan, Yun-Feng; Xu, Tian-Ying; Sheng, Chun-Quan; Wang, Pei; Miao, Chao-Yu

    2014-01-01

    Calorie restriction (CR) is one of the most reproducible treatments for weight loss and slowing aging. However, how CR induces these metabolic alterations is not fully understood. In this work, we studied whether nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for nicotinamide adenine dinucleotide biosynthesis, plays a role in CR-induced beneficial metabolic effects using a specific inhibitor of NAMPT (FK866). CR upregulated NAMPT mRNA and protein levels in rat skeletal muscle and white adipose tissue. Inhibition of NAMPT activity by FK866 in rats did not affect the SIRT1 upregulation by CR but suppressed the CR-induced SIRT1 activity and deacetylation of Forkhead box protein O1/peroxisome proliferator-activated receptor γ coactivator-1α. Inhibition of NAMPT activity by FK866 also attenuated the CR-induced SIRT3 activity, evidenced by deacetylation of superoxide dismutase-2. Furthermore, FK866 not only weakened the CR-induced decrease of oxidative stress (dichlorofluorescin signal, superoxide , and malondialdehyde levels), but also greatly attenuated the CR-induced improvements of antioxidative activity (total superoxide dismutase, glutathione, and glutathione/oxidized glutathione ratio) and mitochondrial biogenesis (mRNA levels of nuclear respiratory factor 1, cytochrome c oxidase IV, peroxisome proliferator-activated receptor-γ coactivator-1α, and transcription factor A, mitochondrial and citrate synthase activity). At last, FK866 blocked the CR-induced insulin sensitizing, Akt signaling activation, and endothelial nitric oxide synthase phosphorylation. Collectively, our data provide the first evidence that the CR-induced beneficial effects in oxidative stress, mitochondrial biogenesis, and metabolic adaptation require NAMPT. PMID:23946338

  13. Exercise-Induced Neuroprotection of Hippocampus in APP/PS1 Transgenic Mice via Upregulation of Mitochondrial 8-Oxoguanine DNA Glycosylase

    PubMed Central

    Kang, Weimin; Jiang, Ning; Wang, Xun; Zhang, Yong; Ji, Li Li

    2014-01-01

    Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-? (A?) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of A?-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration. PMID:25538817

  14. Exercise-induced neuroprotection of hippocampus in APP/PS1 transgenic mice via upregulation of mitochondrial 8-oxoguanine DNA glycosylase.

    PubMed

    Bo, Hai; Kang, Weimin; Jiang, Ning; Wang, Xun; Zhang, Yong; Ji, Li Li

    2014-01-01

    Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-β (Aβ) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Aβ-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration. PMID:25538817

  15. Lipoamide Acts as an Indirect Antioxidant by Simultaneously Stimulating Mitochondrial Biogenesis and Phase II Antioxidant Enzyme Systems in ARPE-19 Cells

    PubMed Central

    Zhao, Lin; Liu, Zhongbo; Jia, Haiqun; Feng, Zhihui; Liu, Jiankang; Li, Xuesen

    2015-01-01

    In our previous study, we found that pretreatment with lipoamide (LM) more effectively than alpha-lipoic acid (LA) protected retinal pigment epithelial (RPE) cells from the acrolein-induced damage. However, the reasons and mechanisms for the greater effect of LM than LA are unclear. We hypothesize that LM, rather than the more direct antioxidant LA, may act more as an indirect antioxidant. In the present study, we treated ARPE-19 cells with LA and LM and compared their effects on activation of mitochondrial biogenesis and induction of phase II enzyme systems. It is found that LM is more effective than LA on increasing mitochondrial biogenesis and inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation to the nucleus, leading to an increase in expression or activity of phase II antioxidant enzymes (NQO-1, GST, GCL, catalase and Cu/Zn SOD). Further study demonstrated that mitochondrial biogenesis and phase II enzyme induction are closely coupled via energy requirements. These results suggest that LM, compared with the direct antioxidant LA, plays its protective effect on oxidative damage more as an indirect antioxidant to simultaneously stimulate mitochondrial biogenesis and induction of phase II antioxidant enzymes. PMID:26030919

  16. Ammonium Chloride Ingestion Attenuates Exercise-Induced mRNA Levels in Human Muscle

    PubMed Central

    Mündel, Toby; Pilegaard, Henriette; Hawke, Emma; Leikis, Murray; Lopez-Villalobos, Nicolas; Oliveira, Rodrigo S. F.; Bishop, David J.

    2015-01-01

    Minimizing the decrease in intracellular pH during high-intensity exercise training promotes greater improvements in mitochondrial respiration. This raises the intriguing hypothesis that pH may affect the exercise-induced transcription of genes that regulate mitochondrial biogenesis. Eight males performed 10x2-min cycle intervals at 80% V˙O2peak intensity on two occasions separated by ~2 weeks. Participants ingested either ammonium chloride (ACID) or calcium carbonate (PLA) the day before and on the day of the exercise trial in a randomized, counterbalanced order, using a crossover design. Biopsies were taken from the vastus lateralis muscle before and after exercise. The mRNA level of peroxisome proliferator-activated receptor co-activator 1α (PGC-1α), citrate synthase, cytochome c and FOXO1 was elevated at rest following ACID (P<0.05). During the PLA condition, the mRNA content of mitochondrial- and glucose-regulating proteins was elevated immediately following exercise (P<0.05). In the early phase (0–2 h) of post-exercise recovery during ACID, PGC-1α, citrate synthase, cytochome C, FOXO1, GLUT4, and HKII mRNA levels were not different from resting levels (P>0.05); the difference in PGC-1α mRNA content 2 h post-exercise between ACID and PLA was not significant (P = 0.08). Thus, metabolic acidosis abolished the early post-exercise increase of PGC-1α mRNA and the mRNA of downstream mitochondrial and glucose-regulating proteins. These findings indicate that metabolic acidosis may affect mitochondrial biogenesis, with divergent responses in resting and post-exercise skeletal muscle. PMID:26656911

  17. Ammonium Chloride Ingestion Attenuates Exercise-Induced mRNA Levels in Human Muscle.

    PubMed

    Edge, Johann; Mndel, Toby; Pilegaard, Henriette; Hawke, Emma; Leikis, Murray; Lopez-Villalobos, Nicolas; Oliveira, Rodrigo S F; Bishop, David J

    2015-01-01

    Minimizing the decrease in intracellular pH during high-intensity exercise training promotes greater improvements in mitochondrial respiration. This raises the intriguing hypothesis that pH may affect the exercise-induced transcription of genes that regulate mitochondrial biogenesis. Eight males performed 10x2-min cycle intervals at 80% [Formula: see text] intensity on two occasions separated by ~2 weeks. Participants ingested either ammonium chloride (ACID) or calcium carbonate (PLA) the day before and on the day of the exercise trial in a randomized, counterbalanced order, using a crossover design. Biopsies were taken from the vastus lateralis muscle before and after exercise. The mRNA level of peroxisome proliferator-activated receptor co-activator 1? (PGC-1?), citrate synthase, cytochome c and FOXO1 was elevated at rest following ACID (P<0.05). During the PLA condition, the mRNA content of mitochondrial- and glucose-regulating proteins was elevated immediately following exercise (P<0.05). In the early phase (0-2 h) of post-exercise recovery during ACID, PGC-1?, citrate synthase, cytochome C, FOXO1, GLUT4, and HKII mRNA levels were not different from resting levels (P>0.05); the difference in PGC-1? mRNA content 2 h post-exercise between ACID and PLA was not significant (P = 0.08). Thus, metabolic acidosis abolished the early post-exercise increase of PGC-1? mRNA and the mRNA of downstream mitochondrial and glucose-regulating proteins. These findings indicate that metabolic acidosis may affect mitochondrial biogenesis, with divergent responses in resting and post-exercise skeletal muscle. PMID:26656911

  18. Epigenetic Modifications of the PGC-1? Promoter during Exercise Induced Expression in Mice

    PubMed Central

    Lochmann, Timothy L.; Thomas, Ravindar R.; Bennett, James P.; Taylor, Shirley M.

    2015-01-01

    The transcriptional coactivator, PGC-1?, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7kb upstream of the canonical PGC-1? promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1? mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1? transcripts. Although the ?2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1? promoter B, it is not yet known what molecular changes occur to facilitate PGC-1? promoter B activation following exercise. We sought to determine whether epigenetic modifications were involved in this exercise response in mouse skeletal muscle. We found that DNA hydroxymethylation correlated to increased basal mRNA levels from PGC-1? promoter A, but that DNA methylation appeared to play no role in the exercise-induced activation of PGC-1? promoter B. The level of the activating histone mark H3K4me3 increased with exercise 24 fold across PGC-1? promoter B, but remained unaltered past the canonical PGC-1? transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1? isoforms. PMID:26053857

  19. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

    PubMed Central

    Srivastava, Shireesh; Kashiwaya, Yoshihiro; King, M. Todd; Baxa, Ulrich; Tam, Joseph; Niu, Gang; Chen, Xiaoyuan; Clarke, Kieran; Veech, Richard L.

    2012-01-01

    We measured the effects of a diet in which d-?-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-?-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [18F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.Srivastava, S., Kashiwaya, Y., King, M. T. Baxa, U., Tam, J., Niu, G., Chen, X., Clarke, K., Veech, R. L. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. PMID:22362892

  20. Inhibition of akt phosphorylation diminishes mitochondrial biogenesis regulators, tricarboxylic acid cycle activity and exacerbates recognition memory deficit in rat model of Alzheimer's disease.

    PubMed

    Shaerzadeh, Fatemeh; Motamedi, Fereshteh; Khodagholi, Fariba

    2014-11-01

    3-Methyladenine (3-MA), as a PI3K inhibitor, is widely used for inhibition of autophagy. Inhibition of PI3K class I leads to inhibition of Akt phosphorylation, a central molecule involved in diverse arrays of intracellular cascades in nervous system. Accordingly, in the present study, we aimed to determine the alterations of specific mitochondrial biogenesis markers and mitochondrial function in 3-MA-injected rats following amyloid beta (A?) insult. Our data revealed that inhibition of Akt phosphorylation downregulates master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?). Our data also showed that decrease in PGC-1? level presumably is due to decrease in the phosphorylation of cAMP-response element binding and AMP-activated kinase, two upstream activators of PGC-1?. As a consequence, the level of some mitochondrial biogenesis factors including nuclear respiratory factor-1, mitochondrial transcription factor A, and Cytochrome c decreased significantly. Also, activities of tricarboxylic acid cycle (TCA) enzymes such as Aconitase, a-ketoglutarate dehydrogenase, and malate dehydrogenase reduced in the presence of 3-MA with or without A? insult. Decrease in mitochondrial biogenesis factors and TCA enzyme activity in the rats receiving 3-MA and A? were more compared to the rats that received either alone; indicating the additive destructive effects of these two agents. In agreement with our molecular results, data obtained from behavioral test (using novel objective recognition test) indicated that inhibition of Akt phosphorylation with or without A? injection impaired novel recognition (non-spatial) memory. Our results suggest that 3-MA amplified deleterious effects of A? by targeting central molecule Akt. PMID:25135709

  1. The Neurogenic Basic Helix-Loop-Helix Transcription Factor NeuroD6 Enhances Mitochondrial Biogenesis and Bioenergetics to Confer Tolerance of Neuronal PC12-NeuroD6 Cells to the Mitochondrial Stressor Rotenone

    PubMed Central

    Baxter, Kristin Kathleen; Uittenbogaard, Martine; Chiaramello, Anne

    2012-01-01

    The fundamental question of how and which neuronal specific transcription factors tailor mitochondrial bioenergetics to the need of developing neuronal cells has remained largely unexplored. In this study, we report that the neurogenic basic helix-loop-helix transcription factor NeuroD6 possesses mitochondrial biogenic properties by amplifying the mitochondrial DNA content and TFAM expression levels, a key regulator for mitochondrial biogenesis. NeuroD6-mediated increase in mitochondrial biogenesis in the neuronal progenitor-like PC12-NEUROD6 cells is concomitant with enhanced mitochondrial bioenergetic functions, including increased expression levels of specific subunits of respiratory complexes of the electron transport chain, elevated mitochondrial membrane potential and ATP levels produced by oxidative phosphorylation. Thus, NeuroD6 augments the bioenergetic capacity of PC12-NEUROD6 cells to generate an energetic reserve, which confers tolerance to the mitochondrial stressor, rotenone. We found that NeuroD6 induces an adaptive bioenergetic response throughout rotenone treatment involving maintenance of the mitochondrial membrane potential and ATP levels in conjunction with preservation of the actin network. In conclusion, our results support the concept that NeuroD6 plays an integrative role in regulating and coordinating the onset of neuronal differentiation with acquisition of adequate mitochondrial mass and energetic capacity to ensure energy demanding events, such as cytoskeletal remodeling, plasmalemmal expansion, and growth cone formation. PMID:22814253

  2. Dietary wolfberry up-regulates carotenoid metabolic genes and enhances mitochondrial biogenesis in the retina of db/db diabetic mice

    PubMed Central

    Yu, Huifeng; Wark, Logan; Ji, Hua; Willard, Lloyd; Jaing, Yu; Han, Jing; He, Hui; Ortiz, Edlin; Zhang, Yunong; Medeiros, Denis M; Lin, Dingbo

    2013-01-01

    Scope Our aim was to investigate whether dietary wolfberry altered carotenoid metabolic gene expression and enhanced mitochondrial biogenesis in the retina of diabetic mice. Methods and Results Six-week-old male db/db and wild type mice were fed the control or wolfberry diets for 8 weeks. At study termination, liver and retinal tissues were collected for analysis by transmission electron microscopy, real-time PCR, immunoprecipitation, Western blot, and HPLC. Wolfberry elevated zeaxanthin and lutein levels in the liver and retinal tissues and stimulated expression of retinal scavenger receptor class B type I, glutathione S-transferase Pi 1, and β,β-carotene 9’,10’-oxygenase 2, and induced activation and nuclear enrichment of retinal AMP-activated protein kinase α2 (AMPKα2). Furthermore, wolfberry attenuated hypoxia and mitochondrial stress as demonstrated by declined expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, and heat shock protein 60. Wolfberry enhanced retinal mitochondrial biogenesis in diabetic retinas as demonstrated by reversed mitochondrial dispersion in the retinal pigment epithelium, increased mitochondrial copy number, elevated citrate synthase activity, and up-regulated expression of peroxisome proliferator-activated receptor γ co-activator 1 α, nuclear respiratory factor 1, and mitochondrial transcription factor A. Conclusion Consumption of dietary wolfberry could be beneficial to retinoprotection through reversal of mitochondrial function in diabetic mice. PMID:23505020

  3. CREB-1? Is Recruited to and Mediates Upregulation of the Cytochrome c Promoter during Enhanced Mitochondrial Biogenesis Accompanying Skeletal Muscle Differentiation?

    PubMed Central

    Franko, Andras; Mayer, Sabine; Thiel, Gerald; Mercy, Ludovic; Arnould, Thierry; Hornig-Do, Hue-Tran; Wiesner, Rudolf J.; Goffart, Steffi

    2008-01-01

    To further understand pathways coordinating the expression of nuclear genes encoding mitochondrial proteins, we studied mitochondrial biogenesis during differentiation of myoblasts to myotubes. This energy-demanding process was accompanied by a fivefold increase of ATP turnover, covered by an eightfold increase of mitochondrial activity. While no change in mitochondrial DNA copy number was observed, mRNAs as well as proteins for nucleus-encoded cytochrome c, cytochrome c oxidase subunit IV, and mitochondrial transcription factor A (TFAM) increased, together with total cellular RNA and protein levels. Detailed analysis of the cytochrome c promoter by luciferase reporter, binding affinity, and electrophoretic mobility shift assays as well as mutagenesis studies revealed a critical role for cyclic AMP responsive element binding protein 1 (CREB-1) for promoter activation. Expression of two CREB-1 isoforms was observed by using specific antibodies and quantitative reverse transcription-PCR, and a shift from phosphorylated CREB-1? in myoblasts to phosphorylated CREB-1? protein in myotubes was shown, while mRNA ratios remained unchanged. Chromatin immunoprecipitation assays confirmed preferential binding of CREB-1? in situ to the cytochrome c promoter in myotubes. Overexpression of constitutively active and dominant-negative forms supported the key role of CREB-1 in regulating the expression of genes encoding mitochondrial proteins during myogenesis and probably also in other situations of enhanced mitochondrial biogenesis. PMID:18227154

  4. Elevated mitochondrial oxidative stress impairs metabolic adaptations to exercise in skeletal muscle.

    PubMed

    Crane, Justin D; Abadi, Arkan; Hettinga, Bart P; Ogborn, Daniel I; MacNeil, Lauren G; Steinberg, Gregory R; Tarnopolsky, Mark A

    2013-01-01

    Mitochondrial oxidative stress is a complex phenomenon that is inherently tied to energy provision and is implicated in many metabolic disorders. Exercise training increases mitochondrial oxidative capacity in skeletal muscle yet it remains unclear if oxidative stress plays a role in regulating these adaptations. We demonstrate that the chronic elevation in mitochondrial oxidative stress present in Sod2 (+/-) mice impairs the functional and biochemical mitochondrial adaptations to exercise. Following exercise training Sod2 (+/-) mice fail to increase maximal work capacity, mitochondrial enzyme activity and mtDNA copy number, despite a normal augmentation of mitochondrial proteins. Additionally, exercised Sod2 (+/-) mice cannot compensate for their higher amount of basal mitochondrial oxidative damage and exhibit poor electron transport chain complex assembly that accounts for their compromised adaptation. Overall, these results demonstrate that chronic skeletal muscle mitochondrial oxidative stress does not impact exercise induced mitochondrial biogenesis, but impairs the resulting mitochondrial protein function and can limit metabolic plasticity. PMID:24324727

  5. Elevated Mitochondrial Oxidative Stress Impairs Metabolic Adaptations to Exercise in Skeletal Muscle

    PubMed Central

    Crane, Justin D.; Abadi, Arkan; Hettinga, Bart P.; Ogborn, Daniel I.; MacNeil, Lauren G.; Steinberg, Gregory R.; Tarnopolsky, Mark A.

    2013-01-01

    Mitochondrial oxidative stress is a complex phenomenon that is inherently tied to energy provision and is implicated in many metabolic disorders. Exercise training increases mitochondrial oxidative capacity in skeletal muscle yet it remains unclear if oxidative stress plays a role in regulating these adaptations. We demonstrate that the chronic elevation in mitochondrial oxidative stress present in Sod2+/- mice impairs the functional and biochemical mitochondrial adaptations to exercise. Following exercise training Sod2+/- mice fail to increase maximal work capacity, mitochondrial enzyme activity and mtDNA copy number, despite a normal augmentation of mitochondrial proteins. Additionally, exercised Sod2+/- mice cannot compensate for their higher amount of basal mitochondrial oxidative damage and exhibit poor electron transport chain complex assembly that accounts for their compromised adaptation. Overall, these results demonstrate that chronic skeletal muscle mitochondrial oxidative stress does not impact exercise induced mitochondrial biogenesis, but impairs the resulting mitochondrial protein function and can limit metabolic plasticity. PMID:24324727

  6. trans-Cinnamaldehyde stimulates mitochondrial biogenesis through PGC-1? and PPAR?/? leading to enhanced GLUT4 expression.

    PubMed

    Gannon, Nicholas P; Schnuck, Jamie K; Mermier, Christine M; Conn, Carole A; Vaughan, Roger A

    2015-12-01

    Type 2 diabetes is characterized by insulin resistance and chronic hyperglycemia, and is increasing in incidence and severity. This work explored the effects of trans-cinnamaldehyde (CA) on carbohydrate metabolism, mitochondrial content, and related metabolic gene and protein expression in cultured myotubes treated with various concentrations of CA for up to 24h. CA treatment increased myotube myocyte enhancer factor 2 (MEF2) along with glucose transporter 4 (GLUT4) content. CA treatment also significantly increased expression of markers of improved oxidative metabolism including 5' adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor ? coactivator 1 ? (PGC-1?), cytochrome c (CytC), as well as peroxisome proliferator-activated receptor ? (PPAR?) and PPAR?/?. Despite increased expression of proteins associated with improved oxidative metabolism and glucose uptake, CA-treated myotubes exhibited significantly reduced oxidative metabolism compared with controlled cells. Additionally, CA treatment increased markers of glucose-mediated lipid biosynthesis without elevated PPAR? and sterol receptor element binding protein 1c (SREBP-1c) expression. The ability of CA to stimulate mitochondrial biogenesis and GLUT4 expression suggests CA may offer possible benefits for metabolic disease. However, increases in markers of fatty acid synthesis with simultaneously reduced oxidative metabolism suggest CA may have counterproductive effects for metabolic disease, warranting a need for further investigation. PMID:26449747

  7. IKK/NF-?B regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis

    PubMed Central

    Bakkar, Nadine; Wang, Jingxin; Ladner, Katherine J.; Wang, Huating; Dahlman, Jason M.; Carathers, Micheal; Acharyya, Swarnali; Rudnicki, Michael A.; Hollenbach, Andrew D.; Guttridge, Denis C.

    2008-01-01

    Nuclear factor ?B (NF-?B) is involved in multiple skeletal muscle disorders, but how it functions in differentiation remains elusive given that both anti- and promyogenic activities have been described. In this study, we resolve this by showing that myogenesis is controlled by opposing NF-?B signaling pathways. We find that myogenesis is enhanced in MyoD-expressing fibroblasts deficient in classical pathway components RelA/p65, inhibitor of ?B kinase ? (IKK?), or IKK?. Similar increases occur in myoblasts lacking RelA/p65 or IKK?, and muscles from RelA/p65 or IKK? mutant mice also contain higher fiber numbers. Moreover, we show that during differentiation, classical NF-?B signaling decreases, whereas the induction of alternative members IKK?, RelB, and p52 occurs late in myogenesis. Myotube formation does not require alternative signaling, but it is important for myotube maintenance in response to metabolic stress. Furthermore, overexpression or knockdown of IKK? regulates mitochondrial content and function, suggesting that alternative signaling stimulates mitochondrial biogenesis. Together, these data reveal a unique IKK/NF-?B signaling switch that functions to both inhibit differentiation and promote myotube homeostasis. PMID:18299349

  8. Agonism of the 5-hydroxytryptamine 1F receptor promotes mitochondrial biogenesis and recovery from acute kidney injury.

    PubMed

    Garrett, Sara M; Whitaker, Ryan M; Beeson, Craig C; Schnellmann, Rick G

    2014-08-01

    Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1-100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone-uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase ?, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1? subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferator-activated receptor coactivator 1-?, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction. PMID:24849926

  9. Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

    PubMed Central

    Garrett, Sara M.; Whitaker, Ryan M.; Beeson, Craig C.

    2014-01-01

    Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazoneuncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase ?, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1? subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferatoractivated receptor coactivator 1-?, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction. PMID:24849926

  10. Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells

    PubMed Central

    Beręsewicz, Małgorzata; Dymkowska, Dorota; Zabłocki, Krzysztof; Zabłocka, Barbara

    2015-01-01

    Mitofusin 2 (Mfn2), mitochondrial outer membrane protein which is involved in rearrangement of these organelles, was first described in pathology of hypertension and diabetes, and more recently much attention is paid to its functions in Charcot-Marie-Tooth type 2A neuropathy (CMT2A). Here, cellular energy metabolism was investigated in mouse embryonic fibroblasts (MEF) differing in the presence of the Mfn2 gene; control (MEFwt) and with Mfn2 gene depleted MEFMfn2-/-. These two cell lines were compared in terms of various parameters characterizing mitochondrial bioenergetics. Here, we have shown that relative rate of proliferation of MEFMfn2-/- cells versus control fibroblasts depend on serum supplementation of the growth media. Moreover, MEFMfn2-/- cells exhibited significantly increased respiration rate in comparison to MEFwt, regardless of serum supplementation of the medium. This effect was correlated with increased level of mitochondrial markers (TOM20 and NAO) as well as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein levels and unchanged total ATP content. Interestingly, mitochondrial DNA content in MEFMfn2-/- cells was not reduced. Fundamentally, these results are in contrast to a commonly accepted belief that mitofusin 2 deficiency inevitably results in debilitation of mitochondrial energy metabolism. However, we suggest a balance between negative metabolic consequences of mitofusin 2 deficiency and adaptive processes exemplified by increased level of PGC-1α and TFAM transcription factor which prevent an excessive depletion of mtDNA and severe impairment of cell metabolism. PMID:26230519

  11. Acute exercise induces tumour suppressor protein p53 translocation to the mitochondria and promotes a p53–Tfam–mitochondrial DNA complex in skeletal muscle

    PubMed Central

    Saleem, Ayesha; Hood, David A

    2013-01-01

    The major tumour suppressor protein p53 plays an important role in maintaining mitochondrial content and function in skeletal muscle. p53 has been shown to reside in the mitochondria complexed with mitochondrial DNA (mtDNA); however, the physiological repercussions of mitochondrial p53 remain unknown. We endeavoured to elucidate whether an acute bout of endurance exercise could mediate an increase in mitochondrial p53 levels. C57Bl6 mice (n= 6 per group) were randomly assigned to sedentary, acute exercise (AE, 15 m min−1 for 90 min) or acute exercise + 3 h recovery (AER) groups. Exercise concomitantly increased the mRNA content of nuclear-encoded (PGC-1α, Tfam, NRF-1, COX-IV, citrate synthase) and mtDNA-encoded (COX-I) genes in the AE group, and further by ∼5-fold in the AER group. Nuclear p53 protein levels were reduced in the AE and AER groups, while in contrast, the abundance of p53 was drastically enhanced by ∼2.4-fold and ∼3.9-fold in subsarcolemmal and intermyofibrillar mitochondria, respectively, in the AER conditions. Within the mitochondria, the interaction of p53 with mtDNA at the D-loop and with Tfam was elevated by ∼4.6-fold and ∼3.6-fold, respectively, in the AER group. In the absence of p53, the enhanced COX-I mRNA content observed with AE and AER was abrogated. This study is the first to indicate that endurance exercise can signal to localize p53 to the mitochondria where it may serve to positively modulate the activity of the mitochondrial transcription factor Tfam. Our findings help us understand the mechanisms underlying the effects of exercise as a therapeutic intervention designed to trigger the pro-metabolic functions of p53. PMID:23690562

  12. The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis

    PubMed Central

    Gurd, Brendon J; Yoshida, Yuko; Lally, James; Holloway, Graham P; Bonen, Arend

    2009-01-01

    Deacetylation of PGC-1α by SIRT1 is thought to be an important step in increasing PGC-1α transcriptional activity, since in muscle cell lines SIRT1 induces PGC-1α protein expression and mitochondrial biogenesis. We examined the relationship between SIRT1 protein and activity, PGC-1α and markers of mitochondrial density, (a) across a range of metabolically heterogeneous skeletal muscles and the heart, and when mitochondrial biogenesis was stimulated by (b) chronic muscle stimulation (7 days) and (c) AICAR administration (5 days), and finally, (d) we also examined the effects of SIRT1 overexpression on mitochondrial biogenesis and PGC-1α. SIRT1 protein and activity were correlated (r= 0.97). There were negative correlations between SIRT1 protein and PGC-1α (r=−0.95), COX IV (r=−0.94) and citrate synthase (r=−0.97). Chronic muscle stimulation and AICAR upregulated PGC-1α protein (22–159%) and oxidative capacity (COX IV, 20–69%); in each instance SIRT1 protein was downregulated by 20–40%, while SIRT1 intrinsic activity was increased. SIRT1 overexpression in rodent muscle increased SIRT1 protein (+240%) and doubled SIRT1 activity, but PGC-1α (−25%), mtTFA (−14%) and COX IV (−10%) proteins were downregulated. Taken altogether these experiments are not consistent with the notion that SIRT1 protein plays an obligatory regulatory role in the process of PGC-1α-mediated mitochondrial biogenesis in mammalian muscle. PMID:19237425

  13. Chromosomal localization of mitochondrial transcription factor A (TCF6), single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG), three human housekeeping genes involving in mitochondrial biogenesis

    SciTech Connect

    Tiranti, V.; Rossi, G.; DiDonato, S.

    1995-01-20

    By using a PCR-based screening of a somatic cell hybrid panel and FISH, we have assigned the loci of mitochondrial single-stranded DNA-binding protein (SSBP), mitochondrial transcription factor A (TCF6), and mitochondrial endonuclease G (ENDOG) genes to human chromosomes 7q34, 10q21, and 9q34.1, respectively. The products of these three genes are involved in fundamental aspects of mitochondrial biogenesis, such as replication and transcription of the mitochondrial genome. The chromosomal localization of these genes is important to testing whether the corresponding proteins may play a role in the etiopathogenesis of human disorders associated with qualitative or quantitative abnormalities of mitochondrial DNA. 20 refs., 1 fig., 2 tabs.

  14. Exercise-induced asthma (image)

    MedlinePLUS

    Exercise-induced asthma is distinct from allergic asthma in that it does not produce long-term increase ... activity. People who only experience asthma when they exercise may be able to control their symptoms with ...

  15. Exercise-Induced Bronchoconstriction Quiz

    MedlinePLUS

    ... avoid exercise because of bad experiences as a child. Question 3 Pick the sport that is least likely to trigger exercise-induced bronchoconstriction: Soccer Distance running Baseball Cross country skiing Baseball: Sports ...

  16. Exercise-induced asthma.

    PubMed

    Mahler, D A

    1993-05-01

    Bronchoconstriction associated with exercise can occur in nearly all individuals with asthma and in 35-40% of those with allergic rhinitis/hay fever symptoms. This represents approximately 12-15% of the population. Exercise-induced asthma (EIA) is a clinical syndrome characterized by transient airflow obstruction typically 5-15 min after cessation of physical exertion. Symptoms may include chest tightness, breathlessness, coughing, and/or wheezing. Some individuals may experience delayed bronchoconstriction (late phase response) 6-10 h after completing exercise. Approximately 40-50% of those with asthma exhibit a "refractory period", i.e., diminished bronchoconstriction to exercise performed within 2 h. The pathophysiology of EIA is related to thermal events within the intrathoracic airways. Alterations in the temperature of the airways and/or osmolarity in the epithelial lining fluid cause release of mediators in the airways and the development of bronchoconstriction. Although EIA can be strongly suspected by an appropriate history, pulmonary function testing is necessary to make a specific diagnosis. Measurement of lung function is an important first diagnostic test. If there is no evidence of airflow obstruction at rest, then either bronchoprovocation testing or exercise challenge testing is indicated. Nonpharmacologic therapy includes "warm-up" exercise prior to training or competition to induce a "refractory period" and to prevent/reduce bronchoconstriction. An inhaled beta 2-adrenergic agonist, e.g., albuterol, is usually effective for preventing/treating EIA. Cromolyn sodium is an alternative class of medication that inhibits both the early and late phase responses. Other bronchodilator agents are available if combination therapy with an inhaled beta 2-adrenergic agonist and cromolyn sodium is not effective.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8492682

  17. Sam50 Functions in Mitochondrial Intermembrane Space Bridging and Biogenesis of Respiratory Complexes

    PubMed Central

    Ott, Christine; Ross, Katharina; Straub, Sebastian; Thiede, Bernd; Götz, Monika; Goosmann, Christian; Krischke, Markus; Mueller, Martin J.; Krohne, Georg

    2012-01-01

    Mitochondria possess an outer membrane (OMM) and an inner membrane (IMM), which folds into invaginations called cristae. Lipid composition, membrane potential, and proteins in the IMM influence organization of cristae. Here we show an essential role of the OMM protein Sam50 in the maintenance of the structure of cristae. Sam50 is a part of the sorting and assembly machinery (SAM) necessary for the assembly of β-barrel proteins in the OMM. We provide evidence that the SAM components exist in a large protein complex together with the IMM proteins mitofilin and CHCHD3, which we term the mitochondrial intermembrane space bridging (MIB) complex. Interactions between OMM and IMM components of the MIB complex are crucial for the preservation of cristae. After destabilization of the MIB complex, we observed deficiency in the assembly of respiratory chain complexes. Long-term depletion of Sam50 influences the amounts of proteins from all large respiratory complexes that contain mitochondrially encoded subunits, pointing to a connection between the structural integrity of cristae, assembly of respiratory complexes, and/or the maintenance of mitochondrial DNA (mtDNA). PMID:22252321

  18. The CDP-Ethanolamine Pathway Regulates Skeletal Muscle Diacylglycerol Content and Mitochondrial Biogenesis without Altering Insulin Sensitivity.

    PubMed

    Selathurai, Ahrathy; Kowalski, Greg M; Burch, Micah L; Sepulveda, Patricio; Risis, Steve; Lee-Young, Robert S; Lamon, Severine; Meikle, Peter J; Genders, Amanda J; McGee, Sean L; Watt, Matthew J; Russell, Aaron P; Frank, Matthew; Jackowski, Suzanne; Febbraio, Mark A; Bruce, Clinton R

    2015-05-01

    Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. WhilePtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis. PMID:25955207

  19. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells.

    PubMed

    Zhu, Lu; Liu, Zhongbo; Feng, Zhihui; Hao, Jiejie; Shen, Weili; Li, Xuesen; Sun, Lijuan; Sharman, Edward; Wang, Ying; Wertz, Karin; Weber, Peter; Shi, Xianglin; Liu, Jiankang

    2010-11-01

    Studies in this laboratory have previously shown that hydroxytyrosol, the major antioxidant polyphenol in olives, protects ARPE-19 human retinal pigment epithelial cells from oxidative damage induced by acrolein, an environmental toxin and endogenous end product of lipid oxidation, that occurs at increased levels in age-related macular degeneration lesions. A proposed mechanism for this is that protection by hydroxytyrosol against oxidative stress is conferred by the simultaneous activation of two critically important pathways, viz., induction of phase II detoxifying enzymes and stimulation of mitochondrial biogenesis. Cultured ARPE-19 cells were pretreated with hydroxytyrosol and challenged with acrolein. The protective effects of hydroxytyrosol on key factors of mitochondrial biogenesis and phase II detoxifying enzyme systems were examined. Hydroxytyrosol treatment simultaneously protected against acrolein-induced inhibition of nuclear factor-E2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor coactivator 1 alpha (PPARGC1?) in ARPE-19 cells. The activation of Nrf2 led to activation of phase II detoxifying enzymes, including ?-glutamyl-cysteinyl-ligase, NADPH (nicotinamide adenine dinucleotide phosphate)-quinone-oxidoreductase 1, heme-oxygenase-1, superoxide dismutase, peroxiredoxin and thioredoxin as well as other antioxidant enzymes, while the activation of PPARGC1? led to increased protein expression of mitochondrial transcription factor A, uncoupling protein 2 and mitochondrial complexes. These results suggest that hydroxytyrosol is a potent inducer of phase II detoxifying enzymes and an enhancer of mitochondrial biogenesis. Dietary supplementation of hydroxytyrosol may contribute to eye health by preventing the degeneration of retinal pigment epithelial cells induced by oxidative stress. PMID:20149621

  20. A Cardiac-Specific Robotized Cellular Assay Identified Families of Human Ligands as Inducers of PGC-1? Expression and Mitochondrial Biogenesis

    PubMed Central

    Ruiz, Matthieu; Courilleau, Delphine; Jullian, Jean-Christophe; Fortin, Dominique; Ventura-Clapier, Rene; Blondeau, Jean-Paul; Garnier, Anne

    2012-01-01

    Background Mitochondrial function is dramatically altered in heart failure (HF). This is associated with a decrease in the expression of the transcriptional coactivator PGC-1?, which plays a key role in the coordination of energy metabolism. Identification of compounds able to activate PGC-1? transcription could be of future therapeutic significance. Methodology/Principal Findings We thus developed a robotized cellular assay to screen molecules in order to identify new activators of PGC-1? in a cardiac-like cell line. This screening assay was based on both the assessment of activity and gene expression of a secreted luciferase under the control of the human PGC-1? promoter, stably expressed in H9c2 cells. We screened part of a library of human endogenous ligands and steroid hormones, B vitamins and fatty acids were identified as activators of PGC-1? expression. The most responsive compounds of these families were then tested for PGC-1? gene expression in adult rat cardiomyocytes. These data highly confirmed the primary screening, and the increase in PGC-1? mRNA correlated with an increase in several downstream markers of mitochondrial biogenesis. Moreover, respiration rates of H9c2 cells treated with these compounds were increased evidencing their effectiveness on mitochondrial biogenesis. Conclusions/Significance Using our cellular reporter assay we could identify three original families, able to activate mitochondrial biogenesis both in cell line and adult cardiomyocytes. This first screening can be extended to chemical libraries in order to increase our knowledge on PGC-1? regulation in the heart and to identify potential therapeutic compounds able to improve mitochondrial function in HF. PMID:23056435

  1. Suppressing the activity of ERR? in 3T3-L1 adipocytes reduces mitochondrial biogenesis but enhances glycolysis and basal glucose uptake

    PubMed Central

    Nie, Yaohui; Wong, Chiwai

    2009-01-01

    Estrogen-related receptor ? (ERR?) is thought to primarily regulate lipid oxidation and control the transcription of genes in the oxidative phosphorylation pathway in skeletal and cardiac muscles. However, its role in white adipose tissue is not well studied. In this study, we aimed to establish a role for ERR? in adipocytes by down-regulating its activity through its inverse agonist XCT-790 in differentiated 3T3-L1 adipocytes. We found that XCT-790 differentially reduced the expression of ERR? target genes. Specifically, XCT-790 reduced the expressions of peroxisome proliferator-activated receptor ? co-activator-1? (PGC-1?), resulting in reductions of mitochondrial biogenesis, adiogenesis and lipogeneis. Through suppressing the expression of another ERR? target gene pyruvate dehydrogenase kinase 2 (PDK2), we found that XCT-790 not only enhanced the conversion of pyruvate to acetyl-CoA and hyper-activated the tricarboxylic acid (TCA) cycle, but also led to higher levels of mitochondrial membrane potential and reactive oxidant species (ROS) production. Additionally, XCT-790 treatment also resulted in enhanced rates of glycolysis and basal glucose uptake. Therefore, ERR? stands at the crossroad of glucose and fatty acid utilization and acts as a homeostatic switch to regulate the flux of TCA cycle, mitochondrial membrane potential and glycolysis to maintain a steady level of ATP production, particularly, when mitochondrial biogenesis is reduced. PMID:18544047

  2. Mitochondria in exercise-induced oxidative stress.

    PubMed

    Di Meo, S; Venditti, P

    2001-01-01

    In recent years it has been suggested that reactive oxygen species (ROS) are involved in the damage to muscle and other tissues induced by acute exercise. Despite the small availability of direct evidence for ROS production during exercise, there is an abundance of literature providing indirect support that oxidative stress occurs during exercise. The electron transport associated with the mitochondrial respiratory chain is considered the major process leading to ROS production at rest and during exercise. It is widely assumed that during exercise the increased electron flow through the mitochondrial electron transport chain leads to an increased rate of ROS production. On the other hand, results obtained by in vitro experiments indicate that mitochondrial ROS production is lower in state 3 (ADP-stimulated) than in state 4 (basal) respiration. It is possible, however, that factors, such as temperature, that are modified in vivo during intense physical activity induce changes (uncoupling associated with loss of cytochrome oxidase activity) leading to increased ROS production. The mitochondrial respiratory chain could also be a potential source of ROS in tissues, such as liver, kidney and nonworking muscles, that during exercise undergo partial ischemia because of reduced blood supply. Sufficient oxygen is available to interact with the increasingly reduced respiratory chain and enhance the ROS generation. At the cessation of exercise, blood flow to hypoxic tissues resumes leading to their reoxygenation. This mimics the ischemia-reperfusion phenomenon, which is known to cause excessive production of free radicals. Apart from a theoretical rise in ROS, there is little evidence that exercise-induced oxidative stress is due to its increased mitochondrial generation. On the other hand, if mitochondrial production of ROS supplies a remarkable contribution to exercise-induced oxidative stress, mitochondria should be a primary target of oxidative damage. Unfortunately, there are controversial reports concerning the exercise effects on structural and functional characteristics of mitochondria. However, the isolation of mitochondrial fractions by differential centrifugation has shown that the amount of damaged mitochondria, recovered in the lightest fraction, is remarkably increased by long-lasting exercise. PMID:11223645

  3. Effects of Nitric Oxide Synthase Inhibition on Fiber-Type Composition, Mitochondrial Biogenesis, and SIRT1 Expression in Rat Skeletal Muscle.

    PubMed

    Suwa, Masataka; Nakano, Hiroshi; Radak, Zsolt; Kumagai, Shuzo

    2015-09-01

    It was hypothesized that nitric oxide synthases (NOS) regulated SIRT1 expression and lead to a corresponding changes of contractile and metabolic properties in skeletal muscle. The purpose of the present study was to investigate the influence of long-term inhibition of nitric oxide synthases (NOS) on the fiber-type composition, metabolic regulators such as and silent information regulator of transcription 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and components of mitochondrial biogenesis in the soleus and plantaris muscles of rats. Rats were assigned to two groups: control and NOS inhibitor (N (ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), ingested for 8 weeks in drinking water)-treated groups. The percentage of Type I fibers in the L-NAME group was significantly lower than that in the control group, and the percentage of Type IIA fibers was concomitantly higher in soleus muscle. In plantaris muscle, muscle fiber composition was not altered by L-NAME treatment. L-NAME treatment decreased the cytochrome C protein expression and activity of mitochondrial oxidative enzymes in the plantaris muscle but not in soleus muscle. NOS inhibition reduced the SIRT1 protein expression level in both the soleus and plantaris muscles, whereas it did not affect the PGC-1α protein expression. L-NAME treatment also reduced the glucose transporter 4 protein expression in both muscles. These results suggest that NOS plays a role in maintaining SIRT1 protein expression, muscle fiber composition and components of mitochondrial biogenesis in skeletal muscle. Key pointsNOS inhibition by L-NAME treatment decreased the SIRT1 protein expression in skeletal muscle.NOS inhibition induced the Type I to Type IIA fiber type transformation in soleus muscle.NOS inhibition reduced the components of mitochondrial biogenesis and glucose metabolism in skeletal muscle. PMID:26336341

  4. Effects of Nitric Oxide Synthase Inhibition on Fiber-Type Composition, Mitochondrial Biogenesis, and SIRT1 Expression in Rat Skeletal Muscle

    PubMed Central

    Suwa, Masataka; Nakano, Hiroshi; Radak, Zsolt; Kumagai, Shuzo

    2015-01-01

    It was hypothesized that nitric oxide synthases (NOS) regulated SIRT1 expression and lead to a corresponding changes of contractile and metabolic properties in skeletal muscle. The purpose of the present study was to investigate the influence of long-term inhibition of nitric oxide synthases (NOS) on the fiber-type composition, metabolic regulators such as and silent information regulator of transcription 1 (SIRT1) and peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), and components of mitochondrial biogenesis in the soleus and plantaris muscles of rats. Rats were assigned to two groups: control and NOS inhibitor (N?-nitro-L-arginine methyl ester hydrochloride (L-NAME), ingested for 8 weeks in drinking water)-treated groups. The percentage of Type I fibers in the L-NAME group was significantly lower than that in the control group, and the percentage of Type IIA fibers was concomitantly higher in soleus muscle. In plantaris muscle, muscle fiber composition was not altered by L-NAME treatment. L-NAME treatment decreased the cytochrome C protein expression and activity of mitochondrial oxidative enzymes in the plantaris muscle but not in soleus muscle. NOS inhibition reduced the SIRT1 protein expression level in both the soleus and plantaris muscles, whereas it did not affect the PGC-1? protein expression. L-NAME treatment also reduced the glucose transporter 4 protein expression in both muscles. These results suggest that NOS plays a role in maintaining SIRT1 protein expression, muscle fiber composition and components of mitochondrial biogenesis in skeletal muscle. Key points NOS inhibition by L-NAME treatment decreased the SIRT1 protein expression in skeletal muscle. NOS inhibition induced the Type I to Type IIA fiber type transformation in soleus muscle. NOS inhibition reduced the components of mitochondrial biogenesis and glucose metabolism in skeletal muscle. PMID:26336341

  5. 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-? coactivator 1-? (PGC-1?) 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. PMID:26519208

  6. Exercise-induced metabolic fluctuations influence AMPK, p38-MAPK and CaMKII phosphorylation in human skeletal muscle

    PubMed Central

    Combes, Adrien; Dekerle, Jeanne; Webborn, Nick; Watt, Peter; Bougault, Valérie; Daussin, Frédéric N

    2015-01-01

    During transition from rest to exercise, metabolic reaction rates increase substantially to sustain intracellular ATP use. These metabolic demands activate several kinases that initiate signal transduction pathways which modulate transcriptional regulation of mitochondrial biogenesis. The purpose of this study was to determine whether metabolic fluctuations per se affect the signaling cascades known to regulate peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). On two separate occasions, nine men performed a continuous (30-min) and an intermittent exercise (30 × 1-min intervals separated by 1-min of recovery) at 70% of . Skeletal muscle biopsies from the vastus lateralis were taken at rest and at +0 h and +3 h after each exercise. Metabolic fluctuations that correspond to exercise-induced variation in metabolic rates were determined by analysis of VO2 responses. During intermittent exercise metabolic fluctuations were 2.8-fold higher despite identical total work done to continuous exercise (317 ± 41 vs. 312 ± 56 kJ after intermittent and continuous exercise, respectively). Increased phosphorylation of AMP-activated protein kinase (AMPK) (˜2.9-fold, P < 0.01), calcium/calmodulin-dependent protein kinase II (CaMKII) (˜2.7-fold, P < 0.01) and p38-mitogen-activated protein kinase (MAPK) (˜4.2-fold, P < 0.01) occurred immediately in both exercises and to a greater extent after the intermittent exercise (condition x time interaction, P < 0.05). A single bout of intermittent exercise induces a greater activation of these signaling pathways regulating PGC-1α when compared to a single bout of continuous exercise of matched work and intensity. Chronic adaptations to exercise on mitochondria biogenesis are yet to be investigated. PMID:26359238

  7. Adolescents and Exercise Induced Asthma

    ERIC Educational Resources Information Center

    Hansen, Pamela; Bickanse, Shanna; Bogenreif, Mike; VanSickle, Kyle

    2008-01-01

    This article defines asthma and exercise induced asthma, and provides information on the triggers, signs, and symptoms of an attack. It also gives treatments for these conditions, along with prevention guidelines on how to handle an attack in the classroom or on the practice field. (Contains 2 tables and 1 figure.)

  8. Overexpression of human selenoprotein H in neuronal cells enhances mitochondrial biogenesis and function through activation of protein kinase A, protein kinase B, and cyclic adenosine monophosphate response element-binding protein pathway

    PubMed Central

    Mehta, Suresh L.; Mendelev, Natalia; Kumari, Santosh; Li, P. Andy

    2013-01-01

    Mitochondrial biogenesis is activated by nuclear encoded transcription co-activator peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), which is regulated by several upstream factors including protein kinase A and Akt/protein kinase B. We have previously shown that selenoprotein H enhances the levels of nuclear regulators for mitochondrial biogenesis, increases mitochondrial mass and improves mitochondrial respiratory rate, under physiological condition. Furthermore, overexpression of selenoprotein H protects neuronal HT22 cells from ultraviolet B irradiation-induced cell damage by lowering reactive oxygen species production, and inhibiting activation of caspase-3 and -9, as well as p53. The objective of this study is to identify the cell signaling pathways by which selenoprotein H initiates mitochondrial biogenesis. We first confirmed our previous observation that selenoprotein H transfected HT22 cells increased the protein levels of nuclear-encoded mitochondrial biogenesis factors, peroxisome proliferator–activated receptor γ coactivator-1α, nuclear respiratory factor 1 and mitochondrial.transcription factor A, We then observed that total and phosphorylation of protein kinase A, Akt/protein kinase B and cyclic adenosine monophosphate response element-binding protein (CREB) were significantly increased in selenoprotein H transfected cells compared to vector transfected HT22 cells. To verify whether the observed stimulating effects on mitochondrial biogenesis pathways are caused by selenoprotein H and mediated through CREB, we knocked down selenoprotein H mRNA level using siRNA and inhibited CREB with napthol AS-E phosphate in selenoprotein H transfected cells and repeated the measurements of the aforementioned biomarkers. Our results revealed that silencing of selenoprotein H not only decreased the protein levels of PGC-1α, nuclear respiratory factor 1 and mitochondrial transcription factor A, but also decreased the total and phosphorylation levels of protein kinase A, protein kinase B, and CREB. Similarly, CREB inhibition reduced CREB activation and PGC-1α protein levels in selenoprotein H transfected cells. Moreover, selenoprotein H transfection increased the activity of mitochondrial complexes and prevented the ultraviolet B induced fall of mitochondrial membrane potential. We conclude that the effects of selenoprotein H on mitochondrial biogenesis and mitochondrial function are probably mediated through protein kinase A- CREB- PGC-1α and Akt/proetin kinase B- CREB- PGC-1α pathways. PMID:23220172

  9. Conjugated linoleic acid (CLA) stimulates mitochondrial biogenesis signaling by the upregulation of PPAR? coactivator 1? (PGC-1?) in C2C12 cells.

    PubMed

    Kim, Yoo; Park, Yeonhwa

    2015-04-01

    Along with its effect on body fat reduction, dietary conjugated linoleic acid (CLA) has been reported to improve physical activity and endurance capacity in mice. It has been suggested these effects may in part be due to physiological changes in skeletal muscle, however, the mode of action is not completely understood. Thus, the purpose of this study was to determine the relevant mechanisms of CLA isomers for mitochondrial biogenesis, one of the most important adaptive responses in skeletal muscle. Both cis-9,trans-11 (c9,t11) and trans-10,cis-12 (t10,c12) CLA isomers increased the expression of peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?), however, only the t10,c12 isomer, but not c9,t11, increased phosphorylation of AMP-activated protein kinase (AMPK) compared to the control. Among downstream biomarkers of PGC-1?, the CLA mixed isomer enhanced the expression of peroxisome proliferator-activated receptor-? (PPAR?). Both c9,t11 and t10,c12 CLA isomers increased expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (Tfam), while the c9,t11 increased expression of cytochrome c (Cyt C) and t10,c12 CLA increased expression of voltage-dependent anion channel (VDAC), respectively. Both CLA isomers significantly increased mitochondrial DNA copy number compared to that of control. These findings suggest that the individual CLA isomers potentiate mitochondrial biogenesis via PGC-1?-NRF-1-Tfam signaling cascade, although downstream regulation may be isomer dependent. PMID:25720738

  10. Relative abundance of the human mitochondrial transcription system and distinct roles for h-mtTFB1 and h-mtTFB2 in mitochondrial biogenesis and gene expression.

    PubMed

    Cotney, Justin; Wang, Zhibo; Shadel, Gerald S

    2007-01-01

    Human mitochondrial transcription requires the bacteriophage-related RNA polymerase, POLRMT, the mtDNA-binding protein, h-mtTFA/TFAM, and two transcription factors/rRNA methyltransferases, h-mtTFB1 and h-mtTFB2. Here, we determined the steady-state levels of these core transcription components and examined the consequences of purposeful elevation of h-mtTFB1 or h-mtTFB2 in HeLa cells. On a per molecule basis, we find an approximately 6-fold excess of POLRMT to mtDNA and approximately 3-fold more h-mtTFB2 than h-mtTFB1. We also estimate h-mtTFA at approximately 50 molecules/mtDNA, a ratio predicted to support robust transcription, but not to coat mtDNA. Consistent with a role for h-mtTFB2 in transcription and transcription-primed replication, increased mitochondrial DNA and transcripts result from its over-expression. This is accompanied by increased translation rates of most, but not all mtDNA-encoded proteins. Over-expression of h-mtTFB1 did not significantly influence these parameters, but did result in increased mitochondrial biogenesis. Furthermore, h-mtTFB1 mRNA and protein are elevated in response to h-mtTFB2 over-expression, suggesting the existence of a retrograde signal to the nucleus to coordinately regulate expression of these related factors. Altogether, our results provide a framework for understanding the regulation of human mitochondrial transcription in vivo and define distinct roles for h-mtTFB1 and h-mtTFB2 in mitochondrial biogenesis and gene expression that together likely fine-tune mitochondrial function. PMID:17557812

  11. Dietary Fucoxanthin Increases Metabolic Rate and Upregulated mRNA Expressions of the PGC-1alpha Network, Mitochondrial Biogenesis and Fusion Genes in White Adipose Tissues of Mice

    PubMed Central

    Wu, Meng-Ting; Chou, Hong-Nong; Huang, Ching-jang

    2014-01-01

    The mechanism for how fucoxanthin (FX) suppressed adipose accumulation is unclear. We aim to investigate the effects of FX on metabolic rate and expressions of genes related to thermogenesis, mitochondria biogenesis and homeostasis. Using a 2 2 factorial design, four groups of mice were respectively fed a high sucrose (50% sucrose) or a high-fat diet (23% butter + 7% soybean oil) supplemented with or without 0.2% FX. FX significantly increased oxygen consumption and carbon dioxide production and reduced white adipose tissue (WAT) mass. The mRNA expressions of peroxisome proliferator-activated receptor (PPAR) ? coactivator-1? (PGC-1?), cell death-inducing DFFA-like effecter a (CIDEA), PPAR?, PPAR?, estrogen-related receptor ? (ERR?), ?3-adrenergic receptor (?3-AR) and deiodinase 2 (Dio2) were significantly upregulated in inguinal WAT (iWAT) and epididymal WAT (eWAT) by FX. Mitochondrial biogenic genes, nuclear respiratory factor 1 (NRF1) and NRF2, were increased in eWAT by FX. Noticeably, FX upregulated genes of mitochondrial fusion, mitofusin 1 (Mfn1), Mfn2 and optic atrophy 1 (OPA1), but not mitochondrial fission, Fission 1, in both iWAT and eWAT. In conclusion, dietary FX enhanced the metabolic rate and lowered adipose mass irrespective of the diet. These were associated with upregulated genes of the PGC-1? network and mitochondrial fusion in eWAT and iWAT. PMID:24534841

  12. Dietary fucoxanthin increases metabolic rate and upregulated mRNA expressions of the PGC-1alpha network, mitochondrial biogenesis and fusion genes in white adipose tissues of mice.

    PubMed

    Wu, Meng-Ting; Chou, Hong-Nong; Huang, Ching-jang

    2014-02-01

    The mechanism for how fucoxanthin (FX) suppressed adipose accumulation is unclear. We aim to investigate the effects of FX on metabolic rate and expressions of genes related to thermogenesis, mitochondria biogenesis and homeostasis. Using a 2 2 factorial design, four groups of mice were respectively fed a high sucrose (50% sucrose) or a high-fat diet (23% butter + 7% soybean oil) supplemented with or without 0.2% FX. FX significantly increased oxygen consumption and carbon dioxide production and reduced white adipose tissue (WAT) mass. The mRNA expressions of peroxisome proliferator-activated receptor (PPAR) ? coactivator-1? (PGC-1?), cell death-inducing DFFA-like effecter a (CIDEA), PPAR?, PPAR?, estrogen-related receptor ? (ERR?), ?3-adrenergic receptor (?3-AR) and deiodinase 2 (Dio2) were significantly upregulated in inguinal WAT (iWAT) and epididymal WAT (eWAT) by FX. Mitochondrial biogenic genes, nuclear respiratory factor 1 (NRF1) and NRF2, were increased in eWAT by FX. Noticeably, FX upregulated genes of mitochondrial fusion, mitofusin 1 (Mfn1), Mfn2 and optic atrophy 1 (OPA1), but not mitochondrial fission, Fission 1, in both iWAT and eWAT. In conclusion, dietary FX enhanced the metabolic rate and lowered adipose mass irrespective of the diet. These were associated with upregulated genes of the PGC-1? network and mitochondrial fusion in eWAT and iWAT. PMID:24534841

  13. Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes.

    PubMed

    Biala, Agnieszka; Tauriainen, Eveliina; Siltanen, Antti; Shi, Jin; Merasto, Saara; Louhelainen, Marjut; Martonen, Essi; Finckenberg, Piet; Muller, Dominik N; Mervaala, Eero

    2010-06-01

    There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis. PMID:20429690

  14. Activation of the iron regulon by the yeast Aft1/Aft2 transcription factors depends on mitochondrial but not cytosolic iron-sulfur protein biogenesis.

    PubMed

    Rutherford, Julian C; Ojeda, Luis; Balk, Janneke; Mhlenhoff, Ulrich; Lill, Roland; Winge, Dennis R

    2005-03-18

    Two transcriptional activators, Aft1 and Aft2, regulate iron homeostasis in Saccharomyces cerevisiae. These factors induce the expression of iron regulon genes in iron-deficient yeast but are inactivated in iron-replete cells. Iron inhibition of Aft1/Aft2 is abrogated in cells defective for Fe-S cluster biogenesis within the mitochondrial matrix (Chen, O. S., Crisp, R. J., Valachovic, M., Bard, M., Winge, D. R., and Kaplan, J. (2004) J. Biol. Chem. 279, 29513-29518). To determine whether iron sensing by Aft1/Aft2 requires the function of the mitochondrial Fe-S export and cytosolic Fe-S protein assembly systems, we evaluated the expression of the iron regulon in cells depleted of glutathione and in cells depleted of Atm1, Nar1, Cfd1, and Nbp35. The iron regulon is induced in cells depleted of Atm1 with Aft1 largely responsible for the induced gene expression. Aft2 is activated at a later time in Atm1-depleted cells. Likewise, the iron regulon is induced in cells depleted of glutathione. In contrast, repression of NAR1, CFD1, or NBP35 fails to induce the iron regulon despite strong inhibition of cytosolic/nuclear Fe-S protein assembly. Thus, iron sensing by Aft1/Aft2 is not linked to the maturation of cytosolic/nuclear Fe-S proteins, but the mitochondrial inner membrane transporter Atm1 is important to transport the inhibitory signal. Although Aft1 and Aft2 sense a signal emanating from the Fe-S cluster biogenesis pathway, there is no indication that the proteins are inhibited by direct binding of an Fe-S cluster. PMID:15649888

  15. Maternal stress predicts altered biogenesis and the profile of mitochondrial proteins in the frontal cortex and hippocampus of adult offspring rats.

    PubMed

    Głombik, Katarzyna; Stachowicz, Aneta; Ślusarczyk, Joanna; Trojan, Ewa; Budziszewska, Bogusława; Suski, Maciej; Kubera, Marta; Lasoń, Władysław; Wędzony, Krzysztof; Olszanecki, Rafał; Basta-Kaim, Agnieszka

    2015-10-01

    Currently, much attention is focused on the influence of mitochondrial disturbances at the onset of depression. The goal of this study was to investigate the impact of prenatal stress (an animal model of depression) on the mitochondrial biogenesis proteins and mitoproteome profile in the frontal cortex and hippocampus of adult 3-month-old male rats following a prenatal stress procedure. Our results show that rats that were exposed to prenatal stress stimuli displayed depression-like behaviors based on the sucrose preference and elevated plus maze tests. It has been found that the level of the PGC-1α protein was reduced in the frontal cortex and hippocampus of the adult offspring after the prenatal stress procedure. Moreover, in the frontal cortex, the level of the pro-apoptotic protein Bax was up-regulated. Two-dimensional electrophoresis coupled with mass spectrometry showed the statistically significant down-regulation of the mitochondrial ribosomal protein L12 (Mrpl12) and mitochondrial NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2) as well as the up-regulation of the Tubulin Polymerization Promoting Proteins (Tppp/p25) in the frontal cortex. In contrast, in the hippocampus, the mitochondrial pyruvate dehydrogenase E1 component subunit beta, the voltage-dependent anion-selective channel protein 2 (VDAC2), and the GTP-binding nuclear protein RAN (RAN) were down-regulated and the expression of phosphatidylethanolamine-binding protein 1 (PEBP-1) was enhanced. These findings provide new evidence that stress during pregnancy may lead not only to behavioral deficits, but also to disturbances in the brain mitoproteome profile in adult rat offspring. PMID:26143539

  16. OM2, a Novel Oligomannuronate-Chromium(III) Complex, Promotes Mitochondrial Biogenesis and Lipid Metabolism in 3T3-L1 Adipocytes via the AMPK-PGC1α Pathway

    PubMed Central

    Hao, Jiejie; Hao, Cui; Zhang, Lijuan; Liu, Xin; Zhou, Xiaolin; Dun, Yunlou; Li, Haihua; Li, Guangsheng; Zhao, Xiaoliang; An, Yuanyuan; Liu, Jiankang; Yu, Guangli

    2015-01-01

    Background In our previous studies, we prepared novel oligomannuronate-chromium(III) complexes (OM2, OM4) from marine alginate, and found that these compounds sensitize insulin action better than oligomannuronate(OM), chromium, and metformin in C2C12 skeletal muscle cells. In the present study, we studied their effects on mitochondrial biogenesis, lipid metabolism, and the underlying molecular mechanisms in differentiated 3T3-L1 adipocytes. Methodology/Principal Findings We firstly used the pGL3-PGC1α and pGL3-ATGL promoter plasmids to compare their effects on PGC1α and ATGL transcription activities. Then mitochondrial biogenesis was quantified by transmission electron microscopy and MitoTracker staining. Mitochondrial oxygen consumption and fatty acid oxidation were measured by an oxygen biosensor system and ³H-labelled water scintillation. The mitochondrial DNA and mRNA involved in mitochondrial biogenesis and lipid oxidation were evaluated by real-time PCR. AMPK together with other protein expression levels were measured by western blotting. The inhibitor compound C and siRNA of PGC1α were used to inhibit the OM2-induced AMPK-PGC1α signaling pathway. And we found that OM2 stimulated AMPK-PGC1α pathway in the 3T3-L1 adipocytes, which were correlated with induced mitochondrial biogenesis, improved mitochondrial function, and reduced lipid accumulation by enhanced fatty acid β-oxidation and augmented ATGL protein expression. Conclusions/Significance Our data indicated that the marine oligosaccharide-derived OM2 might represent a novel class of molecules that could be useful for type 2 diabetes prevention and treatment by up-regulating AMPK-PGC1α signaling pathway. PMID:26176781

  17. PPR2263, a DYW-Subgroup Pentatricopeptide Repeat Protein, Is Required for Mitochondrial nad5 and cob Transcript Editing, Mitochondrion Biogenesis, and Maize Growth[C][W

    PubMed Central

    Sosso, Davide; Mbelo, Sylvie; Vernoud, Vanessa; Gendrot, Ghislaine; Dedieu, Annick; Chambrier, Pierre; Dauzat, Myriam; Heurtevin, Laure; Guyon, Virginie; Takenaka, Mizuki; Rogowsky, Peter M.

    2012-01-01

    RNA editing plays an important role in organelle gene expression in various organisms, including flowering plants, changing the nucleotide information at precise sites. Here, we present evidence that the maize (Zea mays) nuclear gene Pentatricopeptide repeat 2263 (PPR2263) encoding a DYW domain–containing PPR protein is required for RNA editing in the mitochondrial NADH dehydrogenase5 (nad5) and cytochrome b (cob) transcripts at the nad5-1550 and cob-908 sites, respectively. Its putative ortholog, MITOCHONDRIAL EDITING FACTOR29, fulfills the same role in Arabidopsis thaliana. Both the maize and the Arabidopsis proteins show preferential localization to mitochondria but are also detected in chloroplasts. In maize, the corresponding ppr2263 mutation causes growth defects in kernels and seedlings. Embryo and endosperm growth are reduced, leading to the production of small but viable kernels. Mutant plants have narrower and shorter leaves, exhibit a strong delay in flowering time, and generally do not reach sexual maturity. Whereas mutant chloroplasts do not have major defects, mutant mitochondria lack complex III and are characterized by a compromised ultrastructure, increased transcript levels, and the induction of alternative oxidase. The results suggest that mitochondrial RNA editing at the cob-908 site is necessary for mitochondrion biogenesis, cell division, and plant growth in maize. PMID:22319053

  18. Exercise-induced leukocyte apoptosis.

    PubMed

    Krüger, Karsten; Mooren, Frank C

    2014-01-01

    Physical exercise is well known to affect leukocyte numbers and function. While regular exercise training has been shown to enhance specific immune functions, acute bouts of intensive exercise often lead to a pro-inflammatory response accompanied by a transient lymphocytopenia and neutrophilia. It can be assumed, that lymphocytopenia can be attributed at least partially to an enhanced lymphocyte apoptosis. In contrast, regulation of neutrophil apoptosis after exercise remains controversial since studies demonstrated both an up-regulation as well as a down-regulation of cell death. However, these discrepancies may be due to differences in exercise protocols, subjects' fitness levels, and to different methodological approaches. Two major signalling pathways of exercise induced apoptosis have been identified. First the external receptor mediated pathway using death receptors, and second the internal, oxidative-mediated pathway which encompasses the mitochondria. Potential apoptosis modulating mediators are reactive oxygen species (ROS), glucocorticoids and cytokines which are part of the systemic inflammatory response evoked after acute intensive exercise. Finally, the physiological impact and clinical relevance of leukocyte apoptosis will be discussed. On the one hand, exercise-induced apoptosis might be a mechanism to remove activated and potentially autoreactive immune cells. On the other hand, apoptosis might be a regulatory mechanism which is necessary for tissue reorganization and adaptational training processes. PMID:24974724

  19. Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease.

    PubMed

    Shirendeb, Ulziibat P; Calkins, Marcus J; Manczak, Maria; Anekonda, Vishwanath; Dufour, Brett; McBride, Jodi L; Mao, Peizhong; Reddy, P Hemachandra

    2012-01-15

    The purpose of this study was to investigate the link between mutant huntingtin (Htt) and neuronal damage in relation to mitochondria in Huntington's disease (HD). In an earlier study, we determined the relationship between mutant Htt and mitochondrial dynamics/synaptic viability in HD patients. We found mitochondrial loss, abnormal mitochondrial dynamics and mutant Htt association with mitochondria in HD patients. In the current study, we sought to expand on our previous findings and further elucidate the relationship between mutant Htt and mitochondrial and synaptic deficiencies. We hypothesized that mutant Htt, in association with mitochondria, alters mitochondrial dynamics, leading to mitochondrial fragmentation and defective axonal transport of mitochondria in HD neurons. In this study, using postmortem HD brains and primary neurons from transgenic BACHD mice, we identified mutant Htt interaction with the mitochondrial protein Drp1 and factors that cause abnormal mitochondrial dynamics, including GTPase Drp1 enzymatic activity. Further, using primary neurons from BACHD mice, for the first time, we studied axonal transport of mitochondria and synaptic degeneration. We also investigated the effect of mutant Htt aggregates and oligomers in synaptic and mitochondrial deficiencies in postmortem HD brains and primary neurons from BACHD mice. We found that mutant Htt interacts with Drp1, elevates GTPase Drp1 enzymatic activity, increases abnormal mitochondrial dynamics and results in defective anterograde mitochondrial movement and synaptic deficiencies. These observations support our hypothesis and provide data that can be utilized to develop therapeutic targets that are capable of inhibiting mutant Htt interaction with Drp1, decreasing mitochondrial fragmentation, enhancing axonal transport of mitochondria and protecting synapses from toxic insults caused by mutant Htt. PMID:21997870

  20. Food related, exercise induced anaphylaxis.

    PubMed Central

    Caffarelli, C; Terzi, V; Perrone, F; Cavagni, G

    1996-01-01

    Four children under 12 years of age with food dependent, exercise induced anaphylaxis (EIAn) were investigated. These children and five controls performed exercise challenges when fasting and one hour after a meal without food suspected to predispose to the reaction. Patients then performed exercise tests after intake of each suspected food. Three out of 15 food-exercise combination challenges were positive, but no reactions were provoked after exercise without prior intake of suspected foods. Patients underwent skin prick tests to foods and serum total and specific IgE antibodies were measured. Skin prick test results were positive and RAST results were positive in two of three instances. In case 3, food-exercise combination challenges did not provoke any clinical reaction. The diagnosis of food dependent EIAn should be considered in young children with EIAn of unknown origin. PMID:8869196

  1. Dual Location of the Mitochondrial Preprotein Transporters B14.7 and Tim23-2 in Complex I and the TIM17:23 Complex in Arabidopsis Links Mitochondrial Activity and Biogenesis[C][W][OA

    PubMed Central

    Wang, Yan; Carrie, Chris; Giraud, Estelle; Elhafez, Dina; Narsai, Reena; Duncan, Owen; Whelan, James; Murcha, Monika W.

    2012-01-01

    Interactions between the respiratory chain and protein import complexes have been previously reported in Saccharomyces cerevisiae, but the biological significance of such interactions remains unknown. Characterization of two mitochondrial preprotein and amino acid transport proteins from Arabidopsis thaliana, NADH dehydrogenase B14.7 like (B14.7 [encoded by At2g42210]) and Translocase of the inner membrane subunit 23-2 (Tim23-2 [encoded by At1g72750]), revealed both proteins are present in respiratory chain complex I and the Translocase of the Inner Membrane 17:23. Whereas depletion of B14.7 by T-DNA insertion is lethal, Tim23-2 can be depleted without lethality. Subtle overexpression of Tim23-2 results in a severe delayed growth phenotype and revealed an unexpected, inverse correlation between the abundance of Tim23-2 and the abundance of respiratory complex I. This newly discovered relationship between protein import and respiratory function was confirmed through the investigation of independent complex I knockout mutants, which were found to have correspondingly increased levels of Tim23-2. This increase in Tim23-2 was also associated with delayed growth phenotypes, increased abundance of other import components, and an increased capacity for mitochondrial protein import. Analysis of the Tim23-2–overexpressing plants through global quantitation of transcript abundance and in-organelle protein synthesis assays revealed widespread alterations in transcript abundance of genes encoding mitochondrial proteins and altered rates of mitochondrial protein translation, indicating a pivotal relationship between the machinery of mitochondrial biogenesis and mitochondrial function. PMID:22730406

  2. High-resolution genomic profiling of thyroid lesions uncovers preferential copy number gains affecting mitochondrial biogenesis loci in the oncocytic variants

    PubMed Central

    Kurelac, Ivana; de Biase, Dario; Calabrese, Claudia; Ceccarelli, Claudio; Ng, Charlotte KY; Lim, Raymond; MacKay, Alan; Weigelt, Britta; Porcelli, Anna Maria; Reis-Filho, Jorge S; Tallini, Giovanni; Gasparre, Giuseppe

    2015-01-01

    Oncocytic change is the result of aberrant mitochondrial hyperplasia, which may occur in both neoplastic and non-neoplastic cells and is not infrequent in the thyroid. Despite being a well-characterized histologic phenotype, the molecular causes underlying such a distinctive cellular change are poorly understood. To identify potential genetic causes for the oncocytic phenotype in thyroid, we analyzed copy number alterations in a set of oncocytic (n=21) and non-oncocytic (n=20) thyroid lesions by high-resolution microarray-based comparative genomic hybridization (aCGH). Each group comprised lesions of diverse histologic types, including hyperplastic nodules, adenomas and carcinomas. Unsupervised hierarchical clustering of categorical aCGH data resulted in two distinct branches, one of which was significantly enriched for samples with the oncocytic phenotype, regardless of histologic type. Analysis of aCGH events showed that the oncocytic group harbored a significantly higher number of genes involved in copy number gains, when compared to that of conventional thyroid lesions. Functional annotation demonstrated an enrichment for copy number gains that affect genes encoding activators of mitochondrial biogenesis in oncocytic cases but not in their non-oncocytic counterparts. Taken together, our data suggest that genomic alterations may represent additional/alternative mechanisms underlying the development of the oncocytic phenotype in the thyroid. PMID:26269756

  3. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis.

    PubMed

    Pondarr, Corinne; Antiochos, Brendan B; Campagna, Dean R; Clarke, Stephen L; Greer, Eric L; Deck, Kathryn M; McDonald, Alice; Han, An-Ping; Medlock, Amy; Kutok, Jeffery L; Anderson, Sheila A; Eisenstein, Richard S; Fleming, Mark D

    2006-03-15

    Proteins with iron-sulfur (Fe-S) clusters participate in multiple metabolic pathways throughout the cell. The mitochondrial ABC half-transporter Abcb7, which is mutated in X-linked sideroblastic anemia with ataxia in humans, is a functional ortholog of yeast Atm1p and is predicted to export a mitochondrially derived metabolite required for cytosolic Fe-S cluster assembly. Using an inducible Cre/loxP system to delete exons 9 and 10 of the Abcb7 gene, we examined the phenotype of mice deficient in Abcb7. We found that Abcb7 was essential in extra-embryonic tissues early in gestation and that the mutant allele exhibits an X-linked parent-of-origin lethality effect. Furthermore, using X-chromosome inactivation assays and tissue-specific deletions, Abcb7 was found to be essential for the development and function of numerous other cell types and tissues. A notable exception to this was liver, where loss of Abcb7 impaired cytosolic Fe-S cluster assembly but was not lethal. In this situation, control of iron regulatory protein 1, a key cytosolic modulator of iron metabolism, which is responsive to the availability of cytosolic Fe-S clusters, was impaired and contributed to the dysregulation of hepatocyte iron metabolism. Altogether, these studies demonstrate the essential nature of Abcb7 in mammals and further substantiate a central role for mitochondria in the biogenesis of cytosolic Fe-S proteins. PMID:16467350

  4. High-resolution genomic profiling of thyroid lesions uncovers preferential copy number gains affecting mitochondrial biogenesis loci in the oncocytic variants.

    PubMed

    Kurelac, Ivana; de Biase, Dario; Calabrese, Claudia; Ceccarelli, Claudio; Ng, Charlotte Ky; Lim, Raymond; MacKay, Alan; Weigelt, Britta; Porcelli, Anna Maria; Reis-Filho, Jorge S; Tallini, Giovanni; Gasparre, Giuseppe

    2015-01-01

    Oncocytic change is the result of aberrant mitochondrial hyperplasia, which may occur in both neoplastic and non-neoplastic cells and is not infrequent in the thyroid. Despite being a well-characterized histologic phenotype, the molecular causes underlying such a distinctive cellular change are poorly understood. To identify potential genetic causes for the oncocytic phenotype in thyroid, we analyzed copy number alterations in a set of oncocytic (n=21) and non-oncocytic (n=20) thyroid lesions by high-resolution microarray-based comparative genomic hybridization (aCGH). Each group comprised lesions of diverse histologic types, including hyperplastic nodules, adenomas and carcinomas. Unsupervised hierarchical clustering of categorical aCGH data resulted in two distinct branches, one of which was significantly enriched for samples with the oncocytic phenotype, regardless of histologic type. Analysis of aCGH events showed that the oncocytic group harbored a significantly higher number of genes involved in copy number gains, when compared to that of conventional thyroid lesions. Functional annotation demonstrated an enrichment for copy number gains that affect genes encoding activators of mitochondrial biogenesis in oncocytic cases but not in their non-oncocytic counterparts. Taken together, our data suggest that genomic alterations may represent additional/alternative mechanisms underlying the development of the oncocytic phenotype in the thyroid. PMID:26269756

  5. Methyl-Arginine Profile of Brain from Aged PINK1-KO+A53T-SNCA Mice Suggests Altered Mitochondrial Biogenesis

    PubMed Central

    Auburger, Georg; Gispert, Suzana

    2016-01-01

    Hereditary Parkinson's disease can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) or the autosomal recessive deficiency of PINK1. We recently showed that the combination of PINK1-knockout with overexpression of A53T-SNCA in double mutant (DM) mice potentiates phenotypes and reduces survival. Now we studied brain hemispheres of DM mice at age of 18 months in a hypothesis-free approach, employing a quantitative label-free global proteomic mass spectrometry scan of posttranslational modifications focusing on methyl-arginine. The strongest effects were documented for the adhesion modulator CMAS, the mRNA decapping/deadenylation factor PATL1, and the synaptic plasticity mediator CRTC1/TORC1. In addition, an intriguing effect was observed for the splicing factor PSF/SFPQ, known to interact with the dopaminergic differentiation factor NURR1 as well as with DJ-1, the protein responsible for the autosomal recessive PARK7 variant of PD. CRTC1, PSF, and DJ-1 are modulators of PGC1alpha and of mitochondrial biogenesis. This pathway was further stressed by dysregulations of oxygen sensor EGLN3 and of nuclear TMPO. PSF and TMPO cooperate with dopaminergic differentiation factors LMX1B and NURR1. Further dysregulations concerned PRR18, TRIO, HNRNPA1, DMWD, WAVE1, ILDR2, DBNDD1, and NFM. Thus, we report selective novel endogenous stress responses in brain, which highlight early dysregulations of mitochondrial homeostasis and midbrain vulnerability.

  6. Posttranslational Modification of Mitochondrial Transcription Factor A in Impaired Mitochondria Biogenesis: Implications in Diabetic Retinopathy and Metabolic Memory Phenomenon

    PubMed Central

    Santos, Julia M.; Mishra, Manish; Kowluru, Renu A.

    2014-01-01

    Mitochondrial transcription factor A (TFAM) is one of the key regulators of the transcription of mtDNA. In diabetes, despite increase in gene transcripts of TFAM, its protein levels in the mitochondria are decreased and mitochondria copy numbers become subnormal. The aim of this study is to investigate the mechanism(s) responsible for decreased mitochondrial TFAM in diabetes. Using retinal endothelial cells, we have investigated the effect of overexpression of cytosolic chaperone, Hsp70, and TFAM on glucose-induced decrease in mitochondrial TFAM levels, and the transcription of mtDNA-encoded genes, NADH dehydrogenase subunit 6 (ND6) and cytochrome b (Cytb). To investigate the role of posttranslational modifications in subnormal mitochondrial TFAM, ubiquitination of TFAM was accessed, and the results were confirmed in the retina from streptozotocin-induced diabetic rats. While overexpression of Hsp70 failed to prevent glucose-induced decrease in mitochondrial TFAM and transcripts of ND6 and Cytb, overexpression of TFAM ameliorated decrease in its mitochondrial protein levels and transcriptional activity. TFAM was ubiquitinated by high glucose, and PYR-41, an inhibitor of ubiquitination, prevented TFAM ubiquitination and restored the transcriptional activity. Similarly, TFAM was ubiquitinated in the retina from diabetic rats, and it continued to be modified after reinstitution of normal glycemia. Our results clearly imply that the ubiquitination of TFAM impedes its transport to the mitochondria resulting in subnormal mtDNA transcription and mitochondria dysfunction, and inhibition of ubiquitination restores mitochondrial homeostasis. Reversal of hyperglycemia does not provide any benefit to TFAM ubiquitination. Thus, strategies targeting posttranslational modification could provide an avenue to preserve mitochondrial homeostasis, and inhibit the development/progression of diabetic retinopathy. PMID:24607487

  7. The Single Nucleotide Polymorphism Gly482Ser in the PGC-1α Gene Impairs Exercise-Induced Slow-Twitch Muscle Fibre Transformation in Humans

    PubMed Central

    Steinbacher, Peter; Feichtinger, René G.; Kedenko, Lyudmyla; Kedenko, Igor; Reinhardt, Sandra; Schönauer, Anna-Lena; Leitner, Isabella; Sänger, Alexandra M.; Stoiber, Walter; Kofler, Barbara; Förster, Holger; Paulweber, Bernhard; Ring-Dimitriou, Susanne

    2015-01-01

    PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α) is an important regulator of mitochondrial biogenesis and a master regulator of enzymes involved in oxidative phosphorylation. Recent evidence demonstrated that the Gly482Ser single nucleotide polymorphism (SNP) in the PGC-1α gene affects insulin sensitivity, blood lipid metabolism and binding to myocyte enhancer factor 2 (MEF2). Individuals carrying this SNP were shown to have a reduced cardiorespiratory fitness and a higher risk to develop type 2 diabetes. Here, we investigated the responses of untrained men with the Gly482Ser SNP to a 10 week programme of endurance training (cycling, 3 x 60 min/week, heart rate at 70-90% VO2peak). Quantitative data from analysis of biopsies from vastus lateralis muscle revealed that the SNP group, in contrast to the control group, lacked a training-induced increase in content of slow contracting oxidative fibres. Capillary supply, mitochondrial density, mitochondrial enzyme activities and intramyocellular lipid content increased similarly in both groups. These results indicate that the impaired binding of MEF2 to PGC-1α in humans with this SNP impedes exercise-induced fast-to-slow muscle fibre transformation. PMID:25886402

  8. The single nucleotide polymorphism Gly482Ser in the PGC-1? gene impairs exercise-induced slow-twitch muscle fibre transformation in humans.

    PubMed

    Steinbacher, Peter; Feichtinger, Ren G; Kedenko, Lyudmyla; Kedenko, Igor; Reinhardt, Sandra; Schnauer, Anna-Lena; Leitner, Isabella; Snger, Alexandra M; Stoiber, Walter; Kofler, Barbara; Frster, Holger; Paulweber, Bernhard; Ring-Dimitriou, Susanne

    2015-01-01

    PGC-1? (peroxisome proliferator-activated receptor ? co-activator 1?) is an important regulator of mitochondrial biogenesis and a master regulator of enzymes involved in oxidative phosphorylation. Recent evidence demonstrated that the Gly482Ser single nucleotide polymorphism (SNP) in the PGC-1? gene affects insulin sensitivity, blood lipid metabolism and binding to myocyte enhancer factor 2 (MEF2). Individuals carrying this SNP were shown to have a reduced cardiorespiratory fitness and a higher risk to develop type 2 diabetes. Here, we investigated the responses of untrained men with the Gly482Ser SNP to a 10 week programme of endurance training (cycling, 3 x 60 min/week, heart rate at 70-90% VO2peak). Quantitative data from analysis of biopsies from vastus lateralis muscle revealed that the SNP group, in contrast to the control group, lacked a training-induced increase in content of slow contracting oxidative fibres. Capillary supply, mitochondrial density, mitochondrial enzyme activities and intramyocellular lipid content increased similarly in both groups. These results indicate that the impaired binding of MEF2 to PGC-1? in humans with this SNP impedes exercise-induced fast-to-slow muscle fibre transformation. PMID:25886402

  9. Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit.

    PubMed

    He, J; Cooper, H M; Reyes, A; Di Re, M; Kazak, L; Wood, S R; Mao, C C; Fearnley, I M; Walker, J E; Holt, I J

    2012-07-01

    The bacterial homologue of C4orf14, YqeH, has been linked to assembly of the small ribosomal subunit. Here, recombinant C4orf14 isolated from human cells, co-purified with the small, 28S subunit of the mitochondrial ribosome and the endogenous protein co-fractionated with the 28S subunit in sucrose gradients. Gene silencing of C4orf14 specifically affected components of the small subunit, leading to decreased protein synthesis in the organelle. The GTPase of C4orf14 was critical to its interaction with the 28S subunit, as was GTP. Therefore, we propose that C4orf14, with bound GTP, binds to components of the 28S subunit facilitating its assembly, and GTP hydrolysis acts as the release mechanism. C4orf14 was also found to be associated with human mitochondrial nucleoids, and C4orf14 gene silencing caused mitochondrial DNA depletion. In vitro C4orf14 is capable of binding to DNA. The association of C4orf14 with mitochondrial translation factors and the mitochondrial nucleoid suggests that the 28S subunit is assembled at the mitochondrial nucleoid, enabling the direct transfer of messenger RNA from the nucleoid to the ribosome in the organelle. PMID:22447445

  10. Exercise-induced arterial hypoxemia.

    PubMed

    Dempsey, J A; Wagner, P D

    1999-12-01

    Exercise-induced arterial hypoxemia (EIAH) at or near sea level is now recognized to occur in a significant number of fit, healthy subjects of both genders and of varying ages. Our review aims to define EIAH and to critically analyze what we currently understand, and do not understand, about its underlying mechanisms and its consequences to exercise performance. Based on the effects on maximal O(2) uptake of preventing EIAH, we suggest that mild EIAH be defined as an arterial O(2) saturation of 93-95% (or 3-4% 25-30 Torr) and inadequate compensatory hyperventilation (arterial PCO(2) >35 Torr) commonly contribute to EIAH, as do acid- and temperature-induced shifts in O(2) dissociation at any given arterial PO(2). In turn, expiratory flow limitation presents a significant mechanical constraint to exercise hyperpnea, whereas ventilation-perfusion ratio maldistribution and diffusion limitation contribute about equally to the excessive A-a DO(2). Exactly how diffusion limitation is incurred or how ventilation-perfusion ratio becomes maldistributed with heavy exercise remains unknown and controversial. Hypotheses linked to extravascular lung water accumulation or inflammatory changes in the "silent" zone of the lung's peripheral airways are in the early stages of exploration. Indirect evidence suggests that an inadequate hyperventilatory response is attributable to feedback inhibition triggered by mechanical constraints and/or reduced sensitivity to existing stimuli; but these mechanisms cannot be verified without a sensitive measure of central neural respiratory motor output. Finally, EIAH has detrimental effects on maximal O(2) uptake, but we have not yet determined the cause or even precisely identified which organ system, involved directly or indirectly with O(2) transport to muscle, is responsible for this limitation. PMID:10601141

  11. Purple sweet potato color attenuates domoic acid-induced cognitive deficits by promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice.

    PubMed

    Lu, Jun; Wu, Dong-mei; Zheng, Yuan-lin; Hu, Bin; Cheng, Wei; Zhang, Zi-feng

    2012-02-01

    Recent findings suggest that endoplasmic reticulum stress may be involved in the pathogenesis of domoic acid-induced neurodegeneration. Purple sweet potato color, a class of naturally occurring anthocyanins, has beneficial health and biological effects. Recent studies have also shown that anthocyanins have estrogenic activity and can enhance estrogen receptor-α expression. In this study, we evaluated the effect of purple sweet potato color on cognitive deficits induced by hippocampal mitochondrial dysfunction in domoic acid-treated mice and explored the potential mechanisms underlying this effect. Our results showed that the oral administration of purple sweet potato color to domoic acid-treated mice significantly improved their behavioral performance in a step-through passive avoidance task and a Morris water maze task. These improvements were mediated, at least in part, by a stimulation of estrogen receptor-α-mediated mitochondrial biogenesis signaling and by decreases in the expression of p47phox and gp91phox. Decreases in reactive oxygen species and protein carbonylation were also observed, along with a blockade of the endoplasmic reticulum stress pathway. Furthermore, purple sweet potato color significantly suppressed endoplasmic reticulum stress-induced apoptosis, which prevented neuron loss and restored the expression of memory-related proteins. However, knockdown of estrogen receptor-α using short hairpin RNA only partially blocked the neuroprotective effects of purple sweet potato color in the hippocampus of mice cotreated with purple sweet potato color and domoic acid, indicating that purple sweet potato color acts through multiple pathways. These results suggest that purple sweet potato color could be a possible candidate for the prevention and treatment of cognitive deficits in excitotoxic and other brain disorders. PMID:22178976

  12. Roles for the lipid-signaling enzyme MitoPLD in mitochondrial dynamics, piRNA biogenesis, and spermatogenesis.

    PubMed

    Gao, Qun; Frohman, Michael A

    2012-01-01

    Phospholipase D (PLD), a superfamily of signaling enzymes that most commonly generate the lipid second messenger Phosphatidic Acid (PA), is found in diverse organisms from bacteria to man and functions in multiple cellular pathways. A fascinating member of the family, MitoPLD, is anchored to the mitochondrial surface and has two reported roles. In the first role, MitoPLD-generated PA regulates mitochondrial shape through facilitating mitochondrial fusion. In the second role, MitoPLD performs a critical function in a pathway that creates a specialized form of RNAi required by developing spermatocytes to suppress transposon mobilization during meiosis. This spermatocyte-specific RNAi, known as piRNA, is generated in the nuage, an electron-dense accumulation of RNA templates and processing proteins that localize adjacent to mitochondria in a structure also called intermitochondrial cement. In this review, we summarize recent findings on these roles for MitoPLD functions, highlighting directions that need to be pursued to define the underlying mechanisms. PMID:22281006

  13. The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes

    PubMed Central

    Sisler, Jennifer D.; Morgan, Magdalena; Raje, Vidisha; Grande, Rebecca C.; Derecka, Marta; Meier, Jeremy; Cantwell, Marc; Szczepanek, Karol; Korzun, William J.; Lesnefsky, Edward J.; Harris, Thurl E.; Croniger, Colleen M.; Larner, Andrew C.

    2015-01-01

    The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1-/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1-/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1-/- mice expressed increased amounts of PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. Since STAT1-/- mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1-/- mice did not lose lipid from WAT. β-adrenergic stimulation of glycerol release from isolated STAT1-/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1-/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1-/- mice. PMID:26689548

  14. Recombinant Human Mitochondrial Transcription Factor A Stimulates Mitochondrial Biogenesis and ATP Synthesis, Improves Motor Function after MPTP, Reduces Oxidative Stress and Increases Survival after Endotoxin

    PubMed Central

    Thomas, Ravindar R.; Khan, Shaharyar M.; Portell, Francisco R.; Smigrodzki, Rafal M.; Bennett, James P.

    2010-01-01

    Recombinant human mitochondrial transcription factor A protein (rhTFAM) was evaluated for its acute effects on cultured cells and chronic effects in mice. Fibroblasts incubated with rhTFAM acutely increased respiration in a chloramphenicol-sensitive manner. SH-SY5Y cells showed rhTFAM concentration-dependent reduction of methylpyridinium (MPP+)-induced oxidative stress and increases in lowered ATP levels and viability. Mice treated with weekly i.v. rhTFAM showed increased mitochondrial gene copy number, complex I protein levels and ATP production rates; oxidative damage to proteins was decreased ~50%. rhTFAM treatment improved motor recovery rate after treatment with MPTP and dose-dependently improved survival in the lipopolysaccharide model of endotoxin sepsis. PMID:20727424

  15. Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I

    PubMed Central

    Kmita, Katarzyna; Wirth, Christophe; Warnau, Judith; Guerrero-Castillo, Sergio; Hunte, Carola; Hummer, Gerhard; Kaila, Ville R. I.; Zwicker, Klaus; Brandt, Ulrich; Zickermann, Volker

    2015-01-01

    Mitochondrial proton-pumping NADH:ubiquinone oxidoreductase (respiratory complex I) comprises more than 40 polypeptides and contains eight canonical FeS clusters. The integration of subunits and insertion of cofactors into the nascent complex is a complicated multistep process that is aided by assembly factors. We show that the accessory NUMM subunit of complex I (human NDUFS6) harbors a Zn-binding site and resolve its position by X-ray crystallography. Chromosomal deletion of the NUMM gene or mutation of Zn-binding residues blocked a late step of complex I assembly. An accumulating assembly intermediate lacked accessory subunit N7BM (NDUFA12), whereas a paralog of this subunit, the assembly factor N7BML (NDUFAF2), was found firmly bound instead. EPR spectroscopic analysis and metal content determination after chromatographic purification of the assembly intermediate showed that NUMM is required for insertion or stabilization of FeS cluster N4. PMID:25902503

  16. Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats

    PubMed Central

    Tran, Melanie; Young, Margaret E; Jefferies, Andrew J; Hryciw, Deanne H; Ward, Michelle M; Fletcher, Erica L; Wlodek, Mary E; Wadley, Glenn D

    2015-01-01

    Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with second hits. The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1? levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction. PMID:26416974

  17. Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats.

    PubMed

    Tran, Melanie; Young, Margaret E; Jefferies, Andrew J; Hryciw, Deanne H; Ward, Michelle M; Fletcher, Erica L; Wlodek, Mary E; Wadley, Glenn D

    2015-09-01

    Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with "second hits." The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1? levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction. PMID:26416974

  18. Carbohydrate restricted recovery from long term endurance exercise does not affect gene responses involved in mitochondrial biogenesis in highly trained athletes

    PubMed Central

    Jensen, Line; Gejl, Kasper D; Ørtenblad, Niels; Nielsen, Jakob L; Bech, Rune D; Nygaard, Tobias; Sahlin, Kent; Frandsen, Ulrik

    2015-01-01

    The aim was to determine if the metabolic adaptations, particularly PGC-1α and downstream metabolic genes were affected by restricting CHO following an endurance exercise bout in trained endurance athletes. A second aim was to compare baseline expression level of these genes to untrained. Elite endurance athletes (VO2max 66 ± 2 mL·kg−1·min−1, n = 15) completed 4 h cycling at ∼56% VO2max. During the first 4 h recovery subjects were provided with either CHO or only H2O and thereafter both groups received CHO. Muscle biopsies were collected before, after, and 4 and 24 h after exercise. Also, resting biopsies were collected from untrained subjects (n = 8). Exercise decreased glycogen by 67.7 ± 4.0% (from 699 ± 26.1 to 239 ± 29.5 mmol·kg−1·dw−1) with no difference between groups. Whereas 4 h of recovery with CHO partly replenished glycogen, the H2O group remained at post exercise level; nevertheless, the gene expression was not different between groups. Glycogen and most gene expression levels returned to baseline by 24 h in both CHO and H2O. Baseline mRNA expression of NRF-1, COX-IV, GLUT4 and PPAR-α gene targets were higher in trained compared to untrained. Additionally, the proportion of type I muscle fibers positively correlated with baseline mRNA for PGC-1α, TFAM, NRF-1, COX-IV, PPAR-α, and GLUT4 for both trained and untrained. CHO restriction during recovery from glycogen depleting exercise does not improve the mRNA response of markers of mitochondrial biogenesis. Further, baseline gene expression of key metabolic pathways is higher in trained than untrained. PMID:25677542

  19. Exercise-induced muscle damage in humans.

    PubMed

    Clarkson, Priscilla M; Hubal, Monica J

    2002-11-01

    Exercise-induced muscle injury in humans frequently occurs after unaccustomed exercise, particularly if the exercise involves a large amount of eccentric (muscle lengthening) contractions. Direct measures of exercise-induced muscle damage include cellular and subcellular disturbances, particularly Z-line streaming. Several indirectly assessed markers of muscle damage after exercise include increases in T2 signal intensity via magnetic resonance imaging techniques, prolonged decreases in force production measured during both voluntary and electrically stimulated contractions (particularly at low stimulation frequencies), increases in inflammatory markers both within the injured muscle and in the blood, increased appearance of muscle proteins in the blood, and muscular soreness. Although the exact mechanisms to explain these changes have not been delineated, the initial injury is ascribed to mechanical disruption of the fiber, and subsequent damage is linked to inflammatory processes and to changes in excitation-contraction coupling within the muscle. Performance of one bout of eccentric exercise induces an adaptation such that the muscle is less vulnerable to a subsequent bout of eccentric exercise. Although several theories have been proposed to explain this "repeated bout effect," including altered motor unit recruitment, an increase in sarcomeres in series, a blunted inflammatory response, and a reduction in stress-susceptible fibers, there is no general agreement as to its cause. In addition, there is controversy concerning the presence of sex differences in the response of muscle to damage-inducing exercise. In contrast to the animal literature, which clearly shows that females experience less damage than males, research using human studies suggests that there is either no difference between men and women or that women are more prone to exercise-induced muscle damage than are men. PMID:12409811

  20. Role of mitochondria in exercise-induced oxidative stress in skeletal muscle from hyperthyroid rats.

    PubMed

    Venditti, P; Bari, A; Di Stefano, L; Di Meo, S

    2007-07-01

    Previous study showed that exercise induces higher oxidative damage and respiratory capacity reduction in hyperthyroid than in euthyroid skeletal muscle. Because impaired cell function can result from mitochondrial dysfunction, we evaluated the changes induced by exercise in oxygen consumption of skeletal muscle mitochondria from euthyroid and hyperthyroid rats. The mitochondrial function was related with indices of oxidative damage and nitric oxide production, scavenger levels and mitochondrial ROS production rates. Our results show that exercise increased state 4 and decreased state 3 respiration, and the highest changes happened in hyperthyroid preparations. This was consistent with the observation that oxidative damage and NO(*) derivative content were increased by T(3) administration and exercise, reaching the highest levels in hyperthyroid exercised rats. Our results also indicate that the high mitochondrial oxidative damage induced by T(3) and exercise is due to enhanced ROS production, which is dependent on increases in mitochondrial content and reduction degree, respectively, of autoxidizable electron carriers. PMID:17395147

  1. Effects of decreased lactate accumulation after dichloroacetate administration on exercise training–induced mitochondrial adaptations in mouse skeletal muscle

    PubMed Central

    Hoshino, Daisuke; Tamura, Yuki; Masuda, Hiroyuki; Matsunaga, Yutaka; Hatta, Hideo

    2015-01-01

    Recent studies suggested that lactate accumulation can be a signal for mitochondrial biogenesis in skeletal muscle. We investigated whether reductions in lactate concentrations in response to dichloroacetate (DCA), an activator of pyruvate dehydrogenase, attenuate mitochondrial adaptations after exercise training in mice. We first confirmed that DCA administration (200 mg/kg BW by i.p. injection) 10 min before exercise decreased muscle and blood lactate concentrations after high-intensity interval exercise (10 bouts of 1 min treadmill running at 40 m/min with a 1 min rest). At the same time, exercise-induced signal cascades did not change by pre-exercise DCA administration. These results suggested that DCA administration affected only lactate concentrations after exercise. We next examined the effects of acute DCA administration on mRNA expressions involved with mitochondrial biogenesis after same high-intensity interval exercise and the effects of chronic DCA administration on mitochondrial adaptations after high-intensity interval training (increasing intensity from 38 to 43 m/min by the end of training period). Acute DCA administration did not change most of the exercise-induced mRNA upregulation. These data suggest that lactate reductions by DCA administration did not affect transcriptional activation after high-intensity interval exercise. However, chronic DCA administration attenuated, in part, mitochondrial adaptations such as training-induced increasing rates of citrate synthase (P = 0.06), β-hydroxyacyl CoA dehydrogenase activity (P < 0.05), cytochrome c oxidase IV (P < 0.05) and a fatty acid transporter, fatty acid translocase/CD36 (P < 0.05), proteins after exercise training. These results suggest that lactate accumulation during high-intensity interval exercise may be associated with mitochondrial adaptations after chronic exercise training. PMID:26416973

  2. Effects of decreased lactate accumulation after dichloroacetate administration on exercise training-induced mitochondrial adaptations in mouse skeletal muscle.

    PubMed

    Hoshino, Daisuke; Tamura, Yuki; Masuda, Hiroyuki; Matsunaga, Yutaka; Hatta, Hideo

    2015-09-01

    Recent studies suggested that lactate accumulation can be a signal for mitochondrial biogenesis in skeletal muscle. We investigated whether reductions in lactate concentrations in response to dichloroacetate (DCA), an activator of pyruvate dehydrogenase, attenuate mitochondrial adaptations after exercise training in mice. We first confirmed that DCA administration (200mg/kg BW by i.p. injection) 10min before exercise decreased muscle and blood lactate concentrations after high-intensity interval exercise (10 bouts of 1min treadmill running at 40m/min with a 1min rest). At the same time, exercise-induced signal cascades did not change by pre-exercise DCA administration. These results suggested that DCA administration affected only lactate concentrations after exercise. We next examined the effects of acute DCA administration on mRNA expressions involved with mitochondrial biogenesis after same high-intensity interval exercise and the effects of chronic DCA administration on mitochondrial adaptations after high-intensity interval training (increasing intensity from 38 to 43m/min by the end of training period). Acute DCA administration did not change most of the exercise-induced mRNA upregulation. These data suggest that lactate reductions by DCA administration did not affect transcriptional activation after high-intensity interval exercise. However, chronic DCA administration attenuated, in part, mitochondrial adaptations such as training-induced increasing rates of citrate synthase (P=0.06), ?-hydroxyacyl CoA dehydrogenase activity (P<0.05), cytochrome c oxidase IV (P<0.05) and a fatty acid transporter, fatty acid translocase/CD36 (P<0.05), proteins after exercise training. These results suggest that lactate accumulation during high-intensity interval exercise may be associated with mitochondrial adaptations after chronic exercise training. PMID:26416973

  3. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice.

    PubMed

    Safdar, Adeel; Bourgeois, Jacqueline M; Ogborn, Daniel I; Little, Jonathan P; Hettinga, Bart P; Akhtar, Mahmood; Thompson, James E; Melov, Simon; Mocellin, Nicholas J; Kujoth, Gregory C; Prolla, Tomas A; Tarnopolsky, Mark A

    2011-03-01

    A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities. PMID:21368114

  4. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

    PubMed Central

    Safdar, Adeel; Bourgeois, Jacqueline M.; Ogborn, Daniel I.; Little, Jonathan P.; Hettinga, Bart P.; Akhtar, Mahmood; Thompson, James E.; Melov, Simon; Mocellin, Nicholas J.; Kujoth, Gregory C.; Prolla, Tomas A.; Tarnopolsky, Mark A.

    2011-01-01

    A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities. PMID:21368114

  5. Vitamin E and vitamin C do not reduce insulin sensitivity but inhibit mitochondrial protein expression in exercising obese rats

    PubMed Central

    Picklo, Matthew J.; Thyfault, John P.

    2016-01-01

    Controversy exists as to whether supplementation with the antioxidants vitamin E and vitamin C blocks adaptation to exercise. Exercise is a first-line means to treat obesity and its complications. While diet-induced obesity alters mitochondrial function and induces insulin resistance (IR), no data exist as to whether supplementation with vitamin E and vitamin C modify responses to exercise in pre-existing obesity. We tested the hypothesis that dietary supplementation with vitamin E (0.4 g α-tocopherol acetate/kg) and vitamin C (0.5 g/kg) blocks exercise-induced improvements on IR and mitochondrial content in obese rats maintained on a high-fat (45% fat energy (en)) diet. Diet-induced obese, sedentary rats had a 2-fold higher homeostasis model assessment of insulin resistance and larger insulin area under the curve following glucose tolerances test than rats fed a low-fat (10% fat en) diet. Exercising (12 weeks at 5 times per week in a motorized wheel) of obese rats normalized IR indices, an effect not modified by vitamin E and vitamin C. Vitamin E and vitamin C supplementation with exercise elevated mtDNA content in adipose and skeletal muscle to a greater extent (20%) than exercise alone in a depot-specific manner. On the other hand, vitamin C and vitamin E decreased exercise-induced increases in mitochondrial protein content for complex I (40%) and nicotinamide nucleotide transhydrogenase (35%) in a muscle-dependent manner. These data indicate that vitamin E and vitamin C supplementation in obese rodents does not modify exercise-induced improvements in insulin sensitivity but that changes in mitochondrial biogenesis and mitochondrial protein expression may be modified by antioxidant supplementation. PMID:25761734

  6. Vitamin E and vitamin C do not reduce insulin sensitivity but inhibit mitochondrial protein expression in exercising obese rats.

    PubMed

    Picklo, Matthew J; Thyfault, John P

    2015-04-01

    Controversy exists as to whether supplementation with the antioxidants vitamin E and vitamin C blocks adaptation to exercise. Exercise is a first-line means to treat obesity and its complications. While diet-induced obesity alters mitochondrial function and induces insulin resistance (IR), no data exist as to whether supplementation with vitamin E and vitamin C modify responses to exercise in pre-existing obesity. We tested the hypothesis that dietary supplementation with vitamin E (0.4 g ?-tocopherol acetate/kg) and vitamin C (0.5 g/kg) blocks exercise-induced improvements on IR and mitochondrial content in obese rats maintained on a high-fat (45% fat energy (en)) diet. Diet-induced obese, sedentary rats had a 2-fold higher homeostasis model assessment of insulin resistance and larger insulin area under the curve following glucose tolerances test than rats fed a low-fat (10% fat en) diet. Exercising (12 weeks at 5 times per week in a motorized wheel) of obese rats normalized IR indices, an effect not modified by vitamin E and vitamin C. Vitamin E and vitamin C supplementation with exercise elevated mtDNA content in adipose and skeletal muscle to a greater extent (20%) than exercise alone in a depot-specific manner. On the other hand, vitamin C and vitamin E decreased exercise-induced increases in mitochondrial protein content for complex I (40%) and nicotinamide nucleotide transhydrogenase (35%) in a muscle-dependent manner. These data indicate that vitamin E and vitamin C supplementation in obese rodents does not modify exercise-induced improvements in insulin sensitivity but that changes in mitochondrial biogenesis and mitochondrial protein expression may be modified by antioxidant supplementation. PMID:25761734

  7. Update on exercise-induced pulmonary hemorrhage.

    PubMed

    Sullivan, Stacey; Hinchcliff, Kenneth

    2015-04-01

    Exercise-induced pulmonary hemorrhage (EIPH) is an important disease of horses that perform high-intensity athletic activity. EIPH is an ongoing concern for the racing industry because of its high prevalence; potential impact on performance; welfare concerns; and use of prophylactic medications, such as furosemide, on race day. During the last 10 years, significant progress has been made in understanding the pathogenesis and risk factors for EIPH and the impact of the disease on performance and career. This article summarizes the most recent advances in EIPH. PMID:25770069

  8. Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain.

    PubMed

    Steib, Kathrin; Schffner, Iris; Jagasia, Ravi; Ebert, Birgit; Lie, D Chichung

    2014-05-01

    Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity. PMID:24806687

  9. The functional interaction of mitochondrial Hsp70s with the escort protein Zim17 is critical for Fe/S biogenesis and substrate interaction at the inner membrane preprotein translocase.

    PubMed

    Lewrenz, Ilka; Rietzschel, Nicole; Guiard, Bernard; Lill, Roland; van der Laan, Martin; Voos, Wolfgang

    2013-10-25

    The yeast protein Zim17 belongs to a unique class of co-chaperones that maintain the solubility of Hsp70 proteins in mitochondria and plastids of eukaryotic cells. However, little is known about the functional cooperation between Zim17 and mitochondrial Hsp70 proteins in vivo. To analyze the effects of a loss of Zim17 function in the authentic environment, we introduced novel conditional mutations within the ZIM17 gene of the model organism Saccharomyces cerevisiae that allowed a recovery of temperature-sensitive but respiratory competent zim17 mutant cells. On fermentable growth medium, the mutant cells were prone to acquire respiratory deficits and showed a strong aggregation of the mitochondrial Hsp70 Ssq1 together with a concomitant defect in Fe/S protein biogenesis. In contrast, under respiring conditions, the mitochondrial Hsp70s Ssc1 and Ssq1 exhibited only a partial aggregation. We show that the induction of the zim17 mutant phenotype leads to strong import defects for Ssc1-dependent matrix-targeted precursor proteins that correlate with a significantly reduced binding of newly imported substrate proteins to Ssc1. We conclude that Zim17 is not only required for the maintenance of mtHsp70 solubility but also directly assists the functional interaction of mtHsp70 with substrate proteins in a J-type co-chaperone-dependent manner. PMID:24030826

  10. The Functional Interaction of Mitochondrial Hsp70s with the Escort Protein Zim17 Is Critical for Fe/S Biogenesis and Substrate Interaction at the Inner Membrane Preprotein Translocase*

    PubMed Central

    Lewrenz, Ilka; Rietzschel, Nicole; Guiard, Bernard; Lill, Roland; van der Laan, Martin; Voos, Wolfgang

    2013-01-01

    The yeast protein Zim17 belongs to a unique class of co-chaperones that maintain the solubility of Hsp70 proteins in mitochondria and plastids of eukaryotic cells. However, little is known about the functional cooperation between Zim17 and mitochondrial Hsp70 proteins in vivo. To analyze the effects of a loss of Zim17 function in the authentic environment, we introduced novel conditional mutations within the ZIM17 gene of the model organism Saccharomyces cerevisiae that allowed a recovery of temperature-sensitive but respiratory competent zim17 mutant cells. On fermentable growth medium, the mutant cells were prone to acquire respiratory deficits and showed a strong aggregation of the mitochondrial Hsp70 Ssq1 together with a concomitant defect in Fe/S protein biogenesis. In contrast, under respiring conditions, the mitochondrial Hsp70s Ssc1 and Ssq1 exhibited only a partial aggregation. We show that the induction of the zim17 mutant phenotype leads to strong import defects for Ssc1-dependent matrix-targeted precursor proteins that correlate with a significantly reduced binding of newly imported substrate proteins to Ssc1. We conclude that Zim17 is not only required for the maintenance of mtHsp70 solubility but also directly assists the functional interaction of mtHsp70 with substrate proteins in a J-type co-chaperone-dependent manner. PMID:24030826

  11. Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury

    PubMed Central

    Smith, Joshua A.; Stallons, L. Jay; Collier, Justin B.; Chavin, Kenneth D.

    2015-01-01

    Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiologic feature of sepsis-induced acute kidney injury (AKI), the molecular mechanisms responsible for this phenomenon are unknown. In this study, we examined the signaling pathways responsible for the suppression of MB in a mouse model of lipopolysaccharide (LPS)-induced AKI. Downregulation of peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), a master regulator of MB, was noted at the mRNA level at 3 hours and protein level at 18 hours in the renal cortex, and was associated with loss of renal function after LPS treatment. LPS-mediated suppression of PGC-1? led to reduced expression of downstream regulators of MB and electron transport chain proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, Toll-like receptor 4 (TLR4) knockout mice were protected from renal injury and disruption of MB after LPS exposure. Immunoblot analysis revealed activation of tumor progression locus 2/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (TPL-2/MEK/ERK) signaling in the renal cortex by LPS. Pharmacologic inhibition of MEK/ERK signaling attenuated renal dysfunction and loss of PGC-1?, and was associated with a reduction in proinflammatory cytokine (e.g., tumor necrosis factor-? [TNF-?], interleukin-1?) expression at 3 hours after LPS exposure. Neutralization of TNF-? also blocked PGC-1? suppression, but not renal dysfunction, after LPS-induced AKI. Finally, systemic administration of recombinant tumor necrosis factor-? alone was sufficient to produce AKI and disrupt mitochondrial homeostasis. These findings indicate an important role for the TLR4/MEK/ERK pathway in both LPS-induced renal dysfunction and suppression of MB. TLR4/MEK/ERK/TNF-? signaling may represent a novel therapeutic target to prevent mitochondrial dysfunction and AKI produced by sepsis. PMID:25503387

  12. Exercise-induced anaphylaxis and antileukotriene montelukast

    PubMed Central

    Gajbhiye, Sapna; Agrawal, Rajendra Prasad; Atal, Shubham; Tiwari, Vikalp; Phadnis, Pradeep

    2015-01-01

    We report a rare case of exercise-induced anaphylaxis (EIA), occurring exclusively with exercise, without any other associated trigger, detected in the prodromal phase, and prevented from additional anaphylaxis episodes by treatment with cetirizine and 10 mg daily of antileukotriene montelukast to date. EIA is a syndrome in which patients experience a spectrum of the symptoms of anaphylaxis ranging from mild cutaneous signs to severe systemic manifestations such as hypotension, syncope, and even death after increased physical activity. Many people have triggers, such as, a variety of foods, various medications, alcohol, cold weather, humidity, and seasonal and hormonal changes along with exercise that cause the symptoms. Typically, either exercise or the specific trigger alone will rarely cause symptoms. It is differentiated from cholinergic urticaria by the absence of response to passive body warming and emotional stress. PMID:26312002

  13. Nutritional Support for Exercise-Induced Injuries.

    PubMed

    Tipton, Kevin D

    2015-11-01

    Nutrition is one method to counter the negative impact of an exercise-induced injury. Deficiencies of energy, protein and other nutrients should be avoided. Claims for the effectiveness of many other nutrients following injuries are rampant, but the evidence is equivocal. The results of an exercise-induced injury may vary widely depending on the nature of the injury and severity. Injuries typically result in cessation, or at least a reduction, in participation in sport and decreased physical activity. Limb immobility may be necessary with some injuries, contributing to reduced activity and training. Following an injury, an inflammatory response is initiated and while excess inflammation may be harmful, given the importance of the inflammatory process for wound healing, attempting to drastically reduce inflammation may not be ideal for optimal recovery. Injuries severe enough for immobilization of a limb result in loss of muscle mass and reduced muscle strength and function. Loss of muscle results from reductions in basal muscle protein synthesis and the resistance of muscle to anabolic stimulation. Energy balance is critical. Higher protein intakes (2-2.5 g/kg/day) seem to be warranted during immobilization. At the very least, care should be taken not to reduce the absolute amount of protein intake when energy intake is reduced. There is promising, albeit preliminary, evidence for the use of omega-3 fatty acids and creatine to counter muscle loss and enhance hypertrophy, respectively. The overriding nutritional recommendation for injured exercisers should be to consume a well-balanced diet based on whole, minimally processed foods or ingredients made from whole foods. The diet composition should be carefully assessed and changes considered as the injury heals and activity patterns change. PMID:26553492

  14. DEMONSTRATION BULLETIN: BIOGENESIS SOIL WASHING TECHNOLOGY - BIOGENESIS

    EPA Science Inventory

    The BioGenesisSM soil washing technology was developed by BioGenesis Enterprises, Inc. to remove organic compounds from soil. The technology uses a proprietary solution (BioGenesisSM cleaner) to transfer organic compounds from the soil matrix to a liquid phase. BioGenesis claims...

  15. Mitochondrial adaptations evoked with exercise are associated with a reduction in age-induced testicular atrophy in Fischer-344 rats.

    PubMed

    Joseph, A-M; Nguyen, L M-D; Welter, A E; Dominguez, J M; Behnke, B J; Adhihetty, P J

    2014-01-01

    Mitochondrial dysfunction in various tissues has been associated with numerous conditions including aging. In testes, aging induces atrophy and a decline in male reproductive function but the involvement of mitochondria is not clear. The purpose of this study was to examine whether the mitochondrial profile differed with (1) aging, and (2) 10-weeks of treadmill exercise training, in the testes of young (6 month) and old (24 month) Fischer-344 (F344) animals. Old animals exhibited significant atrophy (30 % decline; P < 0.05) in testes compared to young animals. However, relative mitochondrial content was not reduced with age and this was consistent with the lack of change in the mitochondrial biogenesis regulator protein, peroxisome proliferator-activated receptor gamma coactivator 1-alpha and its downstream targets nuclear respiratory factor-1 and mitochondrial transcription factor A. No effect was observed in the pro- or anti-apoptotic proteins, Bax and Bcl-2, respectively, but age increased apoptosis inducing factor levels. Endurance training induced beneficial mitochondrial adaptations that were more prominent in old animals including greater increases in relative mtDNA content, biogenesis/remodeling (mitofusin 2), antioxidant capacity (mitochondrial superoxide dismutase) and lower levels of phosphorylated histone H2AX, an early marker of DNA damage (P < 0.05). Importantly, these exercise-induced changes were associated with an attenuation of testes atrophy in older sedentary animals (P < 0.05). Our results indicate that aging-induced atrophy in testes may not be associated with changes in relative mitochondrial content and key regulatory proteins and that exercise started in late-life elicits beneficial changes in mitochondria that may protect against age-induced testicular atrophy. PMID:25108553

  16. Human mitochondrial ferritin improves respiratory function in yeast mutants deficient in ironsulfur cluster biogenesis, but is not a functional homologue of yeast frataxin

    PubMed Central

    Sutak, Robert; Seguin, Alexandra; Garcia-Serres, Ricardo; Oddou, Jean-Louis; Dancis, Andrew; Tachezy, Jan; Latour, Jean-Marc; Camadro, Jean-Michel; Lesuisse, Emmanuel

    2012-01-01

    We overexpressed human mitochondrial ferritin in frataxin-deficient yeast cells (?yfh1), but also in another mutant affected in [Fe-S] assembly (?ggc1). Ferritin was correctly processed and expressed in the mitochondria of these cells, but the fraction of total mitochondrial iron bound to ferritin was very low, and most of the iron remained in the form of insoluble particles of ferric phosphate in these mitochondria, as evidenced by gel filtration analysis of the mitochondrial matrix (fast protein liquid chromatography [FPLC]) and by Mssbauer spectroscopy. Mutant cells in which ferritin was overexpressed still accumulated iron in the mitochondria and remained deficient in [Fe-S] assembly, suggesting that human mitochondrial ferritin is not a functional homologue of yeast frataxin. However, the respiratory function was improved in these mutants, which correlates with an improvement of cytochrome and heme synthesis. Overexpression of mitochondrial ferritin in [Fe-S] mutants resulted in the appearance of a small pool of high-spin ferrous iron in the mitochondria, which was probably responsible for the improvement of heme synthesis and of the respiratory function in these mutants. PMID:22950017

  17. Exercise- and training-induced upregulation of skeletal muscle fatty acid oxidation are not solely dependent on mitochondrial machinery and biogenesis

    PubMed Central

    Yoshida, Yuko; Jain, Swati S; McFarlan, Jay T; Snook, Laelie A; Chabowski, Adrian; Bonen, Arend

    2013-01-01

    Regulation of skeletal muscle fatty acid oxidation (FAO) and adaptation to exercise training have long been thought to depend on delivery of fatty acids (FAs) to muscle, their diffusion into muscle, and muscle mitochondrial content and biochemical machinery. However, FA entry into muscle occurs via a regulatable, protein-mediated mechanism, involving several transport proteins. Among these CD36 is key. Muscle contraction and pharmacological agents induce CD36 to translocate to the cell surface, a response that regulates FA transport, and hence FAO. In exercising CD36 KO mice, exercise duration (?44%), and FA transport (?41%) and oxidation (?37%) are comparably impaired, while carbohydrate metabolism is augmented. In trained CD36 KO mice, training-induced upregulation of FAO is not observed, despite normal training-induced increases in mitochondrial density and enzymes. Transfecting CD36 into sedentary WT muscle (+41%), comparable to training-induced CD36 increases (+44%) in WT muscle, markedly upregulates FAO to rates observed in trained WT mice, but without any changes in mitochondrial density and enzymes. Evidently, in vivo CD36-mediated FA transport is key for muscle fuel selection and training-induced FAO upregulation, independent of mitochondrial adaptations. This CD36 molecular mechanism challenges the view that skeletal muscle FAO is solely regulated by muscle mitochondrial content and machinery. PMID:22890711

  18. The heme synthesis defect of mutants impaired in mitochondrial iron-sulfur protein biogenesis is caused by reversible inhibition of ferrochelatase.

    PubMed

    Lange, Heike; Mhlenhoff, Ulrich; Denzel, Martin; Kispal, Gyula; Lill, Roland

    2004-07-01

    Mitochondria are responsible for the synthesis of both iron-sulfur clusters and heme, but the potential connection between the two major iron-consuming pathways is unknown. Here, we have shown that mutants in the yeast mitochondrial iron-sulfur cluster (ISC) assembly machinery displayed reduced cytochrome levels and diminished activity of the heme-containing cytochrome c oxidase, in addition to iron-sulfur protein defects. In contrast, mutants in components of the mitochondrial ISC export machinery, which are specifically required for maturation of cytosolic iron-sulfur proteins, were not decreased in heme synthesis or cytochrome levels. Heme synthesis does not involve the function of mitochondrial ISC components, because immunological depletion of various ISC proteins from mitochondrial extracts did not affect the formation and amounts of heme. The heme synthesis defects of ISC mutants were found in vivo in isolated mitochondria and in mitochondrial detergent extracts and were confined to an inhibition of ferrochelatase, the enzyme catalyzing the insertion of iron into protoporphyrin IX. In support of these findings, immunopurification of ferrochelatase from ISC mutants restored its activity to wild-type levels. We conclude that the reversible inhibition of ferrochelatase is the molecular reason for the heme deficiency in ISC assembly mutants. This inhibitory mechanism may be used for regulation of iron distribution between the two iron-consuming processes. PMID:15128732

  19. Mechanisms of Exercise-Induced Hypoalgesia

    PubMed Central

    Koltyn, Kelli F.; Brellenthin, Angelique G.; Cook, Dane B.; Sehgal, Nalini; Hillard, Cecilia

    2014-01-01

    The purpose of this study was to examine opioid and endocannabinoid mechanisms of exercise-induced hypoalgesia (EIH). Fifty-eight men and women (mean age = 21 yrs) completed three sessions. During the first session, participants were familiarized with the temporal summation of heat pain and pressure pain protocols. In the exercise sessions, following double-blind administration of either an opioid antagonist (50 mg naltrexone) or placebo, participants rated the intensity of heat pulses and indicated their pressure pain thresholds (PPT) and ratings (PPR) before and after 3 minutes of submaximal isometric exercise. Blood was drawn before and after exercise. Results indicated circulating concentrations of two endocannabinoids, N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) as well as related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), N-docsahexaenoylethanolamine (DHEA), and 2-oleoylglycerol (2-OG) increased significantly (p < 0.05) following exercise. PPT increased significantly (p < 0.05) while PPR decreased significantly (p < 0.05) following exercise. Also, temporal summation ratings were significantly lower (p < 0.05) following exercise. These changes in pain responses did not differ between placebo or naltrexone conditions (p > 0.05). A significant association was found between EIH and DHEA. These results suggest involvement of a non-opioid mechanism in EIH following isometric exercise. PMID:25261342

  20. Exercise-induced cardioprotection: endogenous mechanisms.

    PubMed

    Starnes, Joseph W; Taylor, Ryan P

    2007-09-01

    It is now well established that exercise can result in cardioprotection against ischemia-reperfusion (I-R) injury; however, the adaptations within the heart that provide the protection are still in doubt. The cytoprotective proteins receiving the most attention to date are antioxidant enzymes and heat shock proteins. The extent of I-R injury is dependent on the interactions of several events, including energy depletion, metabolite accumulation, oxidant stress, and calcium overload. Adaptations that directly influence any of these could affect I-R outcome. Thus, the exercise-induced cardioprotective phenotype is likely to include additional cytoprotective proteins beyond antioxidant enzymes or heat shock proteins. In this review, we will consider evidence for some of these in the cytosol, mitochondria, and sarcolemma of the cardiomyocyte. We will not consider potentially important adaptations within vascular tissue or the autonomic nervous system. Results of recent studies support the hypothesis that exercise leads to cardioprotective adaptations that are unique from other forms of preconditioning against I-R injury. PMID:17805086

  1. Wheat-dependent exercise-induced anaphylaxis.

    PubMed

    Scherf, K A; Brockow, K; Biedermann, T; Koehler, P; Wieser, H

    2016-01-01

    Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a rare, but potentially severe food allergy exclusively occurring when wheat ingestion is accompanied by augmenting cofactors. It is clinically characterized by anaphylactic reactions ranging from urticaria and angioedema to dyspnoea, hypotension, collapse, and shock. WDEIA usually develops after ingestion of wheat products followed by physical exercise. Other cofactors are acetylsalicylic acid and other non-steroidal anti-inflammatory drugs, alcohol, and infections. The precise mechanisms of WDEIA remain unclear; exercise and other cofactors might increase gastrointestinal allergen permeability and osmolality, redistribute blood flow, or lower the threshold for IgE-mediated mast cell degranulation. Among wheat proteins, ?5-gliadin and high-molecular-weight glutenin subunits have been reported to be the major allergens. In some patients, WDEIA has been discussed to be caused by epicutaneous sensitization with hydrolysed wheat gluten included in cosmetics. Diagnosis is made based on the patient's history in combination with allergy skin testing, determination of wheat-specific IgE serum antibodies, basophil activation test, histamine release test, and/or exercise challenge test. Acute treatment includes application of adrenaline or antihistamines. The most reliable prophylaxis of WDEIA is a gluten-free diet. In less severe cases, a strict limitation of wheat ingestion before exercise and avoidance of other cofactors may be sufficient. PMID:26381478

  2. 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

  3. Exercise-induced respiratory symptoms not due to asthma.

    PubMed

    Pandit, Chetan A; Batterby, Eugenie; Van Asperen, Peter; Cooper, Peter; Selvadurai, Hiran; Fitzgerald, Dominic A

    2014-10-01

    This manuscript describes two interesting patients who had exercise-induced symptoms that unmasked an alternative underlying diagnosis. The first is an 8-year-old boy who was treated for asthma all his life but really had exercise-induced stridor (labelled as wheeze) causing significant exercise limitation, which was due to a double aortic arch with the right arch compressing the trachea. The second case describes the diagnosis of vocal cord dysfunction in a 13-year-old anxious high achiever. He also initially had exercise-induced symptoms treated as exercise-induced wheeze but again had a stridor due to vocal cord dysfunction. Both these cases demonstrate the importance of detailed history including during exercise, which can unmask alternative diagnosis. Another important message is that if there is no response to bronchodilator treatment with absence of typical signs and symptoms of asthma, alternative diagnosis should be considered. PMID:22050200

  4. Wheezing or Breezing through Exercise-Induced Asthma.

    ERIC Educational Resources Information Center

    McCarthy, Paul

    1989-01-01

    Several physicians discuss the tests they use to diagnose exercise-induced asthma (EIA), the medications they typically prescribe and why, and the importance of properly educating athletes about EIA. (JD)

  5. Asthma Bronchiale and Exercise-Induced Bronchoconstriction.

    PubMed

    Jayasinghe, Harshani; Kopsaftis, Zoe; Carson, Kristin

    2015-01-01

    Exercising regularly has a wide range of beneficial health effects; in particular, it has been well documented to help in the management of chronic illnesses including asthma. However, in some individuals, exertion can also trigger an exacerbation of asthmatic episodes and subsequent acute attacks of breathlessness, coughing, tightness of the chest and wheezing. This physiological process is called exercise-induced bronchoconstriction (EIB) whereby post-exercise forced expiratory volume in 1 s is reduced by 10-15% from baseline. While EIB is highly prevalent in asthmatics and presents with similar respiratory symptoms, asthma and EIB are not mutually exclusive. The aim of this review is to present a broad overview of both conditions in order to enhance the understanding of the similarities and differences distinguishing them as two separate entities. The pathophysiology and mechanisms underlying asthma are well described with research now focussing on defining phenotypes for targeted management strategies. Conversely, the mechanistic understanding of EIB remains largely under-described. Diagnostic pathways for both are established and similar, as are pharmacologic and non-pharmacologic treatments and management approaches, which have enhanced success with early detection. Given the potential for exacerbation of asthma, exercise avoidance is common but counterproductive as current evidence indicates that it is well tolerated and improves quality of life. Literature supporting the benefit of exercise for EIB sufferers is at present favourable, yet extremely limited; therefore, future research should be directed in this area as well as towards further developing the understanding of the pathophysiology and mechanisms underpinning both EIB and asthma. PMID:26068579

  6. Management of Exercise-Induced Bronchospasm in Children

    PubMed Central

    Hendeles, Leslie; Asmus, Michael J.; Chesrown, Sarah

    2003-01-01

    Bronchospasm precipitated by exercise is often indistinguishable from bronchospasm produced by other stimuli. Symptoms result from airflow limitation and include wheezing, cough, chest tightness, dyspnea and sometimes hypoxemia. The prevalence of exercise-induced bronchospasm varies from 30%-90%, but virtually all patients with current asthma will experience a decrease in lung function if the exercise is sufficiently vigorous, especially in cold, dry environmental conditions. Exercise-induced bronchospasm is more prevalent in children than in adults, probably because children are physically more active. It is also more prevalent among elite winter sports athletes. The pathogenesis of exercise-induced bronchospasm involves a defect in respiratory heat exchange that probably triggers mast cell and eosinophil release of bronchoconstricting mediators. The goal of therapy is prevention of symptoms. This may be accomplished by pre-treating patients with isolated exercise-induced bronchospasm using an inhaled rapid-onset ?2-adrenergic agonist before a scheduled activity or by treating the underlying inflammation when exercise-induced bronchospasm is part of the clinical syndrome of persistent asthma. In the later instance, either an inhaled corticosteroid, an oral leukotriene modifier, or a combination of both, depending on severity, may be required to prevent exercise-induced bronchospasm associated with activities of daily living. In addition, some of these patients may still require pre-treatment with a short-acting inhaled ?2-agonist before a scheduled vigorous activity, especially in very cold ambient temperatures. Because the duration of bronchoprotection decreases with daily use (tachyphylaxis), long acting ?2-adrenergic agonists (e.g., formoterol, salmeterol) have a limited role in treating exercise-induced bronchospasm. PMID:23300391

  7. Exercise-induced bronchoconstriction in Tunisian elite athletes is underdiagnosed

    PubMed Central

    Sallaoui, Ridha; Zendah², Ines; Ghedira², Habib; Belhaouz³, Mohcine; Ghrairi³, Mourad; Amri³, Mohamed

    2011-01-01

    Many studies have shown an increased risk of developing exercise-induced bronchoconstriction among the athletic population, particularly at the elite level. Subjective methods for assessing exercise-induced bronchoconstriction such as surveys and questionnaires have been used but have resulted in an underestimation of the prevalence of airway dysfunction when compared with objective measurements. The aim of the present study was to compare the prevalence of exercise-induced bronchoconstriction among Tunisian elite athletes obtained using an objective method with that using a subjective method, and to discuss the possible causes and implications of the observed discrepancy. As the objective method we used spirometry before and after exercise and for the subjective approach we used a medical history questionnaire. All of the recruited 107 elite athletes responded to the questionnaire about respiratory symptoms and medical history and underwent a resting spirometry testing before and after exercise. Post-exercise spirometry revealed the presence of exercise-induced bronchoconstriction in 14 (13%) of the elite athletes, while only 1.8% reported having previously been diagnosed with asthma. In conclusion, our findings indicate that medical history-based diagnoses of exercise-induced bronchoconstriction lead to underestimations of true sufferers. PMID:24198569

  8. Exercise-induced bronchoconstriction in Tunisian elite athletes is underdiagnosed.

    PubMed

    Sallaoui, Ridha; Zendah, Ines; Ghedira, Habib; Belhaouz, Mohcine; Ghrairi, Mourad; Amri, Mohamed

    2011-01-01

    Many studies have shown an increased risk of developing exercise-induced bronchoconstriction among the athletic population, particularly at the elite level. Subjective methods for assessing exercise-induced bronchoconstriction such as surveys and questionnaires have been used but have resulted in an underestimation of the prevalence of airway dysfunction when compared with objective measurements. The aim of the present study was to compare the prevalence of exercise-induced bronchoconstriction among Tunisian elite athletes obtained using an objective method with that using a subjective method, and to discuss the possible causes and implications of the observed discrepancy. As the objective method we used spirometry before and after exercise and for the subjective approach we used a medical history questionnaire. All of the recruited 107 elite athletes responded to the questionnaire about respiratory symptoms and medical history and underwent a resting spirometry testing before and after exercise. Post-exercise spirometry revealed the presence of exercise-induced bronchoconstriction in 14 (13%) of the elite athletes, while only 1.8% reported having previously been diagnosed with asthma. In conclusion, our findings indicate that medical history-based diagnoses of exercise-induced bronchoconstriction lead to underestimations of true sufferers. PMID:24198569

  9. Resveratrol Attenuates Exercise-Induced Adaptive Responses in Rats Selectively Bred for Low Running Performance

    PubMed Central

    Hart, Nikolett; Sarga, Linda; Csende, Zsolt; Koch, Lauren G.; Britton, Steven L.; Davies, Kelvin J.A.; Radak, Zsolt

    2014-01-01

    Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPT-FOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control. PMID:24659933

  10. Dietary supplementation with the microalga Galdieria sulphuraria (Rhodophyta) reduces prolonged exercise-induced oxidative stress in rat tissues.

    PubMed

    Carfagna, Simona; Napolitano, Gaetana; Barone, Daniela; Pinto, Gabriele; Pollio, Antonino; Venditti, Paola

    2015-01-01

    We studied the effects of ten-day 1% Galdieria sulphuraria dietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming) determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle) homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2 mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria. G. sulphuraria supplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2 release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion, G. sulphuraria ability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion. PMID:25874021

  11. Dietary Supplementation with the Microalga Galdieria sulphuraria (Rhodophyta) Reduces Prolonged Exercise-Induced Oxidative Stress in Rat Tissues

    PubMed Central

    Carfagna, Simona; Napolitano, Gaetana; Barone, Daniela; Pinto, Gabriele; Venditti, Paola

    2015-01-01

    We studied the effects of ten-day 1% Galdieria sulphuraria dietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming) determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle) homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2 mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria. G. sulphuraria supplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2 release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion, G. sulphuraria ability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion. PMID:25874021

  12. Rosa rugosa Aqueous Extract Alleviates Endurance Exercise-Induced Stress.

    PubMed

    Seo, Eunjin; You, Yanghee; Yoon, Ho-Geun; Kim, Boemjeong; Kim, Kyungmi; Lee, Yoo-Hyun; Lee, Jeongmin; Chung, Jin Woong; Shim, Sangin; Jun, Woojin

    2015-06-01

    This study was performed to investigate the effect of water extract from Rosa rugosa (RRW) on endurance exercise-induced stress in mice. The mice were orally administered with distilled water or RRW, respectively. The endurance capacity was evaluated by exhaustive swimming using an adjustable-current water pool. Mice administered RRW swam longer before becoming exhausted. Also, RRW administration resulted in less lipid peroxidation, lower muscular antioxidant enzyme activities, and lower cortisol level. The results suggest that RRW can prevent exercise-induced stress by decreasing oxidative stress levels. PMID:25674938

  13. Aspirin may promote mitochondrial biogenesis via the production of hydrogen peroxide and the induction of Sirtuin1/PGC-1α genes

    PubMed Central

    Kamble, Pratibha; Selvarajan, Krithika; Narasimhulu, Chandrakala Aluganti; Nandave, Mukesh; Parthasarathy, Sampath

    2013-01-01

    Based on the rapid hydrolysis of acetyl salicylic acid (ASA, Aspirin) to salicylic acid (SA), the ability of SA to form dihydroxy benzoic acid (DBA), and the latter’s redox reactions to yield hydrogen peroxide (H2O2), we predicted that ASA may have the potential to induce Sirtuin1 (Sirt1) and its downstream effects. We observed that treatment of cultured liver cells with ASA resulted in the induction of Sirt1, peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC-1α), and NAD(P)H quinone oxidoreductase 1 (Nqo1) genes. Paraoxonase 1 (PON1) and Aryl hydrocarbon receptor (AhR) siRNA transfections inhibited the induction of gene expressions by ASA suggesting the need for the acetyl ester hydrolysis and hydroxylation to DHBA. The latter also induced Sirt1, confirming the proposed pathway. As predicted, ASA and SA treatment resulted in the production of H2O2, a known inducer of Sirt1 and confirmed in the current studies. More importantly, ASA treatment resulted in an increase in mitochondria as seen by tracking dyes. We suggest that DHBA, generated from ASA, via its oxidation/reduction reactions mediated by Nqo1 might be involved in the production of O2-. and H2O2. As Sirt1 and PGC-1α profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases. PMID:23228932

  14. Association of RNase mitochondrial RNA processing enzyme with ribonuclease P in higher ordered structures in the nucleolus: a possible coordinate role in ribosome biogenesis.

    PubMed Central

    Lee, B; Matera, A G; Ward, D C; Craft, J

    1996-01-01

    RNase mitochondrial RNA processing enzyme (MRP) is a nucleolar ribonucleoprotein particle that participates in 5.8S ribosomal RNA maturation in eukaryotes. This enzyme shares a polypeptide and an RNA structural motif with ribonuclease P (RNase P), a nuclear endoribonuclease originally described in the nucleus that processes RNA transcripts to generate their mature 5' termini. Both enzymes are also located in mitochondria. This report further characterizes the relationship between RNase MRP and RNase P. Antisense affinity selection with biotinylated 2'-O-methyl oligoribonucleotides and glycerol gradient fractionation experiments demonstrated that small subpopulations of RNase MRP and RNase P associate with each other in vivo in macromolecular complex, possibly 60-80S preribosomes. This latter notion was supported by fluorescence in situ hybridization experiments with antisense oligonucleotides that localized that RNA components of RNase MRP and RNase P to the nucleolus and to discrete cytoplasmic structures. These findings suggest that small subpopulations of RNase MRP and RNase P are physically associated, and that both may function in ribosomal RNA maturation or ribosome assembly. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8876159

  15. Exercise-induced bronchoconstriction and asthma.

    PubMed Central

    Dryden, Donna M; Spooner, Carol H; Stickland, Michael K; Vandermeer, Ben; Tjosvold, Lisa; Bialy, Liza; Wong, Kai; Rowe, Brian H

    2010-01-01

    OBJECTIVES The objectives are: (1) To assess diagnostic test characteristics of six alternative index tests compared with the selected reference standard-a standardized exercise challenge test (ECT) in patients with suspected exercise-induced bronchoconstriction or asthma (EIB/EIA); (2) to determine the efficacy of a single prophylactic dose of four pharmacologic and one nonpharmacologic interventions vs. placebo to attenuate EIB/EIA in patients with diagnosed EIB/EIA; and (3) to determine if regular daily treatment with short-acting or long-acting beta-agonists (SABA or LABA) causes patients with EIA to develop tachyphylaxis when additional prophylactic doses are used pre-exercise. DATA SOURCES A systematic and comprehensive literature search was conducted in 14 electronic databases (Diagnosis) and the Cochrane Airways Register (Therapy). REVIEW METHODS Study selection, quality assessment, and data extraction were conducted independently by two reviewers. The primary outcome was the maximum percent fall in the post-exercise forced expiratory volume in 1 second (percent fall FEV1). The diagnostic threshold for a positive ECT was a percent fall FEV1 of 10% or more. Sensitivity (SN) and specificity (SP) were calculated. For therapy, mean differences (MD) in the percent fall FEV1 and 95% confidence intervals (CI) (random effects model) were calculated. A positive MD indicates the intervention works better than the control. RESULTS For the diagnostic reviews, 5,318 citations yielded 28 relevant studies; for the therapy reviews, 1,634 citations yielded 109 relevant RCTs. Diagnostic test results versus ECT: self-reported history (2 studies) SN=36-8 percent; SP=85-86 percent; sport specific challenges (5 studies) SN=0-100 percent, SP=0-100 percent; eucapnic voluntary hyperpnea (7 studies) SN=25-90 percent, SP=0-71 percent; free running asthma screening test (3 studies) SN=60-67 percent, SP=47-67 percent; mannitol (3 studies) SN=58-96 percent, SP=65-78 percent. All SN and SP calculations indicated substantial heterogeneity that could not be explained by sensitivity or subgroup analyses. Therapy results: SABA offered greater protection than mast cell stabilizers (MCS) (12 studies); MD=6.8 (95 percent CI: 4.5, 9.2) but combining them offered no additional benefit; SABA versus MCS plus SABA (5 studies) MD=1.3 (95 percent CI: -6.3, 8.9). Leukotriene receptor antagonists (LTRA), MCS, ipratropium bromide, and interval warmup routines provided statistically significant attenuation of EIA when compared with placebo; inhaled corticosteroids (ICS) and other warmup routines did not. Single-dose intervention versus placebo results are: LTRA (9 studies) MD=8.9 (95 percent CI: 6.9, 11.0); MCS (nedocromil sodium) (17 studies) MD=15.6 (95 percent CI: 13.2, 18.2); interval warmup versus no warmup (4 studies) MD=10.6 (95 percent CI: 6.5, 14.7); ICS (4 studies) MD=5.0 (95 percent CI: 0.0, 9.9); continuous low intensity warmup versus no warmup (3 studies) MD=12.6 (95 percent CI: -1.5, 26.7); continuous high intensity warmup versus no warmup (2 studies) MD=9.8 (95 percent CI: -6.4, 26.0). After daily LABA (salmeterol) use for 3 to 4 weeks (4 studies), the percent fall FEV1 following an ECT at 2 and 4 weeks was greater than at day 1 in the LABA arm indicating that tachyphylaxis to prophylactic LABA use occurred. Daily SABA use for 1 week (1 study) also indicated development of tachyphylaxis. However, both LABA and SABA continued to have an attenuating effect on EIA. CONCLUSIONS Given the small number of studies comparing EIB/EIA diagnostic tests, the heterogeneity of the study populations, and the varied study methodologies, there is no clear evidence that any of the index tests are a suitable replacement for a standardized ECT to diagnose EIB/EIA in the general population. All bronchodilator agents and most anti-inflammatory agents when used as pretreatment are somewhat effective in attenuating the percent fall FEV1 associated with EIA. PMID:20726625

  16. Exercise-induced arterial hypoxemia: consequences for locomotor muscle fatigue.

    PubMed

    Romer, Lee M; Dempsey, Jerome A; Lovering, Andrew; Eldridge, Marlowe

    2006-01-01

    Reductions in arterial O2 saturation (-5 to -10% SaO2 < rest) occur over time during sustained heavy intensity exercise in a normoxic environment, due primarily to the effects of acid pH and increased temperature on the position of the HbO2 dissociation curve. We prevented the desaturation via increased F1O2 (.23 to .29) and showed that exercise time to exhaustion was increased. We used supramaximal magnetic stimulation (1 - 100 Hz) of the femoral nerve to test for quadriceps fatigue. We used mildly hyperoxic inspirates (F1O2 .23 to .29) to prevent O2 desaturation. We then compared the amount of quadriceps fatigue incurred following cycling exercise at SaO2 98% vs. 91% with each trial carried out at equal exercise intensities (90% Max) and for equal durations. Preventing the normal exercise-induced O2 desaturation prevented about one-half the amount of exercise-induced quadriceps fatigue; plasma lactate and effort perception were also reduced. We conclude that the normal exercise-induced O2 desaturation during heavy intensity endurance exercise contributes significantly to exercise performance limitation in part because of its effect on locomotor muscle fatigue. These effects of EIAH were confirmed in mild environmental hypoxia (FIO2 .17, SaO2 88%) which significantly augmented the magnitude of exercise-induced quadriceps fatigue observed in normoxia. PMID:17089878

  17. EXERCISE-INDUCED PULMONARY HEMORRHAGE AFTER RUNNING A MARATHON

    EPA Science Inventory

    We report on a healthy 26-year-old male who had an exercise-induced pulmonary hemorrhage (EIPH) within 24 hours of running a marathon. There were no symptoms, abnormalities on exam, or radiographic infiltrates. He routinely participated in bronchoscopy research and the EIPH was e...

  18. The parasympathetic system in exercise-induced rhinorrhoea.

    PubMed

    Harris, W E; Giebaly, K; Adair, C; Alsuwaidan, S; Nicholls, D P; Stanford, C F

    1992-03-01

    The present study demonstrates that ipratropium bromide significantly reduces normal resting nasal secretion (p less than 0.05) and also significantly reduces exercise induced rhinorrhoea compared with a placebo (p less than 0.01). It also demonstrates that there may be another non-parasympathetic cause for the increase in nasal secretion with exercise. PMID:1533728

  19. Diagnosis and Management of Exercise-Induced Asthma.

    ERIC Educational Resources Information Center

    Rupp, Ned T.

    1996-01-01

    Exercise-induced asthma (EIA) affects 12-15% of the population. This comprehensive guide suggests that nearly all individuals with EIA can be active, highlighting both pharmacologic and nonpharmacologic management of asthma and stressing the importance of rigorous patient education in controlling underlying asthma and EIA. (SM)

  20. Exercise-induced asthma. What family physicians should do.

    PubMed Central

    D'Urzo, A.

    1995-01-01

    Exercise-induced asthma is described as a transitory increase in airway resistance during or after vigorous exercise. Nearly 90% of patients with chronic asthma and 40% of allergic nonasthmatic patients have the condition. Family physicians should try to educate patients about their asthma and, barring contraindications, encourage them to participate in regular physical activity. PMID:8563507

  1. Coping with Exercise-Induced Asthma in Sports.

    ERIC Educational Resources Information Center

    Katz, Roger M.

    1987-01-01

    This article reviews the history of research on exercise-induced asthma (EIA) and the pathophysiology of the condition, including its development and influencing factors. Four groups of drugs that are effective against EIA--theopyhlline, beta-adrenergic agents, cromolyn sodium, and anticholinergics--are discussed. (Author/CB)

  2. Human Mitochondrial Protein Database

    National Institute of Standards and Technology Data Gateway

    SRD 131 Human Mitochondrial Protein Database (Web, free access)   The Human Mitochondrial Protein Database (HMPDb) provides comprehensive data on mitochondrial and human nuclear encoded proteins involved in mitochondrial biogenesis and function. This database consolidates information from SwissProt, LocusLink, Protein Data Bank (PDB), GenBank, Genome Database (GDB), Online Mendelian Inheritance in Man (OMIM), Human Mitochondrial Genome Database (mtDB), MITOMAP, Neuromuscular Disease Center and Human 2-D PAGE Databases. This database is intended as a tool not only to aid in studying the mitochondrion but in studying the associated diseases.

  3. Exercise-induced rhabdomyolysis from stationary biking: a case report

    PubMed Central

    Inklebarger, J; Galanis, N; Kirkos, J; Kapetanos, G

    2010-01-01

    There are several reports concerning exercise and rabdomyolysis. There has been no report in the English literature of exercise induced rabdomyolisis from a stationary bike. A 63-year-old female recreational athlete presented to our hospital seeking treatment for lower back, leg pain and stiffness after exercising on a stationary bicycle one day prior. Blood work showed a raised CK of 38,120 U/L, a myoglobin of 5330 and an AST 495 U/L with normal urea and electrolytes. Urinalysis remained negative. She was admitted for oral and intravenous hydration and fluid balance monitoring This is a very rare case of rhabdomyolysis due to exercise. This study highlights the difficulties faced by accident and emergency teams in distinguishing delayed onset muscle soreness (DOMS) from exercise-induced rhabdomyolysis, and reinforces the concept that rhabdomyolysis can occur at any level of exercise intensity. PMID:21311638

  4. Lipid Droplet Biogenesis

    PubMed Central

    Wilfling, Florian; Haas, Joel T.; Walther, Tobias C.; Farese, Robert V.

    2015-01-01

    Lipid droplets (LDs) are found in most cells, where they play central roles in energy and membrane lipid metabolism. The de novo biogenesis of LDs is a fascinating, yet poorly understood process involving the formation of a monolayer bound organelle from a bilayer membrane. Additionally, large LDs can form either by growth of existing LDs or by the combination of smaller LDs through several distinct mechanisms. Here, we review recent insights into the molecular process governing LD biogenesis and highlight areas of incomplete knowledge. PMID:24736091

  5. Electron paramagnetic spectroscopic evidence of exercise-induced free radical accumulation in human skeletal muscle.

    PubMed

    Bailey, Damian M; Lawrenson, Leslie; McEneny, Jane; Young, Ian S; James, Philip E; Jackson, Simon K; Henry, Robert R; Mathieu-Costello, Odile; McCord, Joe M; Richardson, Russell S

    2007-02-01

    The present study determined if acute exercise increased free radical formation in human skeletal muscle. Vastus lateralis biopsies were obtained in a randomized balanced order from six males at rest and following single-leg knee extensor exercise performed for 2 min at 50% of maximal work rate (WR(MAX)) and 3 min at 100% WR(MAX). EPR spectroscopy revealed an exercise-induced increase in mitochondrial ubisemiquinone (UQ*-) [0.167 +/- 0.055 vs. rest: 0.106 +/- 0.047 arbitrary units (AU)/g total protein (TP), P < 0.05] and alpha-phenyl-tert-butylnitrone-adducts (112 +/- 41 vs. rest: 29 +/- 9 AU/mg tissue mass, P < 0.05). Intramuscular lipid hydroperoxides also increased (0.320 +/- 0.263 vs. rest: 0.148 +/- 0.071 nmol/mg TP, P < 0.05) despite an uptake of alpha-tocopherol, alpha-carotene and beta-carotene. There were no relationships between mitochondrial volume density and any biomarkers of oxidative stress. These findings provide the first direct evidence for intramuscular free radical accumulation and lipid peroxidation following acute exercise in humans. PMID:17364944

  6. NAMPT regulates mitochondria biogenesis via NAD metabolism and calcium binding proteins during skeletal muscle contraction

    PubMed Central

    Kim, Jeong Seok; Yoon, Chung-Su; Park, Dae Ryoung

    2014-01-01

    [Purpose] The purpose of this study was to investigate the effect that muscle contraction induced NAD metabolism via NAMPT has on mitochondrial biogenesis. [Methods] Primary skeletal muscle cells were isolated from the gastrocnemius in C57BL/6 mice. The muscle cells were stimulated by electrical current at 1Hz for 3 minutes in conditions of normal or NAD metabolism related inhibitor treatment. NAD/NADH level, Sirt1 and mitochondria biogenesis related signal factor’s changes were examined in normal or NAD metabolism related inhibitor treated cells. [Results] Electrical stimulation (ES) induced muscle contractions significantly increased NAD/NADH levels, NAMPT inhibitor FK-866 inhibited ES-induced NAD formation, which caused SIRT1 expression and PGC-1α deacetylation to decrease. Moreover, NAMPT inhibition decreased mitochondrial biogenesis related mRNA, COX-1 and Tfam levels. Along with AMPK inhibitor, compound C decreases SIRT1 expression, PGC-1α deacetylation and muscle contraction induced mitochondrial biogenesis related mRNA increment. These results indicated that the AMPK-NAMPT signal is a key player for muscle contraction induced SIRT1 expression and PGC-1α deacetylation, which influences mitochondrial biogenesis. Inhibition of the AMPK upregulator, Camkkβ, STO-609 decreased AMPK phosphorylation and SIRT1 expression but did not decrease PGC-1α deacetylation. However, CAMKII inhibition via AIP decreased PGC-1α deacetylation. [Conclusion] In conclusion, the results indicate that NAMPT plays an important role in NAD metabolism and mitochondrial biogenesis. However, mitochondrial biogenesis is also controlled by different calcium binding protein signals including Camkkβ and CAMKII. [Keyword] Muscle contraction, NAD metabolism, SIRT1, PGC-1 α, mitochondria biogenesis. PMID:25566462

  7. Mitochondrial Turnover in the Heart

    PubMed Central

    Gustafsson, sa B.

    2010-01-01

    Mitochondrial quality control is increasingly recognized as an essential element in maintaining optimally functioning tissues. Mitochondrial quality control depends upon a balance between biogenesis and autophagic destruction. Mitochondrial dynamics (fusion and fission) allows for the redistribution of mitochondrial components. We speculate that this permits sorting of highly functional components into one end of a mitochondrion, while damaged components are segregated at the other end, to be jettisoned by asymmetric fission followed by selective mitophagy. Ischemic preconditioning requires autophagy/mitophagy, resulting in selective elimination of damaged mitochondria, leaving behind a population of robust mitochondria with a higher threshold for opening of the mitochondrial permeability transition pore. In this review we will consider the factors that regulate mitochondrial biogenesis and destruction, the machinery involved in both processes, and the biomedical consequences associated with altered mitochondrial turnover. PMID:21147177

  8. Molecular Genetics of Mitochondrial Disorders

    ERIC Educational Resources Information Center

    Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA…

  9. Molecular Genetics of Mitochondrial Disorders

    ERIC Educational Resources Information Center

    Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA

  10. The Curious Question of Exercise-Induced Pulmonary Edema

    PubMed Central

    Bates, Melissa L.; Farrell, Emily T.; Eldridge, Marlowe W.

    2011-01-01

    The question of whether pulmonary edema develops during exercise on land is controversial. Yet, the development of pulmonary edema during swimming and diving is well established. This paper addresses the current controversies that exist in the field of exercise-induced pulmonary edema on land and with water immersion. It also discusses the mechanisms by which pulmonary edema can develop during land exercise, swimming, and diving and the current gaps in knowledge that exist. Finally, this paper discusses how these fields can continue to advance and the areas where clinical knowledge is lacking. PMID:21660232

  11. Sedentary aging increases resting and exercise-induced intramuscular free radical formation.

    PubMed

    Bailey, Damian M; McEneny, Jane; Mathieu-Costello, Odile; Henry, Robert R; James, Philip E; McCord, Joe M; Pietri, Sylvia; Young, Ian S; Richardson, Russell S

    2010-08-01

    Mitochondrial free radical formation has been implicated as a potential mechanism underlying degenerative senescence, although human data are lacking. Therefore, the present study was designed to examine if resting and exercise-induced intramuscular free radical-mediated lipid peroxidation is indeed increased across the spectrum of sedentary aging. Biopsies were obtained from the vastus lateralis in six young (26 + or - 6 yr) and six aged (71 + or - 6 yr) sedentary males at rest and after maximal knee extensor exercise. Aged tissue exhibited greater (P < 0.05 vs. the young group) electron paramagnetic resonance signal intensity of the mitochondrial ubisemiquinone radical both at rest (+138 + or - 62%) and during exercise (+143 + or - 40%), and this was further complemented by a greater increase in alpha-phenyl-tert-butylnitrone adducts identified as a combination of lipid-derived alkoxyl-alkyl radicals (+295 + or - 96% and +298 + or - 120%). Lipid hydroperoxides were also elevated at rest (0.190 + or - 0.169 vs. 0.148 + or - 0.071 nmol/mg total protein) and during exercise (0.567 + or - 0.259 vs. 0.320 + or - 0.263 nmol/mg total protein) despite a more marked depletion of ascorbate and uptake of alpha/beta-carotene, retinol, and lycopene (P < 0.05 vs. the young group). The impact of senescence was especially apparent when oxidative stress biomarkers were expressed relative to the age-related decline in mitochondrial volume density and absolute power output at maximal exercise. In conclusion, these findings confirm that intramuscular free radical-mediated lipid peroxidation is elevated at rest and during acute exercise in aged humans. PMID:20507973

  12. Exercise-induced arterial hypoxaemia in active young women.

    PubMed

    Guenette, Jordan A; Sheel, A William

    2007-12-01

    Studies examining pulmonary gas exchange during exercise have primarily focused on young healthy men, whereas the female response to exercise has received limited attention. Evidence is accumulating that the response of the lungs, airways, and (or) respiratory muscles to exercise is less than ideal and this may significantly compromise oxygen transport in certain groups of otherwise healthy, fit, active, male subjects. Women may be even more susceptible to exercise-induced pulmonary limitations than height-matched men, by virtue of their smaller lung volumes, lower maximal expiratory flow rates, and smaller diffusion surface areas. We have recently shown that exercise-induced arterial hypoxaemia (EIAH) is more prevalent and occurs at relatively lower fitness levels in females than in males. Despite this finding, few physiologically based mechanisms have been identified to explain why women may be more susceptible to EIAH than men. Potential mechanisms of EIAH include relative alveolar hypoventilation, ventilation-perfusion inequality, and diffusion limitation. Whether these mechanisms are different between sexes remains controversial. The primary purpose of this review is to summarize the available data on EIAH in women and to discuss potential sex-based mechanisms for gas exchange impairment. Furthermore, we discuss unresolved questions dealing with pulmonary system limitations during exercise in women. PMID:18059604

  13. Exercise-Induced Anaphylaxis: An Update on Diagnosis and Treatment

    PubMed Central

    Barg, Wojciech; Medrala, Wojciech

    2010-01-01

    Exercise-induced anaphylaxis (EIA) and food-dependent, exercise-induced anaphylaxis (FDEIA) are rare but potentially life-threatening clinical syndromes in which association with exercise is crucial. The range of triggering physical activities is broad, including as mild an effort as a stroll. EIA is not fully repeatable (ie, the same exercise may not always result in anaphylaxis in a given patient). In FDEIA, the combined ingestion of sensitizing food and exercise is necessary to precipitate symptoms. Clinical features and management do not differ significantly from other types of anaphylaxis. The pathophysiology of EIA and FDEIA is not fully understood. Different hypotheses concerning the possible influence of exercise on the development of anaphylactic symptoms are taken into consideration. These include increased gastrointestinal permeability, blood flow redistribution, and most likely increased osmolality. This article also describes current diagnostic and therapeutic possibilities, including changes in lifestyle and preventive properties of antiallergic drugs as well as acute treatment of these dangerous syndromes. PMID:20922508

  14. Effect of simulated weightlessness on exercise-induced anaerobic threshold

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Karst, G. M.; Kirby, C. R.; Goldwater, D. J.

    1986-01-01

    The effect of simulated weightlessness, induced by ten days of continuous bedrest (BR) in the -6 deg head-down position, on the exercise-induced anaerobic threshold (AT) was determined by comparing specific ventilatory and gas-exchange measurements during an incremental ergometer test performed before and after BR. The primary index for determining the exercise-induced AT values of each subject was visual identification of the workrate or oxygen uptake (VO2) at which the ratio of the expired minute ventilation volume (VE) to VO2 exhibited a systematic increase without a concomitant increase in the VE/VCO2 value. Following BR, the mean VO2max of the subjects decreased by 7.0 percent, and the AT decreased from a mean of 1.26 L/min VO2 before BR to 0.95 L/min VO2 after BR. The decrease in AT was manifested by a decrease in both absolute and relative workrates. The change in AT correlated significantly with the change in plasma volume but not with the change in VO2max. The results suggest that the reduction in AT cannot be completely explained by the reduction in VO2, and that the AT decrease is associated with the reduction in intravascular fluid volume.

  15. Exercise-Induced Oxidative Stress and Dietary Antioxidants

    PubMed Central

    Yavari, Abbas; Javadi, Maryam; Mirmiran, Parvin; Bahadoran, Zahra

    2015-01-01

    Context: Overproduction of reactive oxygen and nitrogen species during physical exercise, exercise induced oxidative stress and antioxidant supplementation is interesting and controversial concepts that have been considered during the past decades. Evidence Acquisition: In this review, we aimed to summarize current evidence in relation to antioxidant supplementation outcomes during exercise and physical activity. For this aim, we obtained relevant articles through searches of the Medline and PubMed databases between 1980 to 2013. Although major studies have indicated that antioxidants could attenuate biomarkers of exercise-induced oxidative stress and the use of antioxidant supplement is a common phenomenon among athletes and physically active people, there are some doubts regarding the benefits of these. Results: It seems that the best recommendations regarding antioxidants and exercise are having a balanced diet rich in natural antioxidants and phytochemicals. Conclusions: Regular consumption of various fresh fruits and vegetables, whole grains, legumes and beans, sprouts and seeds is an effective and safe way to meet all antioxidant requirements in physically active persons and athletes. PMID:25883776

  16. Inhaled and oral bronchodilator therapy in exercise induced asthma.

    PubMed

    Anderson, S D; Rozea, P J; Dolton, R; Lindsay, D A

    1975-12-01

    Measurements of peak expiratory flow rate during serial exercise tests were used to assess the efficacy of the beta adrenergic stimulants oral terbutaline (5 mg) and fenoterol aerosol (400 micrograms), in preventing post-exercise bronchoconstriction in 18 asthmatic subjects. While both compounds significantly elevated resting levels of peak expiratory flow rate for at least four hours, there were qualitative and quantitative differences in the effects of the two drugs on exercise induced bronchoconstriction. Oral terbulation did not significantly alter the pattern of response to exercise. However, the peak expiratory flow rates before during and after exercise were significantly higher compared with placebo at two, four and six hours after the drug. The importance of examination of actual values for peak expiratory flow rates as well as percentage changes when testing oral bronchodilators is emphasised. Aerosol fenoterol completely blocked post-exercise bronchoconstriction immediately after inhalation and for up to four hours in most subjects. Bronchodilatation occurred in all subjects during exercise in the presence of both the active and placebo drugs. It is postulated that the superiority of the aerosol in blocking exercise induced bronchoconstriction may be function of its activity at the surface of the bronchial mucosa. PMID:779751

  17. Exercise-induced bronchoconstriction and atopy in Tunisian athletes

    PubMed Central

    Sallaoui, Ridha; Chamari, Karim; Mossa, Abbas; Tabka, Zouhair; Chtara, Moktar; Feki, Youssef; Amri, Mohamed

    2009-01-01

    Background This study is a cross sectional analysis, aiming to evaluate if atopy is as a risk factor for exercise induced bronchoconstriction (EIB) among Tunisian athletes. Methods Atopy was defined by a skin prick test result and EIB was defined as a decrease of at least 15% in forced expiratory volume in one second (FEV1) after 8-min running at 80–85% HRmaxTheo. The study population was composed of 326 athletes (age: 20.8 ± 2.7 yrs – mean ± SD; 138 women and 188 men) of whom 107 were elite athletes. Results Atopy was found in 26.9% (88/326) of the athletes. Post exercise spirometry revealed the presence of EIB in 9.8% of the athletes including 13% of the elite athletes. Frequency of atopy in athletes with EIB was significantly higher than in athletes without EIB [62.5% vs 23.1%, respectively]. Conclusion This study showed that atopic Tunisian athletes presented a higher risk of developing exercise induced bronchoconstriction than non-atopic athletes. PMID:19196480

  18. Serotonin is required for exercise-induced adult hippocampal neurogenesis.

    PubMed

    Klempin, Friederike; Beis, Daniel; Mosienko, Valentina; Kempermann, Gerd; Bader, Michael; Alenina, Natalia

    2013-05-01

    Voluntary wheel running has long been known to induce precursor cell proliferation in adult hippocampal neurogenesis in rodents. However, mechanisms that couple activity with the promitotic effect are not yet fully understood. Using tryptophan hydroxylase (TPH) 2 deficient (Tph2-deficient) mice that lack brain serotonin, we explored the relationship between serotonin signaling and exercise-induced neurogenesis. Surprisingly, Tph2-deficient mice exhibit normal baseline hippocampal neurogenesis but impaired activity-induced proliferation. Our data demonstrate that the proproliferative effect of running requires the release of central serotonin in young-adult and aged mice. Lack of brain serotonin further results in alterations at the stage of Sox2-positive precursor cells, suggesting physiological adaptations to changes in serotonin supply to maintain homeostasis in the neurogenic niche. We conclude that serotonin plays a direct and acute regulatory role in activity-dependent hippocampal neurogenesis. The understanding of exercise-induced neurogenesis might offer preventive but also therapeutic opportunities in depression and age-related cognitive decline. PMID:23658167

  19. Acute versus chronic exercise-induced left-ventricular remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2014-11-01

    Exercise-induced cardiac remodeling (EICR) is the process by which the heart adapts to the physiologic stress of exercise. Non-invasive cardiovascular imaging has led to advances in the understanding of EICR, with sport-specific changes in left-ventricular (LV) structure and function being described; however, the majority of data stem from cross-sectional and short-duration longitudinal studies. Due to the paucity of long-term longitudinal EICR studies, the time course of this process and any distinct differentiation between acute and chronic adaptations remain largely unexplored. In order to clarify the natural history of EICR, longer duration longitudinal study is required. Such work will determine whether exercise-induced changes in myocardial structure and function occur in discrete stages. Examination of prolonged exposures to exercise training will also be necessary to determine normative values across the age and training spectrums of athletic patients. This information will help to distinguish the boundary between physiology and pathology in athletic patients. PMID:25300444

  20. Iron-sulfur protein biogenesis in eukaryotes: components and mechanisms.

    PubMed

    Lill, Roland; Mhlenhoff, Ulrich

    2006-01-01

    Iron-sulfur (Fe/S) clusters require a complex set of proteins to become assembled and incorporated into apoproteins in a living cell. Researchers have described three distinct assembly systems in eukaryotes that are involved in the maturation of cellular Fe/S proteins. Mitochondria are central for biogenesis. They contain the ISC-the iron-sulfur cluster assembly machinery that was inherited from a similar system of eubacteria in evolution and is involved in biogenesis of all cellular Fe/S proteins. The basic principle of mitochondrial (and bacterial) Fe/S protein maturation is the synthesis of the Fe/S cluster on a scaffold protein before the cluster is transferred to apoproteins. Biogenesis of cytosolic and nuclear Fe/S proteins is facilitated by the cytosolic iron-sulfur protein assembly (CIA) apparatus. This process requires the participation of mitochondria that export a still unknown component via the ISC export machinery, including an ABC transporter. PMID:16824008

  1. Peroxisome biogenesis: recent advances.

    PubMed

    Nuttall, James M; Motley, Alison; Hettema, Ewald H

    2011-08-01

    In recent years, it has become evident that peroxisomes form part of the endomembrane system. Peroxisomes can form from the ER via a maturation process and they can multiply by growth and division, whereby the ER provides membrane for growth and ongoing fission (Figure 1). Until very recently, it was widely accepted that most peroxisomal membrane proteins (PMPs) insert directly into peroxisomes, whereas a small subset of PMPs traffic via the ER. In this minireview, we focus mainly on PMP biogenesis, and highlight recent advances in peroxisomal matrix protein import, fission and segregation in yeast. PMID:21689915

  2. Peroxisome Biogenesis and Function

    PubMed Central

    Kaur, Navneet; Reumann, Sigrun; Hu, Jianping

    2009-01-01

    Peroxisomes are small and single membrane-delimited organelles that execute numerous metabolic reactions and have pivotal roles in plant growth and development. In recent years, forward and reverse genetic studies along with biochemical and cell biological analyses in Arabidopsis have enabled researchers to identify many peroxisome proteins and elucidate their functions. This review focuses on the advances in our understanding of peroxisome biogenesis and metabolism, and further explores the contribution of large-scale analysis, such as in sillco predictions and proteomics, in augmenting our knowledge of peroxisome function In Arabidopsis. PMID:22303249

  3. Biogenesis and Assembly of Eukaryotic Cytochrome c Oxidase Catalytic Core

    PubMed Central

    Soto, Ileana C.; Fontanesi, Flavia; Liu, Jingjing; Barrientos, Antoni

    2011-01-01

    Eukaryotic cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. COX is a multimeric enzyme formed by subunits of dual genetic origin which assembly is intricate and highly regulated. The COX catalytic core is formed by three mitochondrial DNA encoded subunits, Cox1, Cox2 and Cox3, conserved in the bacterial enzyme. Their biogenesis requires the action of messenger-specific and subunit-specific factors which facilitate the synthesis, membrane insertion, maturation or assembly of the core subunits. The study of yeast strains and human cell lines from patients carrying mutations in structural subunits and COX assembly factors has been invaluable to identify these ancillary factors. Here we review the current state of knowledge of the biogenesis and assembly of the eukaryotic COX catalytic core and discuss the degree of conservation of the players and mechanisms operating from yeast to human. PMID:21958598

  4. Exercise-induced syncope in a sedentary woman.

    PubMed

    Elashery, Ahmad Ramy; Rickard, John W; Zakaria, Sammy

    2014-12-01

    Vasovagal (neurocardiogenic) syncope, a subtype of reflex syncope, has many well-known triggers. However, we found no previous report of vasovagal exercise-induced syncope in a sedentary person. We present the case of a 35-year-old sedentary woman who experienced vasovagal syncope as she underwent an exercise stress test. Results of evaluations, including resting and stress electrocardiography and echocardiography, were normal. Her presentation is highly unusual: syncope has typically not been associated with exercise except in young athletes, people with structural heart abnormalities, or people with a prolonged QT syndrome. To our knowledge, this is the first report of vasovagal syncope associated with exercise in a sedentary patient who had normal cardiac and electrophysiologic function. We suggest possible physiologic mechanisms and diagnostic strategies. PMID:25593529

  5. Exercise-induced arterial hypoxaemia in athletes: a review.

    PubMed

    Prefaut, C; Durand, F; Mucci, P; Caillaud, C

    2000-07-01

    During exercise, healthy individuals are able to maintain arterial oxygenation, whereas highly-trained endurance athletes may exhibit an exercise-induced arterial hypoxaemia (EIAH) that seems to reflect a gas exchange abnormality. The effects of EIAH are currently debated, and different hypotheses have been proposed to explain its pathophysiology. For moderate exercise, it appears that a relative hypoventilation induced by endurance training is involved. For high-intensity exercise, ventilation/perfusion (V(A)/Q) mismatching and/or diffusion limitation are thought to occur. The causes of this diffusion limitation are still under debate, with hypotheses being capillary blood volume changes and interstitial pulmonary oedema. Moreover, histamine is released during exercise in individuals exhibiting EIAH, and questions persist as to its relationship with EIAH and its contribution to interstitial pulmonary oedema. Further investigations are needed to better understand the mechanisms involved and to determine the long term consequences of repetitive hypoxaemia in highly trained endurance athletes. PMID:10907757

  6. Exercise-Induced Syncope in a Sedentary Woman

    PubMed Central

    Rickard, John W.; Zakaria, Sammy

    2014-01-01

    Vasovagal (neurocardiogenic) syncope, a subtype of reflex syncope, has many well-known triggers. However, we found no previous report of vasovagal exercise-induced syncope in a sedentary person. We present the case of a 35-year-old sedentary woman who experienced vasovagal syncope as she underwent an exercise stress test. Results of evaluations, including resting and stress electrocardiography and echocardiography, were normal. Her presentation is highly unusual: syncope has typically not been associated with exercise except in young athletes, people with structural heart abnormalities, or people with a prolonged QT syndrome. To our knowledge, this is the first report of vasovagal syncope associated with exercise in a sedentary patient who had normal cardiac and electrophysiologic function. We suggest possible physiologic mechanisms and diagnostic strategies. PMID:25593529

  7. Dietary strategies to recover from exercise-induced muscle damage.

    PubMed

    Sousa, Mnica; Teixeira, Vtor H; Soares, Jos

    2014-03-01

    Exhaustive or unaccustomed intense exercise can cause exercise-induced muscle damage (EIMD) and its undesirable consequences may decrease the ability to exercise and to adhere to a training programme. This review briefly summarises the muscle damage process, focusing predominantly on oxidative stress and inflammation as contributing factors, and describes how nutrition may be positively used to recover from EIMD. The combined intake of carbohydrates and proteins and the use of antioxidants and/or anti-inflammatory nutrients within physiological ranges are interventions that may assist the recovery process. Although the works studying food instead of nutritional supplements are very scarce, their results seem to indicate that food might be a favourable option as a recovery strategy. To date, the only tested foods were milk, cherries, blueberries and pomegranate with promising results. Other potential solutions are foods rich in protein, carbohydrates, antioxidants and/or anti-inflammatory nutrients. PMID:24180469

  8. Exploring the Relationship between Exercise-Induced Arousal and Cognition Using Fractionated Response Time

    ERIC Educational Resources Information Center

    Chang, Yu-Kai; Etnier, Jennifer L.; Barella, Lisa A.

    2009-01-01

    Although a generally positive effect of acute exercise on cognitive performance has been demonstrated, the specific nature of the relationship between exercise-induced arousal and cognitive performance remains unclear. This study was designed to identify the relationship between exercise-induced arousal and cognitive performance for the central

  9. Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency

    ERIC Educational Resources Information Center

    Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

    2010-01-01

    Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced

  10. Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency

    ERIC Educational Resources Information Center

    Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

    2010-01-01

    Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…

  11. The role of muscle mass in exercise-induced hyperemia

    PubMed Central

    Groot, H. Jonathan; Rossman, Matthew J.; Gifford, Jayson R.; Richardson, Russell S.

    2014-01-01

    Exercise-induced hyperemia is often normalized for muscle mass, and this value is sometimes evaluated at relative exercise intensities to take muscle recruitment into account. Therefore, this study sought to better understand the impact of muscle mass on leg blood flow (LBF) during exercise. LBF was assessed by Doppler ultrasound in 27 young healthy male subjects performing knee-extensor (KE) exercise at three absolute (5, 15, and 25 W) and three relative [20, 40, and 60% of maximum KE (KEmax)] workloads. Thigh muscle mass (5.2–8.1 kg) and LBF were significantly correlated at rest (r = 0.54; P = 0.004). Exercise-induced hyperemia was linearly related to absolute workload, but revealed substantial between-subject variability, documented by the coefficient of variation (5 W: 17%; 15 W: 16%; 25 W: 16%). Quadriceps muscle mass (1.5–2.7 kg) and LBF were not correlated at 5, 15, or 25 W (r = 0.09–0.01; P = 0.7–0.9). Normalizing blood flow for quadriceps muscle mass did not improve the coefficient of variation at each absolute workload (5 W: 21%; 15 W: 21%; 25 W: 22%), while the additional evaluation at relative exercise intensities resulted in even greater variance (20% KEmax: 29%; 40% KEmax: 29%; 60% KEmax: 27%). Similar findings were documented when subjects were parsed into high and low aerobic capacity. Thus, in contrast to rest, blood flow during exercise is unrelated to muscle mass, and simply normalizing for muscle mass or comparing normalized blood flow at a given relative exercise intensity has no effect on the inherent blood flow variability. Therefore, during exercise, muscle mass does not appear to be a determinant of the hyperemic response. PMID:24674856

  12. Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans.

    PubMed

    Layec, Gwenael; Trinity, Joel D; Hart, Corey R; Kim, Seong-Eun; Groot, H Jonathan; Le Fur, Yann; Sorensen, Jacob R; Jeong, Eun-Kee; Richardson, Russell S

    2015-08-15

    Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 2 yr) and old (74 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 8 mM/min) and old (24 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 2.0 and 3.7 1.7 mMmin(-1)W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age. PMID:26041112

  13. Biogenesis of thylakoid membranes.

    PubMed

    Rast, Anna; Heinz, Steffen; Nickelsen, Jrg

    2015-09-01

    Thylakoids mediate photosynthetic electron transfer and represent one of the most elaborate energy-transducing membrane systems. Despite our detailed knowledge of its structure and function, much remains to be learned about how the machinery is put together. The concerted synthesis and assembly of lipids, proteins and low-molecular-weight cofactors like pigments and transition metal ions require a high level of spatiotemporal coordination. While increasing numbers of assembly factors are being functionally characterized, the principles that govern how thylakoid membrane maturation is organized in space are just starting to emerge. In both cyanobacteria and chloroplasts, distinct production lines for the fabrication of photosynthetic complexes, in particular photosystem II, have been identified. This article is part of a Special Issue entitled: Chloroplast Biogenesis. PMID:25615584

  14. Unraveling the complexities of SIRT1-mediated mitochondrial regulation in skeletal muscle.

    PubMed

    Philp, Andrew; Schenk, Simon

    2013-07-01

    Sirtuin 1 (SIRT1) is a purported central regulator of skeletal muscle mitochondrial biogenesis. Herein, we discuss our recent work using conditional mouse models, which highlight the complexities of SIRT1 biology in vivo, and question the role of SIRT1 in regulating mitochondrial function and mitochondrial adaptations to endurance exercise. Furthermore, we discuss the possible contribution of proposed SIRT1 substrates to muscle mitochondrial biogenesis. PMID:23792490

  15. Incidence of exercise-induced arterial hypoxemia in prepubescent females.

    PubMed

    Laursen, Paul B; Tsang, Garry C K; Smith, Gareth J; van Velzen, Min V; Ignatova, B B; Sprules, Erica B; Chu, Kelly S; Coutts, Kenneth D; McKenzie, Donald C

    2002-07-01

    Due to the recent discovery of exercise-induced arterial hypoxemia (EIAH) in healthy active women with normal levels of peak oxygen uptake (V'(O(2)peak), this study examined the incidence of EIAH in prepubescent females. Nineteen healthy, active, prepubescent females (X +/- SD: age = 11.1 +/- 1.6 years; height = 145.8 +/- 9.1 cm; weight = 35.6 +/- 7.0 kg) performed a progressive maximal exercise test on an electronically braked cycle ergometer starting at 0 W and increasing power by 15 W. min(-1). During this test, expired gases, heart rate (HR), and percent arterial oxyhemoglobin saturation (%SaO(2)) were measured. Results for physiological variables at maximal exercise were as follows: V'(O(2)peak) = 43.7 +/- 7.0 ml x kg(-1) x min(-1); HR(max) = 199 +/- 5 beats x min(-1); %SaO(2) = 96.6 +/- 1.2%. For nearly all subjects, the %SaO(2) at maximal exercise was above levels that would reduce V'(O(2)peak). Therefore, in comparison to previous reports of EIAH in adult women with similar V'(O(2)peak), EIAH does not appear to occur in the prepubescent female population. PMID:12112795

  16. Exercise-Induced Pulmonary Edema in a Triathlon.

    PubMed

    Yamanashi, Hirotomo; Koyamatsu, Jun; Nobuyoshi, Masaharu; Murase, Kunihiko; Maeda, Takahiro

    2015-01-01

    Introduction. Family physicians have more opportunities to attend athletic competitions as medical staff at first-aid centers because of the increasing popularity of endurance sports. Case. A 38-year-old man who participated in a triathlon race experienced difficulty in breathing after swimming and was moved to a first-aid center. His initial oxygen saturation was 82% and a thoracic computed tomography scan showed bilateral ground glass opacity in the peripheral lungs. His diagnosis was noncardiogenic pulmonary edema associated with exercise or swimming: exercise-induced pulmonary edema (EIPE) or swimming-induced pulmonary edema (SIPE). Treatment with furosemide and corticosteroid relieved his symptoms of pulmonary edema. Discussion. Noncardiogenic pulmonary edema associated with endurance sports is not common, but knowledge about EIPE/SIPE or neurogenic pulmonary edema associated with hyponatremia, which is called Ayus-Arieff syndrome, is crucial. Knowledge and caution for possible risk factors, such as exposure to cold water or overhydration, are essential for both medical staff and endurance athletes. Conclusion. To determine the presence of pulmonary edema associated with strenuous exercise, oxygen saturation should be used as a screening tool at a first-aid center. To avoid risks for EIPE/SIPE, knowledge about these diseases is essential for medical staff and for athletes who perform extreme exercise. PMID:26229538

  17. Resistance to exercise-induced weight loss: compensatory behavioral adaptations

    PubMed Central

    Melanson, Edward L.; Keadle, Sarah Kozey; Donnelly, Joseph E.; Braun, Barry; King, Neil A.

    2013-01-01

    In many interventions that are based on an exercise program intended to induce weight loss, the mean weight loss observed is modest and sometimes far less than the individual expected. The individual responses are also widely variable, with some individuals losing a substantial amount of weight, others maintaining weight, and a few actually gaining weight. The media have focused on the sub-population that loses little weight, contributing to a public perception that exercise has limited utility to cause weight loss. The purpose of the symposium was to present recent, novel data that help explain how compensatory behaviors contribute to a wide discrepancy in exercise-induced weight loss. The presentations provide evidence that some individuals adopt compensatory behaviors, i.e. increased energy intake and/or reduced activity, that offset the exercise energy expenditure and limit weight loss. The challenge for both scientists and clinicians is to develop effective tools to identify which individuals are susceptible to such behaviors, and to develop strategies to minimize their impact. PMID:23470300

  18. Exercise-Induced Pulmonary Edema in a Triathlon

    PubMed Central

    Yamanashi, Hirotomo; Koyamatsu, Jun; Nobuyoshi, Masaharu; Murase, Kunihiko; Maeda, Takahiro

    2015-01-01

    Introduction. Family physicians have more opportunities to attend athletic competitions as medical staff at first-aid centers because of the increasing popularity of endurance sports. Case. A 38-year-old man who participated in a triathlon race experienced difficulty in breathing after swimming and was moved to a first-aid center. His initial oxygen saturation was 82% and a thoracic computed tomography scan showed bilateral ground glass opacity in the peripheral lungs. His diagnosis was noncardiogenic pulmonary edema associated with exercise or swimming: exercise-induced pulmonary edema (EIPE) or swimming-induced pulmonary edema (SIPE). Treatment with furosemide and corticosteroid relieved his symptoms of pulmonary edema. Discussion. Noncardiogenic pulmonary edema associated with endurance sports is not common, but knowledge about EIPE/SIPE or neurogenic pulmonary edema associated with hyponatremia, which is called Ayus-Arieff syndrome, is crucial. Knowledge and caution for possible risk factors, such as exposure to cold water or overhydration, are essential for both medical staff and endurance athletes. Conclusion. To determine the presence of pulmonary edema associated with strenuous exercise, oxygen saturation should be used as a screening tool at a first-aid center. To avoid risks for EIPE/SIPE, knowledge about these diseases is essential for medical staff and for athletes who perform extreme exercise. PMID:26229538

  19. Exercise-induced knee joint laxity in distance runners.

    PubMed Central

    Johannsen, H V; Lind, T; Jakobsen, B W; Krner, K

    1989-01-01

    The objectives of this study were to evaluate the effect of exercise on knee joint laxity. If exercise induced laxity is physiological, incorporation of this quality into a ligament replacement material would be indicated. Twenty recreational long distance runners average age 41 (range 24 to 50 yr) were tested before and immediately after 30 minutes of running. Using a computerized goniometer type instrument (Acufex KSS), knee flexion, axial tibial rotation and anterior-posterior tibial displacement were simultaneously recorded, while the runners underwent tests of static as well as dynamic knee joint laxity. At 30 degrees of knee flexion, a maximum increase of 16 per cent in mean total anterior-posterior laxity post-exercise was found. At the examination 30 minutes post-exercise, laxity at 30 degrees of knee flexion was still increased. However, laxity at 90 degrees of knee flexion had decreased to pre-exercise levels or below. Anterior tibial displacement, recorded during eccentric quadriceps activity (0 to 90 degrees of knee flexion) with weights attached to the foot, showed a maximum of 18 per cent increase in total anterior-posterior laxity post-exercise. It is suggested that the laxity increase is caused in part by a true ligamentous laxity increase, and in part by a decreased resting tone of the fatigued muscles. PMID:2620230

  20. Exercise-Induced Muscle Damage and Running Economy in Humans

    PubMed Central

    Assumpo, Cludio de Oliveira; Lima, Leonardo Coelho Rabello; Oliveira, Felipe Bruno Dias; Greco, Camila Coelho; Denadai, Benedito Srgio

    2013-01-01

    Running economy (RE), defined as the energy demand for a given velocity of submaximal running, has been identified as a critical factor of overall distance running performance. Plyometric and resistance trainings, performed during a relatively short period of time (~1530 days), have been successfully used to improve RE in trained athletes. However, these exercise types, particularly when they are unaccustomed activities for the individuals, may cause delayed onset muscle soreness, swelling, and reduced muscle strength. Some studies have demonstrated that exercise-induced muscle damage has a negative impact on endurance running performance. Specifically, the muscular damage induced by an acute bout of downhill running has been shown to reduce RE during subsequent moderate and high-intensity exercise (>65% VO2max). However, strength exercise (i.e., jumps, isoinertial and isokinetic eccentric exercises) seems to impair RE only for subsequent high-intensity exercise (~90% VO2max). Finally, a single session of resistance exercise or downhill running (i.e., repeated bout effect) attenuates changes in indirect markers of muscle damage and blunts changes in RE. PMID:23431253

  1. Peroxisomal Biogenesis in Ischemic Brain

    PubMed Central

    Young, Jennifer M.; Nelson, Jonathan W.; Cheng, Jian; Zhang, Wenri; Mader, Sarah; Davis, Catherine M.; Morrison, Richard S.

    2015-01-01

    Abstract Aims: Peroxisomes are highly adaptable and dynamic organelles, adjusting their size, number, and enzyme composition to changing environmental and metabolic demands. We determined whether peroxisomes respond to ischemia, and whether peroxisomal biogenesis is an adaptive response to cerebral ischemia. Results: Focal cerebral ischemia induced peroxisomal biogenesis in peri-infarct neurons, which was associated with a corresponding increase in peroxisomal antioxidant enzyme catalase. Peroxisomal biogenesis was also observed in primary cultured cortical neurons subjected to ischemic insult induced by oxygen-glucose deprivation (OGD). A catalase inhibitor increased OGD-induced neuronal death. Moreover, preventing peroxisomal proliferation by knocking down dynamin-related protein 1 (Drp1) exacerbated neuronal death induced by OGD, whereas enhancing peroxisomal biogenesis pharmacologically using a peroxisome proliferator-activated receptor-alpha agonist protected against neuronal death induced by OGD. Innovation: This is the first documentation of ischemia-induced peroxisomal biogenesis in mammalian brain using a combined in vivo and in vitro approach, electron microscopy, high-resolution laser-scanning confocal microscopy, and super-resolution structured illumination microscopy. Conclusion: Our findings suggest that neurons respond to ischemic injury by increasing peroxisome biogenesis, which serves a protective function, likely mediated by enhanced antioxidant capacity of neurons. Antioxid. Redox Signal. 22, 109120. PMID:25226217

  2. Mitochondrial Therapeutics for Cardioprotection

    PubMed Central

    Carreira, Raquel S.; Lee, Pamela; Gottlieb, Roberta A.

    2013-01-01

    Mitochondria represent approximately one-third of the mass of the heart and play a critical role in maintaining cellular function—however, they are also a potent source of free radicals and pro-apoptotic factors. As such, maintaining mitochondrial homeostasis is essential to cell survival. As the dominant source of ATP, continuous quality control is mandatory to ensure their ongoing optimal function. Mitochondrial quality control is accomplished by the dynamic interplay of fusion, fission, autophagy, and mitochondrial biogenesis. This review examines these processes in the heart and considers their role in the context of ischemia-reperfusion injury. Interventions that modulate mitochondrial turnover, including pharmacologic agents, exercise, and caloric restriction are discussed as a means to improve mitochondrial quality control, ameliorate cardiovascular dysfunction, and enhance longevity. PMID:21718247

  3. The role of antioxidant vitamins and enzymes in the prevention of exercise-induced muscle damage.

    PubMed

    Dekkers, J C; van Doornen, L J; Kemper, H C

    1996-03-01

    A growing amount of evidence indicates that free radicals play an important role as mediators of skeletal muscle damage and inflammation after strenuous exercise. It has been postulated that the generation of oxygen free radicals is increased during exercise as a result of increases in mitochondrial oxygen consumption and electron transport flux, inducing lipid peroxidation. The literature suggests that dietary antioxidants are able to detoxify the peroxides produced during exercise, which could otherwise result in lipid peroxidation, and that they are capable of scavenging peroxyl radicals and therefore may prevent muscle damage. Endogenous antioxidant enzymes also play a protective role in the process of lipid peroxidation. The studies reviewed (rodent and human) show significant increases of malondialdehyde (a product of lipid peroxidation) after exercise to exhaustion, and also favourable changes in plasma antioxidant levels and in antioxidant enzyme activity. In trained individuals and trained rats, the antioxidant enzyme activity increases markedly. In this way, the increased oxidative stress induced by exercise is compromised by increased antioxidant activity, preventing lipid peroxidation. Human studies have shown that dietary supplementation with antioxidant vitamins has favourable effects on lipid peroxidation after exercise. Although several points of discussion still exist, the question whether antioxidant vitamins and antioxidant enzymes play a protective role in exercise-induced muscle damage can be answered affirmatively. The human studies reviewed indicate that antioxidant vitamin supplementation can be recommended to individuals performing regular heavy exercise. Moreover, trained individuals have an advantage compared with untrained individuals, as training results in increased activity of several major antioxidant enzymes and overall antioxidant status. However, future studies are needed in order to be able to give more specific information and recommendations on this topic. PMID:8776010

  4. [Advances of studies on acupuncture and moxibustion for exercise-induced fatigue].

    PubMed

    Zhang, Yan-hong; Liu, Jun; Li, Xiao-feng; Jia, Chun-sheng

    2010-03-01

    This paper introduces recent advances in research and clinical trials on treating exercise-induced fatigue with acupuncture, focusing on the areas of oxygen free radical scavenging and anti-lipid peroxidation activity, the regulation of immune function, prevention of dysfunction exercise induced hypothalamus-pituitary-gonadal axis, improvement of energy metabolism, the ability to maintain internal environment, the ability to alleviate delayed-on set muscle soreness (DOMS), and anti-central nervous system fatigue. This paper is intended to explain that because of its safety, effectiveness, less adverse reactions, and not involving stimulants, acupuncture has great potential to protect against exercise-induced fatigue. However, there are problems of acupoints selection, manipulation and indicators. Therefore, it needs further investigations to explore the advantages of acupuncture treatment for the exercise-induced fatigue. PMID:20496745

  5. Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease.

    PubMed

    Perez-Schindler, Joaquin; Philp, Andrew

    2015-10-01

    Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease. PMID:26186742

  6. MicroRNA-27b Regulates Mitochondria Biogenesis in Myocytes

    PubMed Central

    Zhang, Shunhua; Du, Jingjing; Bai, Lin; Zhang, Yi; Jiang, Yanzhi; Li, Xuewei; Wang, Jinyong; Zhu, Li

    2016-01-01

    MicroRNAs (miRNAs) are small, non-coding RNAs that affect the post-transcriptional regulation of various biological pathways. To date, it is not fully understood how miRNAs regulate mitochondrial biogenesis. This study aimed at the identification of the role of miRNA-27b in mitochondria biogenesis. The mitochondria content in C2C12 cells was significantly increased during myogenic differentiation and accompanied by a marked decrease of miRNA-27b expression. Furthermore, the expression of the predicted target gene of miRNA-27b, forkhead box j3 (Foxj3), was also increased during myogenic differentiation. Luciferase activity assays confirmed that miRNA-27b directly targets the 3’-untranslated region (3’-UTR) of Foxj3. Overexpression of miRNA-27b provoked a decrease of mitochondria content and diminished expression of related mitochondrial genes and Foxj3 both at mRNA and protein levels. The expression levels of downstream genes of Foxj3, such as Mef2c, PGC1α, NRF1 and mtTFA, were also decreased in C2C12 cells upon overexpression of miRNA-27b. These results suggested that miRNA-27b may affect mitochondria biogenesis by down-regulation of Foxj3 during myocyte differentiation. PMID:26849429

  7. Noninvasive profiling of exercise-induced hypoxemia in competitive cyclists.

    PubMed

    Siegler, Jason C; Robergs, Robert A; Faria, Eric W; Wyatt, Frank B; McCarthy, Jason

    2007-01-01

    The purpose of this case study was to profile maximal exercise and the incidence of exercise-induced arterial hypoxemia (EIAH) at three different altitudes within a group of competitive cyclists residing and training at 1,500 m. Ten male cyclists (category I or II professional road cyclists: ages, 27.7 +/- 6.1; weight, 69.9 +/- 6.9 kg) participated in three randomly assigned VO2max tests at sea level (SL), 1,500 m and 3000 m. Arterial saturation (pulse oximetry), ventilation, and power output (PO) were recorded continuously throughout the test. The SaO2 percentages at VO2max were significantly higher at SL when compared with 1500 m (p < 0.001); however, no difference was observed between VO2max values at either altitude (SL: 72.3 +/- 2.5 mL.kg-1.min-1, 1,500 m: 70.6 +/- 2.3 mL.kg-1.min-1), only when compared with 3,000 m: 63.9 +/- 2.1 mL.kg-1.min-1, p < 0.021. Percent SaO2 did correspond with maximal PO, and there was an overall main effect observed between POs as they continually declined from SL to 3,000 m (SL: 403.3 +/- 10.6 W; 1,500 m: 376.1 +/- 9.8 W; 3,000 m: 353.9 +/- 7.8 W; p < 0.0001). The results of this case study revealed that training and residing at 1,500 m did not reduce the incidence of EIAH during maximal exercise at 1,500 m for this selected group of cyclists. PMID:17365952

  8. Supraglottoplasty as treatment of exercise induced laryngeal obstruction (EILO).

    PubMed

    Mehlum, Camilla Slot; Walsted, Emil Schwarz; Godballe, Christian; Backer, Vibeke

    2016-04-01

    Breathing difficulties during exertion may be caused by exercise-induced laryngeal obstruction (EILO). The diagnosis depends on visualization of the larynx during exercise, i.e. by continuous laryngoscopic exercise (CLE) test. In case of severe supraglottic collapse and pronounced symptoms during strenuous exertion, surgical treatment (supraglottoplasty) has been suggested. The aims of this study were to evaluate outcome and patient satisfaction after supraglottoplasty for EILO and to compare our results with previously reported data. During the period December 2010 to October 2013, 17 patients diagnosed with moderate to severe supraglottic EILO were treated by supraglottoplasty with microlaryngoscopic laser technique at our institutions. The severity of patients symptoms (VAS score) and CLE scores was evaluated pre- and postoperatively. We found a decrease in patients symptoms from median 80 points VAS score preoperatively to 20 points postoperatively (p < 0.001) and a decrease in CLE sum score from median 4.0 points to 2.5 points (p < 0.05). Several previous studies have recommended surgery for selected patients with supraglottic involvement, but these have mainly been based on case reports or on very few patients. This study is the second larger-scale study that documents the positive effect of supraglottoplasty as treatment of EILO in terms of reduced respiratory symptoms and decreased laryngeal obstruction assessed by post-operative CLE test. We suggest that surgery is a well-tolerated and effective treatment option for selected EILO patients with moderate to severe supraglottic obstruction during exercise and a high level of physical activity. PMID:26541712

  9. Air quality and temperature effects on exercise-induced bronchoconstriction.

    PubMed

    Rundell, Kenneth W; Anderson, Sandra D; Sue-Chu, Malcolm; Bougault, Valerie; Boulet, Louis-Philippe

    2015-04-01

    Exercise-induced bronchoconstriction (EIB) is exaggerated constriction of the airways usually soon after cessation of exercise. This is most often a response to airway dehydration in the presence of airway inflammation in a person with a responsive bronchial smooth muscle. Severity is related to water content of inspired air and level of ventilation achieved and sustained. Repetitive hyperpnea of dry air during training is associated with airway inflammatory changes and remodeling. A response during exercise that is related to pollution or allergen is considered EIB. Ozone and particulate matter are the most widespread pollutants of concern for the exercising population; chronic exposure can lead to new-onset asthma and EIB. Freshly generated emissions particulate matter less than 100 nm is most harmful. Evidence for acute and long-term effects from exercise while inhaling high levels of ozone and/or particulate matter exists. Much evidence supports a relationship between development of airway disorders and exercise in the chlorinated pool. Swimmers typically do not respond in the pool; however, a large percentage responds to a dry air exercise challenge. Studies support oxidative stress mediated pathology for pollutants and a more severe acute response occurs in the asthmatic. Winter sport athletes and swimmers have a higher prevalence of EIB, asthma and airway remodeling than other athletes and the general population. Because of fossil fuel powered ice resurfacers in ice rinks, ice rink athletes have shown high rates of EIB and asthma. For the athlete training in the urban environment, training during low traffic hours and in low traffic areas is suggested. PMID:25880506

  10. Modulating exercise-induced hormesis: Does less equal more?

    PubMed

    Peake, Jonathan M; Markworth, James F; Nosaka, Kazunori; Raastad, Truls; Wadley, Glenn D; Coffey, Vernon G

    2015-08-01

    Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional/performance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise. PMID:25977451

  11. Spaceflight suppresses exercise-induced release of bioassayable growth hormone.

    PubMed

    McCall, G E; Goulet, C; Roy, R R; Grindeland, R E; Boorman, G I; Bigbee, A J; Hodgson, J A; Greenisen, M C; Edgerton, V R

    1999-09-01

    We have reported that bed rest suppressed the release of bioassayable growth hormone (BGH) that normally occurs after an acute bout of unilateral plantar flexor exercise (G. E. McCall, C. Goulet, R. E. Grindeland, J. A. Hodgson, A. J. Bigbee, and V. R. Edgerton. J. Appl. Physiol. 83: 2086-2090, 1997). In the present study, the effects of spaceflight on the hormonal responses to this exercise protocol were examined. Four male astronauts on the National Aeronautics and Space Administration Shuttle Transport System (STS-78) mission completed the exercise protocol before, during, and after a 17-day spaceflight. The maximal voluntary contraction torque output at the onset of exercise was similar on all test days. Before spaceflight, plasma BGH increased 114-168% from pre- to postexercise. During spaceflight and after 2 days recovery at normal gravity (1 G), the BGH response to exercise was absent. After 4 days of recovery, this response was restored. Plasma concentrations of immunoassayable growth hormone were similar at all time points. The preexercise plasma immunoassayable insulin-like growth factor I (IGF-I) levels were elevated after 12 or 13 days of microgravity, and a approximately 7% postexercise IGF-I increase was independent of this spaceflight effect. The suppression of the BGH response to exercise during spaceflight indicates that some minimum level of chronic neuromuscular activity and/or loading is necessary to maintain a normal exercise-induced BGH release. Moreover, these results suggest that there is a muscle afferent-pituitary axis that can modulate BGH release. PMID:10484597

  12. Exercise-induced oxidative stress and hypoxic exercise recovery.

    PubMed

    Ballmann, Christopher; McGinnis, Graham; Peters, Bridget; Slivka, Dustin; Cuddy, John; Hailes, Walter; Dumke, Charles; Ruby, Brent; Quindry, John

    2014-04-01

    Hypoxia due to altitude diminishes performance and alters exercise oxidative stress responses. While oxidative stress and exercise are well studied, the independent impact of hypoxia on exercise recovery remains unknown. Accordingly, we investigated hypoxic recovery effects on post-exercise oxidative stress. Physically active males (n = 12) performed normoxic cycle ergometer exercise consisting of ten high:low intensity intervals, 20 min at moderate intensity, and 6 h recovery at 975 m (normoxic) or simulated 5,000 m (hypoxic chamber) in a randomized counter-balanced cross-over design. Oxygen saturation was monitored via finger pulse oximetry. Blood plasma obtained pre- (Pre), post- (Post), 2 h post- (2Hr), 4 h post- (4Hr), and 6 h (6Hr) post-exercise was assayed for Ferric Reducing Ability of Plasma (FRAP), Trolox Equivalent Antioxidant Capacity (TEAC), Lipid Hydroperoxides (LOOH), and Protein Carbonyls (PC). Biopsies from the vastus lateralis obtained Pre and 6Hr were analyzed by real-time PCR quantify expression of Heme oxygenase 1 (HMOX1), Superoxide Dismutase 2 (SOD2), and Nuclear factor (euthyroid-derived2)-like factor (NFE2L2). PCs were not altered between trials, but a time effect (13 % Post-2Hr increase, p = 0.044) indicated exercise-induced blood oxidative stress. Plasma LOOH revealed only a time effect (p = 0.041), including a 120 % Post-4Hr increase. TEAC values were elevated in normoxic recovery versus hypoxic recovery. FRAP values were higher 6Hr (p = 0.045) in normoxic versus hypoxic recovery. Exercise elevated gene expression of NFE2L2 (20 % increase, p = 0.001) and SOD2 (42 % increase, p = 0.003), but hypoxic recovery abolished this response. Data indicate that recovery in a hypoxic environment, independent of exercise, may alter exercise adaptations to oxidative stress and metabolism. PMID:24384982

  13. Deciphering protein-protein interactions during the biogenesis of cytochrome c oxidase from Paracoccus denitrificans.

    PubMed

    Gurumoorthy, Priya; Ludwig, Bernd

    2015-02-01

    Biogenesis of the mitochondrial cytochrome c oxidase (COX) is a complex process due to its numerous subunits encoded by two genomes, as well as the localization of redox centers deep within the membrane. Here, we have assessed the biogenesis of the homologous aa?-type oxidase of the soil bacterium Paracoccus denitrificans. First, protein partners were analyzed using various membrane solubilization strategies to show interactions between COX and CtaG, a chaperone implicated in CuB site metallation. Using an unbiased MS approach after immunological pull-down from untreated or cross-linked membranes, we then extend our view towards a hypothetical 'biogenesis complex' by identifying two further metal-inserting chaperones, Surf1c and Sco, together with enzymes catalyzing heme a synthesis. Our study also tentatively supports previous speculation regarding the existence of a predominantly co-translational mechanism for cofactor insertion during COX biogenesis. PMID:25420759

  14. Iron-sulfur clusters: biogenesis, molecular mechanisms, and their functional significance.

    PubMed

    Xu, Xiang Ming; Mller, Simon Geir

    2011-07-01

    Iron-sulfur clusters [Fe-S] are small, ubiquitous inorganic cofactors representing one of the earliest catalysts during biomolecule evolution and are involved in fundamental biological reactions, including regulation of enzyme activity, mitochondrial respiration, ribosome biogenesis, cofactor biogenesis, gene expression regulation, and nucleotide metabolism. Although simple in structure, [Fe-S] biogenesis requires complex protein machineries and pathways for assembly. [Fe-S] are assembled from cysteine-derived sulfur and iron onto scaffold proteins followed by transfer to recipient apoproteins. Several predominant iron-sulfur biogenesis systems have been identified, including nitrogen fixation (NIF), sulfur utilization factor (SUF), iron-sulfur cluster (ISC), and cytosolic iron-sulfur protein assembly (CIA), and many protein components have been identified and characterized. In eukaryotes ISC is mainly localized to mitochondria, cytosolic iron-sulfur protein assembly to the cytosol, whereas plant sulfur utilization factor is localized mainly to plastids. Because of this spatial separation, evidence suggests cross-talk mediated by organelle export machineries and dual targeting mechanisms. Although research efforts in understanding iron-sulfur biogenesis has been centered on bacteria, yeast, and plants, recent efforts have implicated inappropriate [Fe-S] biogenesis to underlie many human diseases. In this review we detail our current understanding of [Fe-S] biogenesis across species boundaries highlighting evolutionary conservation and divergence and assembling our knowledge into a cellular context. PMID:20812788

  15. Ironsulfur cluster biogenesis and human disease

    PubMed Central

    Rouault, Tracey A.; Tong, Wing Hang

    2008-01-01

    Ironsulfur (FeS) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Human FeS cluster assembly proteins are frequently encoded by single genes, and inherited defects in some of these genes cause disease. Recently, the spectrum of diseases attributable to abnormal FeS cluster biogenesis has extended beyond Friedreich ataxia to include a sideroblastic anemia with deficiency of glutaredoxin 5 and a myopathy associated with a deficiency of a FeS cluster assembly scaffold protein, ISCU. Mutations within other mammalian FeS cluster assembly genes could be causative for human diseases that manifest distinctive combinations of tissue-specific impairments. Thus, defects in the ironsulfur cluster biogenesis pathway could underlie many human diseases. PMID:18606475

  16. Mitochondrial Signaling: Forwards, Backwards, and In Between

    PubMed Central

    Whelan, Sean P.; Zuckerbraun, Brian S.

    2013-01-01

    Mitochondria are semiautonomous organelles that are a defining characteristic of almost all eukaryotic cells. They are vital for energy production, but increasing evidence shows that they play important roles in a wide range of cellular signaling and homeostasis. Our understanding of nuclear control of mitochondrial function has expanded over the past half century with the discovery of multiple transcription factors and cofactors governing mitochondrial biogenesis. More recently, nuclear changes in response to mitochondrial messaging have led to characterization of retrograde mitochondrial signaling, in which mitochondria have the ability to alter nuclear gene expression. Mitochondria are also integral to other components of stress response or quality control including ROS signaling, unfolded protein response, mitochondrial autophagy, and biogenesis. These avenues of mitochondrial signaling are discussed in this review. PMID:23819011

  17. Oxidants, antioxidants, and the beneficial roles of exercise-induced production of reactive species.

    PubMed

    Gomes, Elisa Couto; Silva, Albená Nunes; de Oliveira, Marta Rubino

    2012-01-01

    This review offers an overview of the influence of reactive species produced during exercise and their effect on exercise adaptation. Reactive species and free radicals are unstable molecules that oxidize other molecules in order to become stable. Although they play important roles in our body, they can also lead to oxidative stress impairing diverse cellular functions. During exercise, reactive species can be produced mainly, but not exclusively, by the following mechanisms: electron leak at the mitochondrial electron transport chain, ischemia/reperfusion and activation of endothelial xanthine oxidase, inflammatory response, and autooxidation of catecholamines. Chronic exercise also leads to the upregulation of the body's antioxidant defence mechanism, which helps minimize the oxidative stress that may occur after an acute bout of exercise. Recent studies show a beneficial role of the reactive species, produced during a bout of exercise, that lead to important training adaptations: angiogenesis, mitochondria biogenesis, and muscle hypertrophy. The adaptations occur depending on the mechanic, and consequently biochemical, stimulus within the muscle. This is a new area of study that promises important findings in the sphere of molecular and cellular mechanisms involved in the relationship between oxidative stress and exercise. PMID:22701757

  18. Nitric oxide regulates vascular adaptive mitochondrial dynamics.

    PubMed

    Miller, Matthew W; Knaub, Leslie A; Olivera-Fragoso, Luis F; Keller, Amy C; Balasubramaniam, Vivek; Watson, Peter A; Reusch, Jane E B

    2013-06-15

    Cardiovascular disease risk factors, such as diabetes, hypertension, dyslipidemia, obesity, and physical inactivity, are all correlated with impaired endothelial nitric oxide synthase (eNOS) function and decreased nitric oxide (NO) production. NO-mediated regulation of mitochondrial biogenesis has been established in many tissues, yet the role of eNOS in vascular mitochondrial biogenesis and dynamics is unclear. We hypothesized that genetic eNOS deletion and 3-day nitric oxide synthase (NOS) inhibition in rodents would result in impaired mitochondrial biogenesis and defunct fission/fusion and autophagy profiles within the aorta. We observed a significant, eNOS expression-dependent decrease in mitochondrial electron transport chain (ETC) protein subunits from complexes I, II, III, and V in eNOS heterozygotes and eNOS null mice compared with age-matched controls. In response to NOS inhibition with NG-nitro-L-arginine methyl ester (L-NAME) treatment in Sprague Dawley rats, significant decreases were observed in ETC protein subunits from complexes I, III, and IV as well as voltage-dependent anion channel 1. Decreased protein content of upstream regulators of mitochondrial biogenesis, cAMP response element-binding protein and peroxisome proliferator-activated receptor-? coactivator-1?, were observed in response to 3-day L-NAME treatment. Both genetic eNOS deletion and NOS inhibition resulted in decreased manganese superoxide dismutase protein. L-NAME treatment resulted in significant changes to mitochondrial dynamic protein profiles with decreased fusion, increased fission, and minimally perturbed autophagy. In addition, L-NAME treatment blocked mitochondrial adaptation to an exercise intervention in the aorta. These results suggest that eNOS/NO play a role in basal and adaptive mitochondrial biogenesis in the vasculature and regulation of mitochondrial turnover. PMID:23585138

  19. Cellulose biogenesis in Dictyostelium discoideum

    SciTech Connect

    Blanton, R.L.

    1993-12-31

    Organisms that synthesize cellulose can be found amongst the bacteria, protistans, fungi, and animals, but it is in plants that the importance of cellulose in function (as the major structural constituent of plant cell walls) and economic use (as wood and fiber) can be best appreciated. The structure of cellulose and its biosynthesis have been the subjects of intense investigation. One of the most important insights gained from these studies is that the synthesis of cellulose by living organisms involves much more than simply the polymerization of glucose into a (1{r_arrow}4)-{beta}-linked polymer. The number of glucoses in a polymer (the degree of polymerization), the crystalline form assumed by the glucan chains when they crystallize to form a microfibril, and the dimensions and orientation of the microfibrils are all subject to cellular control. Instead of cellulose biosynthesis, a more appropriate term might be cellulose biogenesis, to emphasize the involvement of cellular structures and mechanisms in controlling polymerization and directing crystallization and deposition. Dictyostelium discoideum is uniquely suitable for the study of cellulose biogenesis because of its amenability to experimental study and manipulation and the extent of our knowledge of its basic cellular mechanisms (as will be evident from the rest of this volume). In this chapter, I will summarize what is known about cellulose biogenesis in D. discoideum, emphasizing its potential to illuminate our understanding both of D. discoideum development and plant cellulose biogenesis.

  20. The effect of treadmill training and N-acetyl-l-cysteine intervention on biogenesis of cytochrome c oxidase (COX).

    PubMed

    Sun, Y; Qi, Z; He, Q; Cui, D; Qian, S; Ji, L; Ding, S

    2015-10-01

    Mitochondrial biogenesis refers to increased content of mitochondria, which has been shown to be promoted by aerobic exercise. During this process, oxidative stress is considered the essential initiator. Even though some studies have addressed the issue as to whether antioxidants would hamper the effects of exercise on mitochondrial biogenesis, no consensus has been achieved. Therefore, the purpose of the present study was to investigate the effects of exercise and antioxidant intervention on mitochondrial biogenesis, as well as COX biogenesis. Thirty-two clean-grade male ICR mice were randomly assigned to a control group (Con), exercise group (Ex), N-acetyl-l-cysteine group (NAC), or NAC plus exercise group (NEx). The NAC and NEx groups were injected with NAC (0.1 mg/g/2 days) intraperitoneally for 3 weeks, whereas the Con and Ex groups were administered saline for the same period of time. Mice assigned to Ex and NEx groups started exercise training 1 week before drug intervention was initiated. After 1 week of acclimatization, the mice were allowed to run at a speed of 28 m/min for 60 min, 6 days a week. The results showed that exercise training caused an increase in mRNA and protein levels of COXIV, whereas NAC intervention lowered the two so significantly that even exercise training could not reverse the effect of NAC intervention. Our data suggest that even though antioxidant intervention could alleviate oxidative damage caused by exercise, it was not necessarily beneficial for mitochondrial biogenesis. PMID:26159509

  1. Exercise-induced arterial hypoxaemia in healthy young women

    PubMed Central

    Harms, Craig A; McClaran, Steven R; Nickele, Glenn A; Pegelow, David F; Nelson, William B; Dempsey, Jerome A

    1998-01-01

    We questioned whether exercise-induced arterial hypoxaemia (EIAH) occurs in healthy active women, who have smaller lungs, reduced lung diffusion, and lower maximal O2 consumption rate () than age- and height-matched men.Twenty-nine healthy young women with widely varying fitness levels ( 57 ± 6 ml kg−1 min−1; range, 35–70 ml kg−1 min−1; or 148 ± 5 %; range, 93–188 % predicted) and normal resting lung function underwent an incremental treadmill test to during the follicular phase of their menstrual cycle. Arterial blood samples were taken at rest and near the end of each workload.Arterial PO2 (Pa,O2) decreased > 10 mmHg below rest in twenty-two of twenty-nine subjects at (Pa,O2, 77.5 ± 0.9 mmHg; range, 67–88 mmHg; arterial O2 saturation (Sa,O2), 92.3 ± 0.2 %; range, 87–94 %). The remaining seven subjects maintained Pa,O2 within 10 mmHg of rest. Pa,O2 at was inversely related to the alveolar to arterial O2 difference (A-aDO2) (r = -0.93; 35–52 mmHg) and to arterial PCO2 (Pa,CO2) (r = -0.62; 26–39 mmHg).EIAH was inversely related to (r = -0.49); however, there were many exceptions. Almost half of the women with significant EIAH had within 15 % of predicted normal values ( 40–55 ml kg−1 min−1); among subjects with very high (55–70 ml kg−1 min−1), the degree of excessive A-aDO2 and EIAH varied markedly (e.g. A-aDO2, 30–50 mmHg; Pa,O2, 68–91 mmHg).In the women with EIAH at many began to experience an excessive widening of their A-aDO2 during moderate intensity exercise, which when combined with a weak ventilatory response, led to a progressive hypoxaemia. Inactive, less fit subjects had no EIAH and narrower A-aDO2 when compared with active, fitter subjects at the same (40–50 ml kg−1 min−1).These data demonstrate that many active healthy young women experience significant EIAH, and at a that is substantially less than those in their active male contemporaries. The onset of EIAH during submaximal exercise, and/or its occurrence at a relatively low implies that lung structure/function subserving alveolar to arterial O2 transport is abnormally compromised in many of these habitually active subjects. PMID:9518719

  2. Exercise-induced arterial hypoxaemia in healthy young women.

    PubMed

    Harms, C A; McClaran, S R; Nickele, G A; Pegelow, D F; Nelson, W B; Dempsey, J A

    1998-03-01

    1. We questioned whether exercise-induced arterial hypoxaemia (EIAH) occurs in healthy active women, who have smaller lungs, reduced lung diffusion, and lower maximal O2 consumption rate (VO2,max) than age- and height-matched men. 2. Twenty-nine healthy young women with widely varying fitness levels (VO2,max, 57 +/- 6 ml kg-1 min-1; range, 35-70 ml kg-1 min-1; or 148 +/- 5%; range, 93-188% predicted) and normal resting lung function underwent an incremental treadmill test to VO2,max during the follicular phase of their menstrual cycle. Arterial blood samples were taken at rest and near the end of each workload. 3. Arterial PO2 (Pa,O2) decreased > 10 mmHg below rest in twenty-two of twenty-nine subjects at VO2,max (Pa,O2, 77.5 +/- 0.9 mmHg; range, 67-88 mmHg; arterial O2 saturation (Sa,O2), 92.3 +/- 0.2%; range, 87-94%). The remaining seven subjects maintained Pa,O2 within 10 mmHg of rest. Pa,O2 at VO2,max was inversely related to the alveolar to arterial O2 difference (A-aDO2) (r = -0.93; 35-52 mmHg) and to arterial PCO2 (Pa,CO2) (r = -0.62; 26-39 mmHg). 4. EIAH was inversely related to VO2,max (r = -0.49); however, there were many exceptions. Almost half of the women with significant EIAH had VO2,max within 15% of predicted normal values (VO2,max, 40-55 ml kg-1 min-1); among subjects with very high VO2,max (55-70 ml kg-1 min-1), the degree of excessive A-aDO2 and EIAH varied markedly (e.g. A-aDO2, 30-50 mmHg; Pa,O2, 68-91 mmHg). 5. In the women with EIAH at VO2,max, many began to experience an excessive widening of their A-aDO2 during moderate intensity exercise, which when combined with a weak ventilatory response, led to a progressive hypoxaemia. Inactive, less fit subjects had no EIAH and narrower A-aDO2 when compared with active, fitter subjects at the same VO2 (40-50 ml kg-1 min-1). 6. These data demonstrate that many active healthy young women experience significant EIAH, and at a VO2,max that is substantially less than those in their active male contemporaries. The onset of EIAH during submaximal exercise, and/or its occurrence at a relatively low VO2,max, implies that lung structure/function subserving alveolar to arterial O2 transport is abnormally compromised in many of these habitually active subjects. PMID:9518719

  3. Iron-sulfur cluster biogenesis systems and their crosstalk.

    PubMed

    Xu, Xiang Ming; Mller, Simon G

    2008-10-13

    The biogenesis of iron-sulfur clusters ([Fe-S]) plays a very important role in many essential functions of life. Several [Fe-S] biogenesis systems have been discovered, such as the NIF (nitrogen fixation), SUF (mobilisation of sulfur) and ISC (iron-sulfur cluster) systems in bacteria, and the ISC-like and CIA (cytosolic iron-sulfur protein assembly) systems in yeast. Experimental evidence has revealed that SUF and ISC in bacteria communicate with each other partly through IscR to coordinate the utilisation of iron and cysteine. The ISC-like system in yeast is localised to the mitochondria, while the ISC-dependent CIA system is localised to the cytosol; this suggests a possible role for the ISC mitochondrial export machinery in mediating crosstalk between the two systems. Based on genetic analysis, the model plant Arabidopsis thaliana contains three [Fe-S] biogenesis systems similar to SUF, ISC and CIA named AtSUF, AtISC and AtCIA. Possible communication between these three systems has been proposed. PMID:18798211

  4. Exercise-Induced Intrapulmonary Arteriovenous Shunt in a Patient Complaining of Dyspnea during Strenuous Exercise

    PubMed Central

    Kim, Tae-Jun; Hong, Seong-Eun; Jung, Dong-Min; Choi, Nan-Young; Kim, Yong-Kyun; Park, Seung-Ah; Kim, Soon-Young; Park, Woo-Jung

    2014-01-01

    A 51-year-old highly fit man presented for dyspnea with strenuous aerobic exercise. The patient was asymptomatic and all tests were normal at rest. With increasing exercise intensity, he suddenly complained of dyspnea and showed a severe exercise-induced hypoxemia with an excessive alveolar-arterial oxygen tension difference. In agitated saline contrast echocardiography at peak exercise, a large amount of left to right shunt was identified after > 5 cardiac cycles, which suggests the presence of exercise-induced intrapulmonary arteriovenous shunt in this patient. PMID:25031800

  5. [Effects of visfatin gene polymorphisms on glycolipid metabolism and exercise-induced weight reduction in obesity].

    PubMed

    Lai, Ai-Ping; Chen, Wen-He

    2012-02-25

    Visfatin, also named nicotinamide phosphoribosyl transferase (NAMPT), is a cytokine secreted from adipose tissue. Visfatin can regulate immune action and is involved in the NAD+ salvage pathway. In addition, recent researches have shown that visfatin helps the regulation of glucose and lipid metabolism, especially in exercise-induced weight reduction for obesity. The aim of this review is to provide an overview of the contribution of visfatin gene polymorphisms to glucose and lipid metabolism and exercise-induced weight reduction in obesity. PMID:22348967

  6. Mitochondrial dysfunction in heart failure

    PubMed Central

    Rosca, Mariana G.; Hoppel, Charles L.

    2013-01-01

    Heart failure (HF) is a complex chronic clinical syndrome. Energy deficit is considered to be a key contributor to the development of both cardiac and skeletal myopathy. In HF several components of cardiac and skeletal muscle bioenergetics are altered, such as oxygen availability, substrate oxidation, mitochondrial ATP production, and ATP transfer to the contractile apparatus via the creatine kinase shuttle. This review focuses on alterations in mitochondrial biogenesis and respirasome organization, substrate oxidation coupled with ATP synthesis in the context of their contribution to the chronic energy deficit, and mechanical dysfunction of the cardiac and skeletal muscle in HF. We conclude that HF is associated with decreased mitochondrial biogenesis and function in both heart and skeletal muscle, supporting the concept of a systemic mitochondrial cytopathy. The sites of mitochondrial defects are located within the electron transport and phosphorylation apparatus, and differ with the etiology and progression of HF in the two mitochondrial populations (subsarcolemmal and interfibrillar) of cardiac and skeletal muscle. The roles of adrenergic stimulation, the renin-angiotensin system, and cytokines are evaluated as factors responsible for the systemic energy deficit. We propose a cylic AMP-mediated mechanism by which increased adrenergic stimulation contributes to the mitochondrial dysfunction. PMID:22948484

  7. Organelle biogenesis and interorganellar connections

    PubMed Central

    Daniele, Tiziana; Schiaffino, Maria Vittoria

    2014-01-01

    Membrane contact sites (MCSs) allow the exchange of molecules and information between organelles, even when their membranes cannot fuse directly. In recent years, a number of functions have been attributed to these contacts, highlighting their critical role in cell homeostasis. Although inter-organellar connections typically involve the endoplasmic reticulum (ER), we recently reported the presence of a novel MCSs between melanosomes and mitochondria. Melanosome-mitochondrion contacts appear mediated by fibrillar bridges resembling the protein tethers linking mitochondria and the ER, both for their ultrastructural features and the involvement of Mitofusin 2. The frequency of these connections correlates spatially and timely with melanosome biogenesis, suggesting a functional link between the 2 processes and in general that organelle biogenesis in the secretory pathway requires interorganellar crosstalks at multiple steps. Here, we summarize the different functions attributed to MCSs, and discuss their possible relevance for the newly identified melanosome-mitochondrion liaison. PMID:25346798

  8. Pharmacological approaches to restore mitochondrial function

    PubMed Central

    Andreux, Pénélope A.; Houtkooper, Riekelt H.; Auwerx, Johan

    2014-01-01

    Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders, but is also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson’s disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models, as well as multicellular organisms, have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for a range of diseases, which has spurred active drug discovery efforts in this area. PMID:23666487

  9. Green Tea Catechin Consumption Enhances Exercise-Induced Abdominal Fat Loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aim: This study evaluated the influence of a green tea catechin beverage on body composition and fat distribution in overweight and obese adults during exercised-induced weight loss. Methods: Participants (N=132) were randomly assigned to receive a 500 mL beverage containing approximately 625 mg of...

  10. Simple Screening Test for Exercise-Induced Bronchospasm in the Middle School Athlete

    ERIC Educational Resources Information Center

    Weiss, Tyler J.; Baker, Rachel H.; Weiss, Jason B.; Weiss, Michelle M.

    2013-01-01

    This article recommends and provides results from a simple screening test that could be incorporated into a standardized school evaluation for all children participating in sports and physical education classes. The test can be employed by physical educators utilizing their own gym to identify children who demonstrate signs of exercise-induced

  11. Increased Protein Maintains Nitrogen Balance during Exercise-Induced Energy Deficit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE: This study examined how a high-protein diet affected nitrogen balance and protein turnover during an exercise-induced energy deficit. METHODS: Twenty-two men completed a 4-d (D1-4) baseline period (BL) of an energy balance diet while maintaining usual physical activity level, followed by 7 ...

  12. Influence of artistic gymnastics on iron nutritional status and exercise-induced hemolysis in female athletes.

    PubMed

    Sureira, Thaiz Mattos; Amancio, Olga Silverio; Pellegrini Braga, Josefina Aparecida

    2012-08-01

    This study evaluates the relationship between body iron losses and gains in artistic gymnastics female athletes. It shows that despite the low iron intake and exercise-induced hemolysis, iron deficiency or iron-deficiency anemia does not occur, but partial changes in the hematological profile do. The hypothesis that gymnasts' nutritional behavior contributes to anemia, which may be aggravated by exercise-induced hemolysis, led to this cross-sectional study, conducted with 43 female artistic gymnasts 6-16 yr old. The control group was formed by 40 nontraining girls, paired by age. Hemogram, serum iron, ferritin, soluble transferrin receptor, haptoglobin, total and fractional bilirubin, Type I urine, and parasitologic and occult fecal blood tests were evaluated. The athletes presented mean hematimetric and serum iron values (p = .020) higher than those of the control group. The bilirubin result discarded any hemolytic alteration in both groups. The haptoglobin results were lower in the athlete group (p = .002), confirming the incidence of exercise-induced hemolysis. Both groups presented low iron intake. The results suggest that artistic gymnastics practice leads to exercise-induced hemolysis and partially changes the hematological profile, although not causing iron deficiency or iron-deficiency anemia, even in the presence of low iron intake. PMID:22645172

  13. The Effects of Creatine Supplementation on Exercise-Induced Muscle Damage.

    ERIC Educational Resources Information Center

    Rawson, Eric S.; Gunn, Bridget; Clarkson, Priscilla M.

    2001-01-01

    Investigated the effects of oral creatine (Cr) supplementation on markers of exercise-induced muscle damage following high-force eccentric exercise in men randomly administered Cr or placebo. Results indicated that 5 days of Cr supplementation did not reduce indirect makers of muscle damage or enhance recovery from high-force eccentric exercise.

  14. Update on Exercise-Induced Asthma. A Report of the Olympic Exercise Asthma Summit Conference.

    ERIC Educational Resources Information Center

    Storms, William W.; Joyner, David M.

    1997-01-01

    Summarizes results from the Olympic Exercise Asthma Summit Conference, offering the latest on identifying and managing exercise-induced asthma (EIA). Concludes that effective pharmacologic and nonpharmacologic treatment is available, but EIA is underrecognized and underdiagnosed. Physicians should look for it in all patients, including school

  15. The Effects of Creatine Supplementation on Exercise-Induced Muscle Damage.

    ERIC Educational Resources Information Center

    Rawson, Eric S.; Gunn, Bridget; Clarkson, Priscilla M.

    2001-01-01

    Investigated the effects of oral creatine (Cr) supplementation on markers of exercise-induced muscle damage following high-force eccentric exercise in men randomly administered Cr or placebo. Results indicated that 5 days of Cr supplementation did not reduce indirect makers of muscle damage or enhance recovery from high-force eccentric exercise.…

  16. Exercise Induced Nausea and Vomiting: Another Sign of Pheochromocytoma and Paraganglioma Preferably in Young Patients?

    PubMed Central

    King, Kathryn S.; Darmani, Nissar; Adams, Karen T.; Pacak, Karel

    2012-01-01

    Objective A cohort of nine patients, mostly young adults, presented with a new symptom of pheochromocytoma/paraganglioma: exercise induced nausea and vomiting. The aim of this report is to present this symptom of pheochromocytoma/paraganglioma and to suggest a hypothesis for the observation. Design This is a prospective study looking at the patient accounts of the reported symptom and the clinical data on the patients disease. Methods Following a 2000 report from a paraganglioma patient of the experience of exercise induced nausea and vomiting, researchers and clinicians at the National Institutes of Health (NIH), pheochromocytoma/paraganglioma protocol, began asking patients about instances of nausea and vomiting induced through exercise. A cohort of nine patients reporting exercise induced nausea and vomiting was found and their clinical data are analyzed and presented here. Results Exercise induced nausea and vomiting in pheochromocytoma/paraganglioma patients is most likely due to the elevation of circulating catecholamines that activate adrenergic receptors of the area postrema, which induces nausea and vomiting. Succinate dehydrogenase subunit B mutations/deletions were prevalent in the patients described. Conclusions Post exercise nausea and vomiting should be considered as a symptom of pheochromocytoma/paraganglioma and should be addressed in the clinical evaluation of these patients, especially in young adults. PMID:20960160

  17. Exercise Challenge for Exercise-Induced Bronchospasm. Confirming Presence, Evaluating Control.

    ERIC Educational Resources Information Center

    Kaplan, Ted A.

    1995-01-01

    Exercise-induced bronchospasm commonly strikes young people, keeping many away from activity. The exercise challenge test (a powerful tool in diagnosing the condition, fine-tuning treatment, and improving patient compliance) can help get patients back in action. Knowing how to interpret and use test results helps physicians expedite effective

  18. Update on Exercise-Induced Asthma. A Report of the Olympic Exercise Asthma Summit Conference.

    ERIC Educational Resources Information Center

    Storms, William W.; Joyner, David M.

    1997-01-01

    Summarizes results from the Olympic Exercise Asthma Summit Conference, offering the latest on identifying and managing exercise-induced asthma (EIA). Concludes that effective pharmacologic and nonpharmacologic treatment is available, but EIA is underrecognized and underdiagnosed. Physicians should look for it in all patients, including school…

  19. High protein diet maintains glucose production during exercise-induced energy deficit: a controlled trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inadequate energy intake induces changes in endogenous glucose production (GP) to preserve muscle mass. Whether addition provision of dietary protein modulates GP response to energy deficit is unclear. The objective was to determine whether exercise-induced energy deficit effects on glucose metaboli...

  20. Postlipopolysaccharide oxidative damage of mitochondrial DNA.

    PubMed

    Suliman, Hagir B; Carraway, Martha S; Piantadosi, Claude A

    2003-02-15

    Selected structural and functional alterations of mitochondria induced by bacterial lipopolysaccharide (LPS) were investigated on the basis of the hypothesis that LPS initiates hepatic mitochondrial DNA (mtDNA) damage by oxidative mechanisms. After a single intraperitoneal injection of Escherichia coli LPS, liver mtDNA copy number decreased, as determined by Southern analysis, within 24 hours relative to nuclear 18S rRNA (p < 0.05). LPS induced a novel oxidant-dependent 3.8-kb mtDNA deletion in the region encoding NADH dehydrogenase subunits 1 and 2 and cytochrome c oxidase subunit I, which correlated with mitochondrial glutathione depletion. Expression of mitochondrial mRNA and transcription of mitochondrial RNA were suppressed, whereas mRNA expression increased for selected nuclear-encoded mitochondrial proteins. Resolution of mtDNA damage was mediated by importation of mitochondrial transcription factor A protein, a central regulator of mtDNA copy number, accompanied by binding of mitochondrial protein extract to the mitochondrial transcription factor A DNA-binding site. Hence, mtDNA integrity and transcriptional capacity after LPS administration appeared to be reinstated by mitochondrial biogenesis. These data provide the first link between LPS-mediated hepatic injury and a specific oxidative mtDNA deletion, which inhibits mitochondrial transcription and is restored by activation of mechanisms that lead to biogenesis. PMID:12480607

  1. Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis.

    PubMed

    Hangen, Emilie; Fraud, Olivier; Lachkar, Sylvie; Mou, Haiwei; Doti, Nunzianna; Fimia, Gian Maria; Lam, Ngoc-Vy; Zhu, Changlian; Godin, Isabelle; Muller, Kevin; Chatzi, Afroditi; Nuebel, Esther; Ciccosanti, Fabiola; Flamant, Stphane; Bnit, Paule; Perfettini, Jean-Luc; Sauvat, Allan; Bennaceur-Griscelli, Annelise; Ser-Le Roux, Karine; Gonin, Patrick; Tokatlidis, Kostas; Rustin, Pierre; Piacentini, Mauro; Ruvo, Menotti; Blomgren, Klas; Kroemer, Guido; Modjtahedi, Nazanine

    2015-06-18

    Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis. PMID:26004228

  2. Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.

    PubMed

    Singh, Franois; Charles, Anne-Laure; Schlagowski, Anna-Isabel; Bouitbir, Jamal; Bonifacio, Annalisa; Piquard, Franois; Krhenbhl, Stephan; Geny, Bernard; Zoll, Joffrey

    2015-07-01

    Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H?O?production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100?M) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon. PMID:25769432

  3. EVALUATION OF THE BIOGENESIS SOIL WASHING TECHNOLOGY

    EPA Science Inventory

    The BioGenesis Enterprises, Inc. (BioGenesis) soil washing technology was demonstrated as part of the US Environmental Protection Agency's (EPA) Superfund Innovative Technology Evaluation (SITE) program in November 1992. he demonstration was conducted over three days at a petrole...

  4. EVALUATION OF THE BIOGENESIS SOIL WASHING TECHNOLOGY

    EPA Science Inventory

    The BioGenesis Enterprises, Inc. (BioGenesis) soil washing technology was demonstrated as part of the US Environmental Protection Agency's (EPA) Superfund Innovative Technology Evaluation (SITE) program in November 1992. The demonstration was conducted over three days at a petrol...

  5. Estrogen receptor-? in mitochondria: implications for mitochondrial bioenergetics and tumorigenesis.

    PubMed

    Liao, Tien-Ling; Tzeng, Chii-Ruey; Yu, Chao-Lan; Wang, Yi-Pei; Kao, Shu-Huei

    2015-09-01

    Estrogen enhances mitochondrial function by enhancing mitochondrial biogenesis and sustaining mitochondrial energy-transducing capacity. Shifts in mitochondrial bioenergetic pathways from oxidative phosphorylation to glycolysis have been hypothesized to be involved in estrogen-induced tumorigenesis. Studies have shown that mitochondria are an important target of estrogen. Estrogen receptor-? (ER?) has been shown to localize to mitochondria in a ligand-dependent or -independent manner and can affect mitochondrial bioenergetics and anti-apoptotic signaling. However, the functional role of mitochondrial ER? in tumorigenesis remains unclear. Clinical studies of ER?-related tumorigenesis have shown that ER? stimulates mitochondrial metabolism to meet the high energy demands of processes such as cell proliferation, cell survival, and transformation. Thus, in elucidating the precise role of mitochondrial ER? in cell transformation and tumorigenesis, it will be particularly valuable to explore new approaches for the development of medical treatments targeting mitochondrial ER?-mediated mitochondrial function and preventing apoptosis. PMID:26301952

  6. Impact-driven, pulmonary emboli of osseous fat in exercise-induced bronchospasm.

    PubMed

    Simkin, Peter A; Snitily, Brian K

    2015-11-01

    Exercise induced bronchospasm (EIB) affects approximately 10% of normal individuals with higher prevalence rates among children, obese adults, and competitive athletes. Although hyperpnea with dry air is the best known cause, the problem is multifactorial with atopy, asthma and chlorine all playing established roles. To date, no clear mechanism has connected musculoskeletal loading with the ensuing pulmonary compromise. This paper reviews evidence that impact-driven pulses in subchondral bone pressure may push osseous fat cells into the local venous sinusoids. The resultant showers of microemboli must then travel to the lung where lysis of membrane phospholipids leads to leukotriene formation with resultant inflammation and bronchial hypersensitivity. Concurrently, the same emboli deliver triglyceride fuels for further physical activity. Thus, pulmonary microemboli derived from osseous fat may resolve the seeming paradox of athletic excellence in persons afflicted with exercise-induced bronchospasm. PMID:26328480

  7. Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes.

    PubMed

    Rundell, Kenneth W; Slee, Joshua B

    2008-08-01

    The prevalence of exercise-induced bronchoconstriction is reported to be high among recreational and elite athletes, yet diagnosis is often symptom-based. Indirect challenges such as the laboratory exercise challenge provide objective criteria for proper diagnosis and treatment. However, a standardized protocol using appropriate exercise intensity, duration, and dry air inhalation is often not implemented, and thus a false-negative test may result. This article reviews and describes the symptom-based diagnosis, the exercise challenge, and other indirect challenges such as eucapnic voluntary hyperpnea, hypertonic saline inhalation, and inhaled powdered mannitol as methods to diagnose and evaluate exercise-induced bronchoconstriction. Advantages and disadvantages of each diagnostic procedure are presented. PMID:18678339

  8. Pathophysiological mechanisms of exercise-induced anaphylaxis: an EAACI position statement.

    PubMed

    Ansley, L; Bonini, M; Delgado, L; Del Giacco, S; Du Toit, G; Khaitov, M; Kurowski, M; Hull, J H; Moreira, A; Robson-Ansley, P J

    2015-10-01

    This document is the result of a consensus on the mechanisms of exercise-induced anaphylaxis (EIAn), an unpredictable and potentially fatal syndrome. A multidisciplinary panel of experts including exercise physiologists, allergists, lung physicians, paediatricians and a biostatistician reached the given consensus. Exercise-induced anaphylaxis (EIAn) describes a rare and potentially fatal syndrome in which anaphylaxis occurs in conjunction with exercise. The pathophysiological mechanisms underlying EIAn have not yet been elucidated although a number of hypotheses have been proposed. This review evaluates the validity of each of the popular theories in relation to exercise physiology and immunology. On the basis of this evidence, it is concluded that proposed mechanisms lack validity, and it is recommended that a global research network is developed with a common approach to the diagnosis and treatment of EIAn in order to gain sufficient power for scientific evaluation. PMID:26100553

  9. All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes.

    PubMed

    Tourniaire, Franck; Musinovic, Hana; Gouranton, Erwan; Astier, Julien; Marcotorchino, Julie; Arreguin, Andrea; Bernot, Denis; Palou, Andreu; Bonet, M Luisa; Ribot, Joan; Landrier, Jean-Franois

    2015-06-01

    A positive effect of all-trans retinoic acid (ATRA) on white adipose tissue (WAT) oxidative and thermogenic capacity has been described and linked to an in vivo fat-lowering effect of ATRA in mice. However, little is known about the effects of ATRA on mitochondria in white fat. Our objective has been to characterize the effect of ATRA on mitochondria biogenesis and oxidative phosphorylation (OXPHOS) capacity in mature white adipocytes. Transcriptome analysis, oxygraphy, analysis of mitochondrial DNA (mtDNA), and flow cytometry-based analysis of mitochondria density were performed in mature 3T3-L1 adipocytes after 24 h incubation with ATRA (2 M) or vehicle. Selected genes linked to mitochondria biogenesis and function and mitochondria immunostaining were analyzed in WAT tissues of ATRA-treated as compared with vehicle-treated mice. ATRA upregulated the expression of a large set of genes linked to mtDNA replication and transcription, mitochondrial biogenesis, and OXPHOS in adipocytes, as indicated by transcriptome analysis. Oxygen consumption rate, mtDNA content, and staining of mitochondria were increased in the ATRA-treated adipocytes. Similar results were obtained in WAT depots of ATRA-treated mice. We conclude that ATRA impacts mitochondria in adipocytes, leading to increased OXPHOS capacity and mitochondrial content in these cells. PMID:25914170

  10. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk.

    PubMed

    Malin, Steven K; Braun, Barry

    2016-01-01

    Combining metformin with exercise has been proposed to improve glucose homeostasis. However, we primarily discuss evidence suggesting that metformin and other pharmacological agents/dietary supplements (e.g., statins, resveratol, or antioxidants) may in fact oppose exercise-induced benefits on insulin sensitivity and cardiometabolic health. We explore the novel hypothesis that attenuation of oxidative stress from exercise by these exogenous compounds blunts metabolic adaptation. PMID:26583801

  11. Exercise excess pressure and exercise-induced albuminuria in patients with type 2 diabetes mellitus.

    PubMed

    Climie, Rachel E D; Srikanth, Velandai; Keith, Laura J; Davies, Justin E; Sharman, James E

    2015-05-01

    Exercise-induced albuminuria is common in patients with type 2 diabetes mellitus (T2DM) in response to maximal exercise, but the response to light-moderate exercise is unclear. Patients with T2DM have abnormal central hemodynamics and greater propensity for exercise hypertension. This study sought to determine the relationship between light-moderate exercise central hemodynamics (including aortic reservoir and excess pressure) and exercise-induced albuminuria. Thirty-nine T2DM (62 9 yr; 49% male) and 39 nondiabetic controls (53 9 yr; 51% male) were examined at rest and during 20 min of light-moderate cycle exercise (30 W; 50 revolutions/min). Albuminuria was assessed by the albumin-creatinine ratio (ACR) at rest and 30 min postexercise. Hemodynamics recorded included brachial and central blood pressure (BP), aortic stiffness, augmented pressure (AP), aortic reservoir pressure, and excess pressure integral (Pexcess). There was no difference in ACR between groups before exercise (P > 0.05). Exercise induced a significant rise in ACR in T2DM but not controls (1.73 1.43 vs. 0.53 1.0 mg/mol, P = 0.002). All central hemodynamic variables were significantly higher during exercise in T2DM (i.e., Pexcess, systolic BP and AP; P < 0.01 all). In T2DM (but not controls), exercise Pexcess was associated with postexercise ACR (r = 0.51, P = 0.002), and this relationship was independent of age, sex, body mass index, heart rate, aortic stiffness, antihypertensive medication, and ambulatory daytime systolic BP (? = 0.003, P = 0.003). Light-moderate exercise induced a significant rise in ACR in T2DM, and this was independently associated with Pexcess, a potential marker of vascular dysfunction. These novel findings suggest that Pexcess could be important for appropriate renal function in T2DM. PMID:25724495

  12. Prevalence of exercise-induced cough in schoolchildren: a pilot study.

    PubMed

    Cichalewski, ?ukasz; Majak, Pawe?; Jerzy?ska, Joanna; Stelmach, W?odzimierz; Kaczmarek, Adam; Malewska, Kamila; Smejda, Katarzyna; Stelmach, Iwona

    2015-01-01

    Association between exercise-induced bronchoconstriction (EIB) and physical activity has not been investigated in a natural school environment in a general pediatric population. Our objective was to determine the prevalence of exercise-induced symptoms (cough, wheeze, chest tightness, dyspnea) and bronchospasm among schoolchildren during physical education (PE). A total of 557 schoolchildren from seven public schools were enrolled. Information regarding demographic characteristic, previously diagnosed asthma was obtained. All children attended 45-minute PE lesson with similar exercise intensity. Pulmonary function tests were performed before and immediately after PE lesson. The diagnosis of EIB was defined as a forced expiratory volume in one second (FEV1) decrease from baseline of more than or equal to 10% with exercise. Cough and dyspnea after exercise were recorded. A total of 557 participants were included into the analysis. After PE lesson, 15.3% children suffered from cough, 0.9% reported dyspnea, and 10.1% had more than 10% fall in FEV1 from baseline. Among all participants, 5.9% had doctors' diagnosed asthma, 4.8% of them were treated with inhaled corticosteroids (ICS). Among children with cough, 21.5% had asthma and 17.6% experienced EIB. Among asthmatics, 48.6% suffered from cough and 18.2% had more than 10% fall in FEV1 from baseline after PE lesson. EIB was not affected by age, gender, body mass index, asthma diagnosis, and ICS use. Only cough (odds ratio: 2.21, 95% confidence interval: 1.16-4.23; p = 0.0161) was independently associated with EIB. This study showed a high prevalence of exercise-induced cough and/or 10% fall in FEV1 during activity lesson in a natural school environment in a large urban population of schoolchildren. Our results call for another studies addressing the impact of environment on exercise-induced symptoms. PMID:25562558

  13. Endurance training modifies exercise-induced activation of blood coagulation: RCT.

    PubMed

    Hilberg, Thomas; Menzel, Kathleen; Wehmeier, Udo F

    2013-06-01

    Randomized controlled trials (RCTs) on the topic of physical training and blood coagulation are rare and the effects are unclear. The aim of this study was to investigate whether endurance training adjusts blood coagulation and fibrinolysis at rest and after exercise. The study included 50 healthy untrained non-smokers randomized into training (TR 49 6 years) or control group (CO 48 6 years). Each subject performed an exercise test adjusted at 80 % individual anaerobic threshold (IAT) for 60 min before and after 12 weeks (80 % IAT: before TR 123 20, CO 125 26 W; after TR 148 23 W, CO 127 25 W; mean SD). Blood was taken at rest and after exercise to determine coagulation (e.g., aPTT, thrombin potential, TAT, F1+2, several coagulation factors) and fibrinolytic (e.g., tPA, PAI) parameters. The training intervention induced an elevation of physical capacity in TR by 17 % (rel. VO2max) that led to a statistical relevant prolongation of aPTT at rest. Although absolute power output during the second exercise test was 20 % higher in TR, we detected an attenuated exercise-induced decrease of aPTT and attenuated increase of F1+2 after training. Resting levels of tPA- and PAI-Ag decreased slightly but not significantly after training. Exercise-induced changes were comparable after training in spite of higher power output in TR. Although the effects are small in healthy men, training modifies exercise-induced blood coagulation positively. The fact that exercise-induced changes in blood coagulation and fibrinolysis are rather attenuated or unchanged in the training group, in spite of a 20 % higher absolute power output during exercise, substantiates the adjusting effect of endurance training and the importance of physical fitness in primary prevention. PMID:23238930

  14. PGC-1? promotes exercise-induced autophagy in mouse skeletal muscle.

    PubMed

    Halling, Jens F; Ringholm, Stine; Nielsen, Maja M; Overby, Peter; Pilegaard, Henriette

    2016-02-01

    Recent evidence suggests that exercise stimulates the degradation of cellular components in skeletal muscle through activation of autophagy, but the time course of the autophagy response during recovery from exercise has not been determined. Furthermore, the regulatory mechanisms behind exercise-induced autophagy remain unclear, although the muscle oxidative phenotype has been linked with basal autophagy levels. Therefore, the aim of this study was to investigate the role of the key regulator of muscle oxidative capacity, PGC-1?, in exercise-induced autophagy at several time points during recovery. Mice with transgenic muscle-specific overexpression (TG) or knockout (MKO) of PGC-1? and their respective littermate controls were subjected to a single 1h bout of treadmill running and euthanized immediately (0h), 2, 6, and 10h after exercise. In the PGC-1? MKO strain, quadriceps protein content of the autophagy marker LC3II was increased from 2h into recovery in lox/lox control, but not in MKO mice. In the PGC-1? TG strain, quadriceps protein content of LC3II was increased from 2h after exercise in TG, but not in WT. Although AMPK and ACC phosphorylation was increased immediately following exercise, the observed exercise-induced autophagy response was not associated with phosphorylation of the AMPK-target ULK1. However, lower protein carbonyl content was observed in lox/lox and TG mice after exercise coinciding with the increased LC3 lipidation. In conclusion, the present results suggest a role of skeletal muscle PGC-1? in coordinating several exercise-induced adaptive responses including autophagic removal of damaged cellular components. PMID:26869683

  15. Suppression of exercise-induced angina by magnesium sulfate in patients with variant angina

    SciTech Connect

    Kugiyama, K.; Yasue, H.; Okumura, K.; Goto, K.; Minoda, K.; Miyagi, H.; Matsuyama, K.; Kojima, A.; Koga, Y.; Takahashi, M.

    1988-11-01

    The effects of intravenous magnesium on exercise-induced angina were examined in 15 patients with variant angina and in 13 patients with stable effort angina and were compared with those of placebo. Symptom-limited bicycle exercise and thallium-201 myocardial scintigraphy were performed after intravenous administration of 0.27 mmol/kg body weight of magnesium sulfate and after placebo on different days. In all patients, serum magnesium levels after administration of magnesium sulfate were about twofold higher than levels after placebo. Exercise-induced angina associated with transient ST segment elevation occurred in 11 patients with variant angina receiving placebo and in only 2 of these patients receiving magnesium (p less than 0.005). On the other hand, exercise-induced angina was not suppressed by magnesium in any patient with stable effort angina. In these patients there was no significant difference in exercise duration after administration of placebo versus after administration of magnesium. The size of the perfusion defect as measured by thallium-201 scintigraphy was significantly less in patients with variant angina receiving magnesium than that in those receiving placebo (p less than 0.001), whereas it was not significantly different in patients with stable effort angina receiving placebo versus magnesium. In conclusion, exercise-induced angina is suppressed by intravenous magnesium in patients with variant angina but not in patients with stable effort angina. This beneficial effect of magnesium in patients with variant angina is most likely due to improvement of regional myocardial blood flow by suppression of coronary artery spasm.

  16. Clinical significance of plasminogen activator inhibitor activity in patients with exercise-induced ischemia

    SciTech Connect

    Sakata, K.; Kurata, C.; Taguchi, T.; Suzuki, S.; Kobayashi, A.; Yamazaki, N.; Rydzewski, A.; Takada, Y.; Takada, A. )

    1990-10-01

    To assess the fibrinolytic system in patients with exercise-induced ischemia and its relation to ischemia and severity of coronary artery disease (CAD), 47 patients with CAD confirmed by results of coronary angiography underwent symptom-limited multistage exercise thallium-201 emission computed tomography. All patients with CAD had exercise-induced ischemia as assessed from thallium-201 images. Pre- and peak exercise blood samples from each patient and preexercise blood samples from control subjects were assayed for several fibrinolytic components and were also assayed for plasma adrenaline. The extent of ischemia was defined as delta visual uptake score (total visual uptake score in delayed images minus total visual uptake score in initial images) and the severity of CAD as the number of diseased vessels. In the basal condition, plasminogen activator inhibitor (PAI) activity was significantly higher in patients with exercise-induced ischemia as compared to control subjects (p less than 0.01), although there were no significant differences in other fibrinolytic variables between the two groups. Moreover, PAI activity in the basal condition displayed a significantly positive correlation with the extent of ischemia (r = 0.47, p less than 0.01). Patients with exercise-induced ischemia were divided into two groups (24 with single-vessel disease and 23 with multivessel disease). There were no significant differences in coronary risk factors, hemodynamics, or plasma adrenaline levels during exercise between single-vessel and multivessel disease except that delta visual uptake score was significantly higher in multivessel disease (p less than 0.01).

  17. Effect of N-2-mercaptopropionyl glycine on exercise-induced cardiac adaptations.

    PubMed

    Nelson, Matthew J; Harris, M Brennan; Boluyt, Marvin O; Hwang, Hyun Seok; Starnes, Joseph W

    2011-04-01

    The purpose of this study was to test the hypothesis that exercise-induced cardiac adaptations would be attenuated by the free radical scavenger N-2-mercaptopropionyl glycine (MPG). Male Sprague-Dawley rats were divided into four groups (n = 9-13 per group) for 3-4 wk: sedentary (S), S+MPG (100 mg/kg ip daily), exercised on a treadmill (E) (60 min/day, 5 days/wk, at a speed of 20 m/min up a 6 grade in a 6C room), or E+MPG given 10 min prior to exercise. Additional rats (n = 55) were used to determine acute exercise effects on myocardial redox state [nonprotein nonglutathione sulfhydryls (NPNGSH)] and PI3K/Akt signaling pathway activation. Compared with S, NPNGSH levels were 48% lower in E (P < 0.05) and unchanged in E+MPG (P > 0.05). MPG also attenuated exercise-induced activation of the signaling proteins Akt and S6. Hearts from the 4-wk groups were weighed, and cardiac function was evaluated using an isolated perfused working heart preparation. Similar increases (P < 0.05) in both exercised groups were observed for heart weight and heart weight-to-body weight ratio. Cardiac function improved in E vs. S, as indicated by greater (P < 0.05) external work performed (cardiac output systolic pressure) and efficiency of external work (work/Vo(2)). MPG prevented these exercise-induced functional improvements. Skeletal muscle mitochondria content increased to similar levels in E and E+MPG. This study provides evidence that free radicals do not play an essential role in the development of exercise-induced cardiac hypertrophy; however, they appear to be involved in functional cardiac adaptations, which may be mediated through the PI3K/Akt pathway. PMID:21307366

  18. The Role of Exercise-Induced Cardiovascular Adaptation in Brain Health.

    PubMed

    Tarumi, Takashi; Zhang, Rong

    2015-10-01

    Regular aerobic exercise improves brain health; however, a potential dose-response relationship and the underling physiological mechanisms remain unclear. Existing data support the following hypotheses: 1) exercise-induced cardiovascular adaptation plays an important role in improving brain perfusion, structure, and function, and 2) a hormetic relation seems to exist between the intensity of exercise and brain health, which needs to be further elucidated. PMID:26196870

  19. Mitochondrial Plasticity in Obesity and Diabetes Mellitus

    PubMed Central

    Jelenik, Tomas

    2013-01-01

    Abstract Significance: Insulin resistance and its related diseases, obesity and type 2 diabetes mellitus (T2DM), have been linked to changes in aerobic metabolism, pointing to a possible role of mitochondria in the development of insulin resistance. Recent Advances: Refined methodology of ex vivo high-resolution respirometry and in vivo magnetic resonance spectroscopy now allows describing several features of mitochondria in humans. In addition to measuring mitochondrial function at baseline and after exercise-induced submaximal energy depletion, the response of mitochondria to endocrine and metabolic challenges, termed mitochondrial plasticity, can be assessed using hyperinsulinemic clamp tests. While insulin resistant states do not uniformly relate to baseline and post-exercise mitochondrial function, mitochondrial plasticity is typically impaired in insulin resistant relatives of T2DM, in overt T2DM and even in type 1 diabetes mellitus (T1DM). Critical Issues: The variability of baseline mitochondrial function in the main target tissue of insulin action, skeletal muscle and liver, may be attributed to inherited and acquired changes in either mitochondrial quantity or quality. In addition to certain gene polymorphisms and aging, circulating glucose and lipid concentrations correlate with both mitochondrial function and plasticity. Future Directions: Despite the associations between features of mitochondrial function and insulin sensitivity, the question of a causal relationship between compromised mitochondrial plasticity and insulin resistance in the development of obesity and T2DM remains to be resolved. Antioxid. Redox Signal. 19, 258268. PMID:22938510

  20. The basic chemistry of exercise-induced DNA oxidation: oxidative damage, redox signaling, and their interplay.

    PubMed

    Cobley, James N; Margaritelis, Nikos V; Morton, James P; Close, Graeme L; Nikolaidis, Michalis G; Malone, John K

    2015-01-01

    Acute exercise increases reactive oxygen and nitrogen species generation. This phenomenon is associated with two major outcomes: (1) redox signaling and (2) macromolecule damage. Mechanistic knowledge of how exercise-induced redox signaling and macromolecule damage are interlinked is limited. This review focuses on the interplay between exercise-induced redox signaling and DNA damage, using hydroxyl radical (()OH) and hydrogen peroxide (H2O2) as exemplars. It is postulated that the biological fate of H2O2 links the two processes and thus represents a bifurcation point between redox signaling and damage. Indeed, H2O2 can participate in two electron signaling reactions but its diffusion and chemical properties permit DNA oxidation following reaction with transition metals and ()OH generation. It is also considered that the sensing of DNA oxidation by repair proteins constitutes a non-canonical redox signaling mechanism. Further layers of interaction are provided by the redox regulation of DNA repair proteins and their capacity to modulate intracellular H2O2 levels. Overall, exercise-induced redox signaling and DNA damage may be interlinked to a greater extent than was previously thought but this requires further investigation. PMID:26136689

  1. Acute exercise induces biphasic increase in respiratory mRNA in skeletal muscle

    SciTech Connect

    Ikeda, Shin-ichi; Kizaki, Takako; Haga, Shukoh; Ohno, Hideki; Takemasa, Tohru

    2008-04-04

    Peroxisome proliferator-activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}) promotes the expression of oxidative enzymes in skeletal muscle. We hypothesized that activation of the p38 MAPK (mitogen-activated protein kinase) in response to exercise was associated with exercise-induced PGC-1{alpha} and respiratory enzymes expression and aimed to demonstrate this under the physiological level. We subjected mice to a single bout of treadmill running and found that the exercise induced a biphasic increase in the expression of respiratory enzymes mRNA. The second phase of the increase was accompanied by an increase in PGC-1{alpha} protein, but the other was not. Administration of SB203580 (SB), an inhibitor of p38 MAPK, suppressed the increase in PGC-1{alpha} expression and respiratory enzymes mRNA in both phases. These data suggest that p38 MAPK is associated with the exercise-induced expression of PGC-1{alpha} and biphasic increase in respiratory enzyme mRNAs in mouse skeletal muscle under physiological conditions.

  2. Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability.

    PubMed

    de Beer, Vincent J; Merkus, Daphne; Bender, Shawn B; Tharp, Darla L; Bowles, Douglas K; Duncker, Dirk J; Laughlin, M Harold

    2013-12-01

    Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity. PMID:24157527

  3. Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

    PubMed Central

    de Beer, Vincent J.; Merkus, Daphne; Bender, Shawn B.; Tharp, Darla L.; Bowles, Douglas K.; Duncker, Dirk J.

    2013-01-01

    Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity. PMID:24157527

  4. The basic chemistry of exercise-induced DNA oxidation: oxidative damage, redox signaling, and their interplay

    PubMed Central

    Cobley, James N.; Margaritelis, Nikos V.; Morton, James P.; Close, Graeme L.; Nikolaidis, Michalis G.; Malone, John K.

    2015-01-01

    Acute exercise increases reactive oxygen and nitrogen species generation. This phenomenon is associated with two major outcomes: (1) redox signaling and (2) macromolecule damage. Mechanistic knowledge of how exercise-induced redox signaling and macromolecule damage are interlinked is limited. This review focuses on the interplay between exercise-induced redox signaling and DNA damage, using hydroxyl radical (OH) and hydrogen peroxide (H2O2) as exemplars. It is postulated that the biological fate of H2O2 links the two processes and thus represents a bifurcation point between redox signaling and damage. Indeed, H2O2 can participate in two electron signaling reactions but its diffusion and chemical properties permit DNA oxidation following reaction with transition metals and OH generation. It is also considered that the sensing of DNA oxidation by repair proteins constitutes a non-canonical redox signaling mechanism. Further layers of interaction are provided by the redox regulation of DNA repair proteins and their capacity to modulate intracellular H2O2 levels. Overall, exercise-induced redox signaling and DNA damage may be interlinked to a greater extent than was previously thought but this requires further investigation. PMID:26136689

  5. Ultra-endurance exercise induces stress and inflammation and affects circulating hematopoietic progenitor cell function.

    PubMed

    Stelzer, I; Krpfl, J M; Fuchs, R; Pekovits, K; Mangge, H; Raggam, R B; Gruber, H-J; Prller, F; Hofmann, P; Truschnig-Wilders, M; Obermayer-Pietsch, B; Haushofer, A C; Kessler, H H; Mchler, P

    2015-10-01

    Although amateur sports have become increasingly competitive within recent decades, there are as yet few studies on the possible health risks for athletes. This study aims to determine the impact of ultra-endurance exercise-induced stress on the number and function of circulating hematopoietic progenitor cells (CPCs) and hematological, inflammatory, clinical, metabolic, and stress parameters in moderately trained amateur athletes. Following ultra-endurance exercise, there were significant increases in leukocytes, platelets, interleukin-6, fibrinogen, tissue enzymes, blood lactate, serum cortisol, and matrix metalloproteinase-9. Ultra-endurance exercise did not influence the number of CPCs but resulted in a highly significant decline of CPC functionality after the competition. Furthermore, Epstein-Barr virus was seen to be reactivated in one of seven athletes. The link between exercise-induced stress and decline of CPC functionality is supported by a negative correlation between cortisol and CPC function. We conclude that ultra-endurance exercise induces metabolic stress and an inflammatory response that affects not only mature hematopoietic cells but also the function of the immature hematopoietic stem and progenitor cell fraction, which make up the immune system and provide for regeneration. PMID:25438993

  6. Hemodynamic effects of high intensity interval training in COPD patients exhibiting exercise-induced dynamic hyperinflation.

    PubMed

    Nasis, I; Kortianou, E; Vasilopoulou, ?; Spetsioti, S; Louvaris, Z; Kaltsakas, G; Davos, C H; Zakynthinos, S; Koulouris, N G; Vogiatzis, I

    2015-10-01

    Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function during exercise in COPD patients. COPD patients with (n = 25) and without (n = 11) exercise-induced DH undertook an incremental (IET) and a constant-load exercise test (CLET) sustained at 75% peak work (WRpeak) prior to and following an interval cycling exercise training regime (set at 100% WRpeak with 30-s work/30-s rest intervals) lasting for 12 weeks. Cardiac output (Q) was assessed by cardio-bio-impedance (PhysioFlow, enduro, PF-O7) to determine Q mean response time (QMRT) at onset (QMRT(ON)) and offset (QMRT(OFF)) of CLET. Post-rehabilitation only those patients exhibiting exercise-induced DH demonstrated significant reductions in QMRT(ON) (from 82.2 4.3 to 61.7 4.2 s) and QMRT(OFF) (from 80.5 3.8 to 57.2 4.9 s ). These post-rehabilitation adaptations were associated with improvements in inspiratory capacity, thereby suggesting that mitigation of the degree of exercise-induced DH improves central hemodynamic responses in COPD patients. PMID:26112284

  7. Peroxisome biogenesis in mammalian cells.

    PubMed

    Fujiki, Yukio; Okumoto, Kanji; Mukai, Satoru; Honsho, Masanori; Tamura, Shigehiko

    2014-01-01

    To investigate peroxisome assembly and human peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome, thirteen different complementation groups (CGs) of Chinese hamster ovary (CHO) cell mutants defective in peroxisome biogenesis have been isolated and established as a model research system. Successful gene-cloning studies by a forward genetic approach utilized a rapid functional complementation assay of CHO cell mutants led to isolation of human peroxin (PEX) genes. Search for pathogenic genes responsible for PBDs of all 14 CGs is now completed together with the homology search by screening the human expressed sequence tag database using yeast PEX genes. Peroxins are divided into three groups: (1) peroxins including Pex3p, Pex16p, and Pex19p, are responsible for peroxisome membrane biogenesis via classes I and II pathways; (2) peroxins that function in matrix protein import; (3) those such as three forms of Pex11p, Pex11p?, Pex11p?, and Pex11p?, are involved in peroxisome proliferation where DLP1, Mff, and Fis1 coordinately function. In membrane assembly, Pex19p forms complexes in the cytosol with newly synthesized PMPs including Pex16p and transports them to the receptor Pex3p, whereby peroxisomal membrane is formed (Class I pathway). Pex19p likewise forms a complex with newly made Pex3p and translocates it to the Pex3p receptor, Pex16p (Class II pathway). In matrix protein import, newly synthesized proteins harboring peroxisome targeting signal type 1 or 2 are recognized by Pex5p or Pex7p in the cytoplasm and are imported to peroxisomes via translocation machinery. In regard to peroxisome-cytoplasmic shuttling of Pex5p, Pex5p initially targets to an 800-kDa docking complex consisting of Pex14p and Pex13p and then translocates to a 500-kDa RING translocation complex. At the terminal step, Pex1p and Pex6p of the AAA family mediate the export of Pex5p, where Cys-ubiquitination of Pex5p is essential for the Pex5p exit. PMID:25177298

  8. Peroxisome biogenesis in mammalian cells

    PubMed Central

    Fujiki, Yukio; Okumoto, Kanji; Mukai, Satoru; Honsho, Masanori; Tamura, Shigehiko

    2014-01-01

    To investigate peroxisome assembly and human peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome, thirteen different complementation groups (CGs) of Chinese hamster ovary (CHO) cell mutants defective in peroxisome biogenesis have been isolated and established as a model research system. Successful gene-cloning studies by a forward genetic approach utilized a rapid functional complementation assay of CHO cell mutants led to isolation of human peroxin (PEX) genes. Search for pathogenic genes responsible for PBDs of all 14 CGs is now completed together with the homology search by screening the human expressed sequence tag database using yeast PEX genes. Peroxins are divided into three groups: (1) peroxins including Pex3p, Pex16p, and Pex19p, are responsible for peroxisome membrane biogenesis via classes I and II pathways; (2) peroxins that function in matrix protein import; (3) those such as three forms of Pex11p, Pex11p?, Pex11p?, and Pex11p?, are involved in peroxisome proliferation where DLP1, Mff, and Fis1 coordinately function. In membrane assembly, Pex19p forms complexes in the cytosol with newly synthesized PMPs including Pex16p and transports them to the receptor Pex3p, whereby peroxisomal membrane is formed (Class I pathway). Pex19p likewise forms a complex with newly made Pex3p and translocates it to the Pex3p receptor, Pex16p (Class II pathway). In matrix protein import, newly synthesized proteins harboring peroxisome targeting signal type 1 or 2 are recognized by Pex5p or Pex7p in the cytoplasm and are imported to peroxisomes via translocation machinery. In regard to peroxisome-cytoplasmic shuttling of Pex5p, Pex5p initially targets to an 800-kDa docking complex consisting of Pex14p and Pex13p and then translocates to a 500-kDa RING translocation complex. At the terminal step, Pex1p and Pex6p of the AAA family mediate the export of Pex5p, where Cys-ubiquitination of Pex5p is essential for the Pex5p exit. PMID:25177298

  9. NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.

    PubMed

    Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza; Marchet, Silvia; Sauve, Anthony A; Li, Wei; Leoni, Valerio; Schon, Eric A; Dantzer, Franoise; Auwerx, Johan; Viscomi, Carlo; Zeviani, Massimo

    2014-06-01

    Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans. PMID:24814483

  10. 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

  11. Biogenesis of light harvesting proteins.

    PubMed

    Dall'Osto, Luca; Bressan, Mauro; Bassi, Roberto

    2015-09-01

    The LHC family includes nuclear-encoded, integral thylakoid membrane proteins, most of which coordinate chlorophyll and xanthophyll chromophores. By assembling with the core complexes of both photosystems, LHCs form a flexible peripheral moiety for enhancing light-harvesting cross-section, regulating its efficiency and providing protection against photo-oxidative stress. Upon its first appearance, LHC proteins underwent evolutionary diversification into a large protein family with a complex genetic redundancy. Such differentiation appears as a crucial event in the adaptation of photosynthetic organisms to changing environmental conditions and land colonization. The structure of photosystems, including nuclear- and chloroplast-encoded subunits, presented the cell with a number of challenges for the control of the light harvesting function. Indeed, LHC-encoding messages are translated in the cytosol, and pre-proteins imported into the chloroplast, processed to their mature size and targeted to the thylakoids where are assembled with chromophores. Thus, a tight coordination between nuclear and plastid gene expression, in response to environmental stimuli, is required to adjust LHC composition during photoacclimation. In recent years, remarkable progress has been achieved in elucidating structure, function and regulatory pathways involving LHCs; however, a number of molecular details still await elucidation. In this review, we will provide an overview on the current knowledge on LHC biogenesis, ranging from organization of pigment-protein complexes to the modulation of gene expression, import and targeting to the photosynthetic membranes, and regulation of LHC assembly and turnover. Genes controlling these events are potential candidate for biotechnological applications aimed at optimizing light use efficiency of photosynthetic organisms. This article is part of a Special Issue entitled: Chloroplast biogenesis. PMID:25687893

  12. Mitochondrial Homeostasis in Acute Organ Failure

    PubMed Central

    Stallons, L. Jay; Funk, Jason A.; Schnellmann, Rick G.

    2013-01-01

    The kidneys compose approximately 0.5% of the body mass but consume about 10% of the oxygen in cellular respiration. This discordance is due to the high energy demands on the kidney for reabsorption of filtered blood components and makes the kidney sensitive to mitochondrial stress, the primary source of cellular ATP. Regardless of the etiology, acute kidney injury (AKI) almost always involves aspects of mitochondrial dysfunction. Recent evidence from experimental models suggests that preserving mitochondrial function or promoting mitochondrial repair rescues renal function during AKI. In this review we discuss the effect of AKI on disruption of mitochondrial homeostasis, and how the dynamic processes of mitochondrial biogenesis, fission/fusion, and mitophagy influence renal injury and recovery. PMID:24386614

  13. Phosphatidylserine Decarboxylase 1 (Psd1) Promotes Mitochondrial Fusion by Regulating the Biophysical Properties of the Mitochondrial Membrane and Alternative Topogenesis of Mitochondrial Genome Maintenance Protein 1 (Mgm1)*

    PubMed Central

    Chan, Eliana Y. L.; McQuibban, G. Angus

    2012-01-01

    Nonbilayer-forming lipids such as cardiolipin, phosphatidic acid, and phosphatidylethanolamine (PE) are proposed to generate negative membrane curvature, promoting membrane fusion. However, the mechanism by which lipids regulate mitochondrial fusion remains poorly understood. Here, we show that mitochondrial-localized Psd1, the key yeast enzyme that synthesizes PE, is required for proper mitochondrial morphology and fusion. Yeast cells lacking Psd1 exhibit fragmented and aggregated mitochondria with impaired mitochondrial fusion during mating. More importantly, we demonstrate that a reduction in PE reduces the rate of lipid mixing during fusion of liposomes with lipid compositions reflecting the mitochondrial membrane. This suggests that the mitochondrial fusion defect in the ?psd1 strain could be due to the altered biophysical properties of the mitochondrial membrane, resulting in reduced fusion kinetics. The ?psd1 strain also has impaired mitochondrial activity such as oxidative phosphorylation and reduced mitochondrial ATP levels which are due to a reduction in mitochondrial PE. The loss of Psd1 also impairs the biogenesis of s-Mgm1, a protein essential for mitochondrial fusion, further exacerbating the mitochondrial fusion defect of the ?psd1 strain. Increasing s-Mgm1 levels in ?psd1 cells markedly reduced mitochondrial aggregation. Our results demonstrate that mitochondrial PE regulates mitochondrial fusion by regulating the biophysical properties of the mitochondrial membrane and by enhancing the biogenesis of s-Mgm1. While several proteins are required to orchestrate the intricate process of membrane fusion, we propose that specific phospholipids of the mitochondrial membrane promote fusion by enhancing lipid mixing kinetics and by regulating the action of profusion proteins. PMID:23045528

  14. Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes

    PubMed Central

    da Cunha, Fernanda Marques; Torelli, Nicole Quesada; Kowaltowski, Alicia J.

    2015-01-01

    Mitochondria are essential organelles for eukaryotic homeostasis. Although these organelles possess their own DNA, the vast majority (>99%) of mitochondrial proteins are encoded in the nucleus. This situation makes systems that allow the communication between mitochondria and the nucleus a requirement not only to coordinate mitochondrial protein synthesis during biogenesis but also to communicate eventual mitochondrial malfunctions, triggering compensatory responses in the nucleus. Mitochondria-to-nucleus retrograde signaling has been described in various organisms, albeit with differences in effector pathways, molecules, and outcomes, as discussed in this review. PMID:26583058

  15. Mitochondrial Dynamics: Functional Link with Apoptosis

    PubMed Central

    Otera, Hidenori; Mihara, Katsuyoshi

    2012-01-01

    Mitochondria participate in a variety of physiologic processes, such as ATP production, lipid metabolism, iron-sulfur cluster biogenesis, and calcium buffering. The morphology of mitochondria changes dynamically due to their frequent fusion and division in response to cellular conditions, and these dynamics are an important constituent of apoptosis. The discovery of large GTPase family proteins that regulate mitochondrial dynamics, together with novel insights into the role of mitochondrial fusion and fission in apoptosis, has provided important clues to understanding the molecular mechanisms of cellular apoptosis. In this paper, we briefly summarize current knowledge of the role of mitochondrial dynamics in apoptosis and cell pathophysiology in mammalian cells. PMID:22536251

  16. Peroxisome assembly: matrix and membrane protein biogenesis.

    PubMed

    Ma, Changle; Agrawal, Gaurav; Subramani, Suresh

    2011-04-01

    The biogenesis of peroxisomal matrix and membrane proteins is substantially different from the biogenesis of proteins of other subcellular compartments, such as mitochondria and chloroplasts, that are of endosymbiotic origin. Proteins are targeted to the peroxisome matrix through interactions between specific targeting sequences and receptor proteins, followed by protein translocation across the peroxisomal membrane. Recent advances have shed light on the nature of the peroxisomal translocon in matrix protein import and the molecular mechanisms of receptor recycling. Furthermore, the endoplasmic reticulum has been shown to play an important role in peroxisomal membrane protein biogenesis. Defining the molecular events in peroxisome assembly may enhance our understanding of the etiology of human peroxisome biogenesis disorders. PMID:21464226

  17. Abnormal expression of key genes and proteins in the canonical Wnt/β-catenin pathway of articular cartilage in a rat model of exercise-induced osteoarthritis

    PubMed Central

    LIU, SHEN-SHEN; ZHOU, PU; ZHANG, YANQIU

    2016-01-01

    To investigate the molecular pathogenesis of the canonical Wnt/β-catenin pathway in exercise-induced osteoarthritis (OA), 30 male healthy Sprague Dawley rats were divided into three groups (control, normal exercise-induced OA and injured exercise-induced OA groups) in order to establish the exercise-induced OA rat model. The mRNA and protein expression levels of Runx-2, BMP-2, Ctnnb1, Sox-9, collagen II, Mmp-13, Wnt-3a and β-catenin in chon-drocytes were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemical staining. The mRNA levels of Runx-2, BMP-2 and Ctnnb1 were upregulated in the normal exercise-induced OA and injured exercise-induced OA groups; while Runx-2 and BMP-2 were upregulated in the injured exercise-induced OA group when compared with the normal exercise-induced OA group. The protein levels of Mmp-13, Wnt-3a and β-catenin were increased and collagen II was reduced in the normal exercise-induced OA and injured exercise-induced OA groups. Ctnnb1, Wnt-3a and β-catenin, which are key genes and proteins in the canonical Wnt/β-catenin pathway, were abnormally expressed in chondrocytes of the exercise-induced OA rat model. Ctnnb1, β-catenin and Wnt-3a were suggested to participate in the pathogenesis of exercise-induced OA by abnormally activating the Wnt/β-catenin pathway during physical exercise due to excessive pressure. The results of the present study may provide an improved understanding of the pathogenesis of exercise-induced OA. PMID:26794964

  18. Number matters: control of mammalian mitochondrial DNA copy number

    PubMed Central

    Clay Montier, Laura L.; Deng, Janice; Bai, Yidong

    2016-01-01

    Regulation of mitochondrial biogenesis is essential for proper cellular functioning. Mitochondrial DNA (mtDNA) depletion and the resulting mitochondrial malfunction have been implicated in cancer, neurodegeneration, diabetes, aging, and many other human diseases. Although it is known that the dynamics of the mammalian mitochondrial genome are not linked with that of the nuclear genome, very little is known about the mechanism of mtDNA propagation. Nevertheless, our understanding of the mode of mtDNA replication has advanced in recent years, though not without some controversies. This review summarizes our current knowledge of mtDNA copy number control in mammalian cells, while focusing on both mtDNA replication and turnover. Although mtDNA copy number is seemingly in excess, we reason that mtDNA copy number control is an important aspect of mitochondrial genetics and biogenesis and is essential for normal cellular function. PMID:19302968

  19. Mitochondrial alteration in type 2 diabetes and obesity

    PubMed Central

    Cheng, Zhiyong; Almeida, Fabio A

    2014-01-01

    The growing epidemic of type 2 diabetes mellitus (T2DM) and obesity is largely attributed to the current lifestyle of over-consumption and physical inactivity. As the primary platform controlling metabolic and energy homeostasis, mitochondria show aberrant changes in T2DM and obese subjects. While the underlying mechanism is under extensive investigation, epigenetic regulation is now emerging to play an important role in mitochondrial biogenesis, function, and dynamics. In line with lifestyle modifications preventing mitochondrial alterations and metabolic disorders, exercise has been shown to change DNA methylation of the promoter of PGC1α to favor gene expression responsible for mitochondrial biogenesis and function. In this article we discuss the epigenetic mechanism of mitochondrial alteration in T2DM and obesity, and the effects of lifestyle on epigenetic regulation. Future studies designed to further explore and integrate the epigenetic mechanisms with lifestyle modification may lead to interdisciplinary interventions and novel preventive options for mitochondrial alteration and metabolic disorders. PMID:24552811

  20. Increased insulin sensitivity and distorted mitochondrial adaptations during muscle unloading.

    PubMed

    Qi, Zhengtang; Zhang, Yuan; Guo, Wei; Ji, Liu; Ding, Shuzhe

    2012-01-01

    We aimed to further investigate mitochondrial adaptations to muscle disuse and the consequent metabolic disorders. Male rats were submitted to hindlimb unloading (HU) for three weeks. Interestingly, HU increased insulin sensitivity index (ISI) and decreased blood level of triglyceride and insulin. In skeletal muscle, HU decreased expression of pyruvate dehydrogenase kinase 4 (PDK4) and its protein level in mitochondria. HU decreased mtDNA content and mitochondrial biogenesis biomarkers. Dynamin-related protein (Drp1) in mitochondria and Mfn2 mRNA level were decreased significantly by HU. Our findings provide more extensive insight into mitochondrial adaptations to muscle disuse, involving the shift of fuel utilization towards glucose, the decreased mitochondrial biogenesis and the distorted mitochondrial dynamics. PMID:23443131

  1. Evidence for Mitochondrial Respiratory Deficiency in Rat Rhabdomyosarcoma Cells

    PubMed Central

    Jahnke, Vanessa E.; Sabido, Odile; Defour, Aurlia; Castells, Josiane; Lefai, Etienne; Roussel, Damien; Freyssenet, Damien

    2010-01-01

    Background Mitochondria can sense signals linked to variations in energy demand to regulate nuclear gene expression. This retrograde signaling pathway is presumed to be involved in the regulation of myoblast proliferation and differentiation. Rhabdomyosarcoma cells are characterized by their failure to both irreversibly exit the cell cycle and complete myogenic differentiation. However, it is currently unknown whether mitochondria are involved in the failure of rhabdomyosarcoma cells to differentiate. Methodology/Principal Findings Mitochondrial biogenesis and metabolism were studied in rat L6E9 myoblasts and R1H rhabdomyosacoma cells during the cell cycle and after 36 hours of differentiation. Using a combination of flow cytometry, polarographic and molecular analyses, we evidenced a marked decrease in the cardiolipin content of R1H cells cultured in growth and differentiation media, together with a significant increase in the content of mitochondrial biogenesis factors and mitochondrial respiratory chain proteins. Altogether, these data indicate that the mitochondrial inner membrane composition and the overall process of mitochondrial biogenesis are markedly altered in R1H cells. Importantly, the dysregulation of protein-to-cardiolipin ratio was associated with major deficiencies in both basal and maximal mitochondrial respiration rates. This deficiency in mitochondrial respiration probably contributes to the inability of R1H cells to decrease mitochondrial H2O2 level at the onset of differentiation. Conclusion/Significance A defect in the regulation of mitochondrial biogenesis and mitochondrial metabolism may thus be an epigenetic mechanism that may contribute to the tumoral behavior of R1H cells. Our data underline the importance of mitochondria in the regulation of myogenic differentiation. PMID:20072609

  2. Loss of functional endothelial connexin40 results in exercise-induced hypertension in mice.

    PubMed

    Morton, Susan K; Chaston, Daniel J; Howitt, Lauren; Heisler, Jillian; Nicholson, Bruce J; Fairweather, Stephen; Brer, Stefan; Ashton, Anthony W; Matthaei, Klaus I; Hill, Caryl E

    2015-03-01

    During activity, coordinated vasodilation of microcirculatory networks with upstream supply vessels increases blood flow to skeletal and cardiac muscles and reduces peripheral resistance. Endothelial dysfunction in humans attenuates activity-dependent vasodilation, resulting in exercise-induced hypertension in otherwise normotensive individuals. Underpinning activity-dependent hyperemia is an ascending vasodilation in which the endothelial gap junction protein, connexin (Cx)40, plays an essential role. Because exercise-induced hypertension is proposed as a forerunner to clinical hypertension, we hypothesized that endothelial disruption of Cx40 function in mice may create an animal model of this condition. To this end, we created mice in which a mutant Cx40T152A was expressed alongside wildtype Cx40 selectively in the endothelium. Expression of the Cx40T152A transgene in Xenopus oocytes and mouse coronary endothelial cells in vitro impaired both electric and chemical conductance and acted as a dominant-negative against wildtype Cx40, Cx43, and Cx45, but not Cx37. Endothelial expression of Cx40T152A in Cx40T152ATg mice attenuated ascending vasodilation, without effect on radial coupling through myoendothelial gap junctions. Using radiotelemetry, Cx40T152ATg mice showed an activity-dependent increase in blood pressure, which was significantly greater than in wildtype mice, but significantly less than in chronically hypertensive, Cx40knockout mice. The increase in heart rate with activity was also greater than in wildtype or Cx40knockout mice. We conclude that the endothelial Cx40T152A mutation attenuates activity-dependent vasodilation, producing a model of exercise-induced hypertension. These data highlight the importance of endothelial coupling through Cx40 in regulating blood pressure during activity. PMID:25547341

  3. The influence of ice slushy on voluntary contraction force following exercise-induced hyperthermia.

    PubMed

    Burdon, Catriona A; Easthope, Christopher S; Johnson, Nathan A; Chapman, Phillip G; O'Connor, Helen

    2014-07-01

    This study aimed to investigate the effect of exercise-induced hyperthermia on central fatigue and force decline in exercised and nonexercised muscles and whether ingestion of ice slushy (ICE) ameliorates fatigue. Eight participants (5 males, 3 females) completed 45 s maximal voluntary isometric contractions (MVIC) with elbow flexors and knee extensors at baseline and following an exercise-induced rectal temperature (Trec) of 39.3 0.2 C. Percutaneous electrical muscle stimulation was superimposed at 15, 30 and 44 s during MVICs to assess muscle activation. To increase Trec to 39.3 C, participants cycled at 60% maximum power output for 42 11 min in 40 C and 50% relative humidity. Immediately prior to each MVIC, participants consumed 50 g of ICE (-1 C) or thermoneutral drink (38 C, CON) made from 7.4% carbohydrate beverage. Participants consumed water (19 C) during exercise to prevent hypohydration. Voluntary muscle force production and activation in both muscle groups were unchanged at Trec 39.3 C with ICE (knee extensors: 209 152 N) versus CON (knee extensors: 255 157 N, p = 0.19). At Trec 39.3 C, quadriceps mean force (232 151 N) decreased versus baseline (302 180 N, p < 0.001) and mean voluntary activation was also decreased (by 15% 11%, p < 0.001). Elbow flexor mean force decreased from 179 67 N to 148 65 N when Trec was increased to 39.3 C (p < 0.001) but mean voluntary activation was not reduced at 39.3 C (5% 25%, p = 0.79). After exercise-induced hyperthermia, ICE had no effect on voluntary activation or force production; however, both were reduced from baseline in the exercised muscle group. Peripheral fatigue was greater than the central component and limited the ability of an intervention designed to alter central fatigue. PMID:24971678

  4. Analysis of exercise-induced Na+-K+ exchange in rat skeletal muscle in vivo.

    PubMed

    Murphy, K T; Nielsen, O B; Clausen, T

    2008-12-01

    We aimed to quantify the Na(+)-K(+) exchange occurring during exercise in rat skeletal muscle in vivo. Intracellular Na(+) and K(+) content, Na(+) permeability ((22)Na(+) influx), Na(+)-K(+) pump activity (ouabain-sensitive (86)Rb(+) uptake) and Na(+)-K(+) pump alpha(2) subunit content ([(3)H]ouabain binding) were measured. Six-week-old rats rested (control animals) or performed intermittent running for 10-60 min and were then killed or were killed at 15 or 90 min following 60 min exercise. In the soleus muscle, intracellular Na(+) was 80% higher than in control rats after 60 min exercise, was still elevated (38%) after 15 min rest and returned to control levels after 90 min rest. Intracellular K(+) showed corresponding decreases after 15-60 min exercise, returning to control levels 90 min postexercise. Exercise induced little change in Na(+) and K(+) in the extensor digitorum longus muscle (EDL). In soleus, the exercise-induced rise in Na(+) and reduction in K(+) were augmented by pretreatment with ouabain or by reducing the content of muscular Na(+)-K(+) pumps by prior K(+) depletion of the animals. Fifteen minutes after 60 min exercise, ouabain-sensitive (86)Rb(+) uptake in the soleus was increased by 30% but was unchanged in EDL, and there was no effect of exercise on [(3)H]ouabain binding measured in vitro or in vivo in either muscle. In conclusion, in the soleus, in vivo exercise induces a rise in intracellular Na(+), which reflects the excitation-induced increase in Na(+) influx and leads to augmented Na(+)-K(+) pump activity without apparent change in Na(+)-K(+) pump capacity. PMID:18586859

  5. Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72.

    PubMed

    Kavazis, Andreas N; Smuder, Ashley J; Min, Kisuk; Tümer, Nihal; Powers, Scott K

    2010-11-01

    Doxorubicin (Dox) is an antitumor agent used in cancer treatment, but its clinical use is limited due to cardiotoxicity. Although exercise training can defend against Dox-mediated cardiac damage, the means for this cardioprotection remain unknown. To investigate the mechanism(s) responsible for exercise training-induced cardioprotection against Dox-mediated cardiotoxicity, we tested a two-pronged hypothesis: 1) exercise training protects against Dox-induced cardiotoxicity by preventing Dox-mediated mitochondrial damage/dysfunction and increased oxidative stress and 2) exercise training-induced cardiac expression of the inducible isoform of the 70-kDa heat shock protein 72 (HSP72) is essential to achieve exercise training-induced cardioprotection against Dox toxicity. Animals were randomly assigned to sedentary or exercise groups and paired with either placebo or Dox treatment (i.e., 20 mg/kg body wt ip Dox hydrochloride 24 h before euthanasia). Dox administration resulted in cardiac mitochondrial dysfunction, activation of proteases, and apoptosis. Exercise training increased cardiac antioxidant enzymes and HSP72 protein abundance and protected cardiac myocytes against Dox-induced mitochondrial damage, protease activation, and apoptosis. To determine whether exercise-induced expression of HSP72 in the heart is required for this cardioprotection, we utilized an innovative experimental strategy that successfully prevented exercise-induced increases in myocardial HSP72 levels. However, prevention of exercise-induced increases in myocardial HSP72 did not eliminate the exerc