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1

Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: implications for mitochondrial biogenesis.  

PubMed

The mechanisms that regulate the enhanced skeletal muscle oxidative capacity observed when training with reduced carbohydrate (CHO) availability are currently unknown. The aim of the present study was to test the hypothesis that reduced CHO availability enhances p53 signaling and expression of genes associated with regulation of mitochondrial biogenesis and substrate utilization in human skeletal muscle. In a repeated-measures design, muscle biopsies (vastus lateralis) were obtained from eight active males before and after performing an acute bout of high-intensity interval running with either high (HIGH) or low CHO availability (LOW). Resting muscle glycogen (HIGH, 467 ± 19; LOW, 103 ± 9 mmol/kg dry wt) was greater in HIGH compared with LOW (P < 0.05). Phosphorylation (P-) of ACC(Ser79) (HIGH, 1.4 ± 0.4; LOW, 2.9 ± 0.9) and p53(Ser15) (HIGH, 0.9 ± 0.4; LOW, 2.6 ± 0.8) was higher in LOW immediately postexercise and 3 h postexercise, respectively (P < 0.05). Before and 3 h postexercise, mRNA content of pyruvate dehydrogenase kinase 4, mitochondrial transcription factor A, cytochrome-c oxidase IV, and PGC-1? were greater in LOW compared with HIGH (P < 0.05), whereas carnitine palmitoyltransferase-1 showed a trend toward significance (P = 0.09). However, only PGC-1? expression was increased by exercise (P < 0.05), where three-fold increases occurred independently of CHO availability. We conclude that the exercise-induced increase in p53 phosphorylation is enhanced in conditions of reduced CHO availability, which may be related to upstream signaling through AMPK. Given the emergence of p53 as a molecular regulator of mitochondrial biogenesis, such nutritional modulation of contraction-induced p53 activation has implications for both athletic and clinical populations. PMID:23364526

Bartlett, Jonathan D; Louhelainen, Jari; Iqbal, Zafar; Cochran, Andrew J; Gibala, Martin J; Gregson, Warren; Close, Graeme L; Drust, Barry; Morton, James P

2013-03-15

2

Mitochondrial Biogenesis and Turnover  

PubMed Central

Mitochondrial biogenesis is a complex process involving the coordinated expression of mitochondrial and nuclear genes, the import of the products of the latter into the organelle and turnover. The mechanisms associated with these events have been intensively studied in the last twenty years and our understanding of their details is much improved. Mitochondrial biogenesis requires the participation of calcium signaling that activates a series of calcium dependent protein kinases that in turn activate transcription factors and coactivators such as PGC-1? that regulates the expression of genes coding for mitochondrial components. In addition, mitochondrial biogenesis involves the balance of mitochondrial fission-fusion. Mitochondrial malfunction or defects in any of the many pathways involved in mitochondrial biogenesis can lead to degenerative diseases and possibly play an important part in aging.

Diaz, Francisca; Moraes, Carlos T.

2011-01-01

3

Redox Regulation of Mitochondrial Biogenesis  

PubMed Central

Background The cell renews, adapts, or expands its mitochondrial population during episodes of cell damage or periods of intensified energy demand by the induction of mitochondrial biogenesis. This bi-genomic program is modulated by redox-sensitive signals that respond to physiological nitric oxide (NO), carbon monoxide (CO), and mitochondrial reactive oxygen species (ROS) production. Scope of Review This review summarizes our current ideas about the pathways involved in the activation of mitochondrial biogenesis by the physiological gases leading to changes in the redox milieu of the cell with an emphasis on the responses to oxidative stress and inflammation. Major Conclusions The cell’s energy supply is protected from conditions that damage mitochondria by an inducible transcriptional program of mitochondrial biogenesis that operates in large part through redox signals involving the nitric oxide synthase and the heme oxygenase-1/CO systems. These redox events stimulate the coordinated activities of several multifunctional transcription factors and co-activators also involved in the elimination of defective mitochondria and the expression of counter-inflammatory and anti-oxidant genes, such as IL10 and Sod2, as part of a unified damage-control network. General Significance The redox-regulated mechanisms of mitochondrial biogenesis schematically outlined in the graphical abstract link mitochondrial quality control to an enhanced capacity to support the cell’s metabolic needs while improving its resistance to metabolic failure and avoidance of cell death during periods of oxidative stress.

Piantadosi, Claude A.; Suliman, Hagir B.

2013-01-01

4

Transcriptional integration of mitochondrial biogenesis  

PubMed Central

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.

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

2012-01-01

5

Resveratrol induces mitochondrial biogenesis in endothelial cells.  

PubMed

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

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

6

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

PubMed

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 VO2, 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, PDHE1?) 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

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

2014-06-15

7

Mitochondrial biogenesis in exercise and in ageing  

Microsoft Academic Search

Mitochondrial biogenesis is critical for the normal function of cells. It is well known that mitochondria are produced and eventually after normal functioning they are degraded. Thus, the actual level of mitochondria in cells is dependent both on the synthesis and the degradation. Ever since the proposal of the mitochondrial theory of ageing by Jaime Miquel in the 70's, it

Jose Viña; Mari Carmen Gomez-Cabrera; Consuelo Borras; Teresa Froio; Fabian Sanchis-Gomar; Vladimir E. Martinez-Bello; Federico V. Pallardo

2009-01-01

8

Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease.  

PubMed

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) brain. Our prior studies demonstrated reduced mitochondrial number in susceptible hippocampal neurons in the brain from AD patients and in M17 cells over-expressing familial AD-causing amyloid precursor protein (APP) mutant (APPswe). In the current study, we investigated whether alterations in mitochondrial biogenesis contribute to mitochondrial abnormalities in AD. Mitochondrial biogenesis is regulated by the peroxisome proliferator activator receptor gamma-coactivator 1? (PGC-1?)-nuclear respiratory factor (NRF)-mitochondrial transcription factor A pathway. Expression levels of PGC-1?, NRF 1, NRF 2, and mitochondrial transcription factor A were significantly decreased in both AD hippocampal tissues and APPswe M17 cells, suggesting a reduced mitochondrial biogenesis. Indeed, APPswe M17 cells demonstrated decreased mitochondrial DNA/nuclear DNA ratio, correlated with reduced ATP content, and decreased cytochrome C oxidase activity. Importantly, over-expression of PGC-1? could completely rescue while knockdown of PGC-1? could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in APPswe M17 cells, suggesting reduced mitochondrial biogenesis is likely involved in APPswe-induced mitochondrial deficits. We further demonstrated that reduced expression of p-CREB and PGC-1? in APPswe M17 cells could be rescued by cAMP in a dose-dependent manner, which could be inhibited by PKA inhibitor H89, suggesting that the PKA/CREB pathway plays a critical role in the regulation of PGC-1? expression in APPswe M17 cells. Overall, this study demonstrated that impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD. PMID:22077634

Sheng, Baiyang; Wang, Xinglong; Su, Bo; Lee, Hyoung-gon; Casadesus, Gemma; Perry, George; Zhu, Xiongwei

2012-02-01

9

Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis.  

PubMed

Mitochondria are highly dynamic organelles and their proper function is crucial for the maintenance of cellular homeostasis. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The tight regulation between these opposing processes is essential for cellular adaptation in response to cellular metabolic state, stress and other intracellular or environmental signals. Interestingly, imbalance between mitochondrial proliferation and degradation process results in progressive development of numerous pathologic conditions. Here we review recent studies that highlight the intricate interplay between mitochondrial biogenesis and mitophagy, mainly focusing on the molecular mechanisms that govern the coordination of these processes and their involvement in age-related pathologies and ageing. PMID:24486129

Palikaras, Konstantinos; Tavernarakis, Nektarios

2014-08-01

10

Mitochondrial Biogenesis and Function in Arabidopsis†  

PubMed Central

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.

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

2008-01-01

11

Estrogenic Control of Mitochondrial Function and Biogenesis  

PubMed Central

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.

Klinge, Carolyn M.

2008-01-01

12

Reperfusion Promotes Mitochondrial Biogenesis following Focal Cerebral Ischemia in Rats  

PubMed Central

Background and Purpose Reperfusion after transient cerebral ischemia causes severe damage to mitochondria; however, little is known regarding the continuous change in mitochondrial biogenesis during reperfusion. Mitochondrial biogenesis causes an increase in the individual mitochondrial mass of neurons and maintains their aerobic set-point in the face of declining function. The aim of this study was to examine mitochondrial biogenesis in the cortex during reperfusion following focal cerebral ischemia. Methods Male Wistar rats were subjected to transient focal cerebral ischemia. The relative amount of cortical mitochondrial DNA was analyzed using quantitative real-time PCR at 0 h, 24 h, 72 h, and 7 d after reperfusion. Three critical transcriptional regulators of mitochondrial biogenesis were measured by semi-quantitative reverse-transcription PCR. The protein expression of cytochrome C oxidase subunits I and IV was detected by Western blotting. Results Evidence of increased mitochondrial biogenesis was observed after reperfusion. The cortical mitochondrial DNA content increased after 24 h, peaked after 72 h, and maintained a high level for 7 d. The cortical expression of three critical genes for the transcriptional regulation of mitochondrial biogenesis, namely, peroxisome proliferator-activated receptor coactivator-1?, nuclear respiratory factor-1, and mitochondrial transcription factor A, also increased at 24 h and 72 h. The expression of peroxisome proliferator-activated receptor coactivator-1? returned to the baseline level at 7 d, but two other factors maintained higher levels compared with the controls. Moreover, the expression of cytochrome C oxidase subunits I and IV was increased in the cortex. Conclusions These results indicate that reperfusion increased mitochondrial biogenesis following focal cerebral ischemia, and this tendency was exacerbated as the reperfusion time was extended. Reperfusion-induced mitochondrial biogenesis was mediated through up-regulation of critical transcriptional regulators of mitochondrial biogenesis.

Xie, Yuying; Li, Jun; Fan, Guibo; Qi, Sihua; Li, Bing

2014-01-01

13

A high throughput respirometric assay for mitochondrial biogenesis and toxicity  

PubMed Central

Mitochondria are a common target of toxicity for drugs and other chemicals, and results in decreased aerobic metabolism and cell death. In contrast, mitochondrial biogenesis restores cell vitality and there is a need for new agents to induce biogenesis. Current cell-based models of mitochondrial biogenesis or toxicity are inadequate because cultured cell lines are highly glycolytic with minimal aerobic metabolism and altered mitochondrial physiology. In addition, there are no high-throughput, real-time assays that assess mitochondrial function. We adapted primary cultures of renal proximal tubular cells (RPTC) that exhibit in vivo levels of aerobic metabolism, are not glycolytic, and retain higher levels of differentiated functions and used the Seahorse Biosciences analyzer to measure mitochondrial function in real time in multi-well plates. Using uncoupled respiration as a marker of electron transport chain (ETC) integrity, the nephrotoxicants cisplatin, HgCl2 and gentamicin exhibited mitochondrial toxicity prior to decreases in basal respiration and cell death. Conversely, using FCCP-uncoupled respiration as a marker of maximal ETC activity, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), SRT1720, resveratrol, daidzein, and metformin produced mitochondrial biogenesis in RPTC. The merger of the RPTC model and multi-well respirometry results in a single high throughput assay to measure mitochondrial biogenesis and toxicity, and nephrotoxic potential.

Beeson, Craig C.; Beeson, Gyda C.; Schnellmann, Rick G.

2010-01-01

14

Hyperglycemia decreases mitochondrial function: The regulatory role of mitochondrial biogenesis  

SciTech Connect

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.

Palmeira, Carlos M. [Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004-517 Coimbra (Portugal)], E-mail: palmeira@ci.uc.pt; Rolo, Anabela P. [Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004-517 Coimbra (Portugal); Berthiaume, Jessica; Bjork, James A.; Wallace, Kendall B. [Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, Duluth, MN (United States)

2007-12-01

15

Hyperglycemia decreases mitochondrial function: the regulatory role of mitochondrial biogenesis.  

PubMed

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. PMID:17761203

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

2007-12-01

16

Mitochondrial biogenesis and the development of diabetic retinopathy  

Microsoft Academic Search

Retinal mitochondria become dysfunctional and their DNA (mtDNA) is damaged in diabetes. The biogenesis of mitochondrial DNA is tightly controlled by nuclear–mitochondrial transcriptional factors, and translocation of transcription factor A (TFAM) to the mitochondria is essential for transcription and replication. Our aim is to investigate the effects of diabetes on nuclear–mitochondrial communication in the retina and its role in the

Julia M. Santos; Shikha Tewari; Andrew F. X. Goldberg; Renu A. Kowluru

2011-01-01

17

Diabetes regulates mitochondrial biogenesis and fission in mouse neurons  

Microsoft Academic Search

Aims\\/hypothesis  Normal mitochondrial activity is a critical component of neuronal metabolism and function. Disruption of mitochondrial activity\\u000a by altered mitochondrial fission and fusion is the root cause of both neurodegenerative disorders and Charcot–Marie–Tooth\\u000a type 2A inherited neuropathy. This study addressed the role of mitochondrial fission in the pathogenesis of diabetic neuropathy.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Mitochondrial biogenesis and fission were assayed in both in vivo

J. L. Edwards; A. Quattrini; S. I. Lentz; C. Figueroa-Romero; F. Cerri; C. Backus; Y. Hong; E. L. Feldman

2010-01-01

18

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

PubMed Central

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.

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

19

Diabetes regulates mitochondrial biogenesis and fission in neurons  

PubMed Central

Aims Normal mitochondrial (Mt) activity is a critical component of neuronal metabolism and function. Disruption of Mt activity by altered Mt fission and fusion is the root cause of both neurodegenerative disorders and Charcot-Marie-Tooth Type 2A inherited neuropathy. The current study addressed the role of Mt fission in the pathogenesis of diabetic neuropathy (DN). Methods Mt biogenesis and fission were assayed in both in vivo and in vitro models of DN. Gene, protein, mitochondrial DNA and ultrastructural analyses were used to assess Mt biogenesis and fission. Results Our data reveal increased Mt biogenesis in dorsal root ganglion (DRG) neurons from diabetic compared to non-diabetic mice. An essential step in Mt biogenesis is Mt fission, regulated by the Mt fission protein Drp1. Evaluation of in vivo diabetic neurons indicated small, fragmented Mt, suggesting increased fission. In vitro studies reveal short-term hyperglycemic exposure increased expression of Drp1. The influence of hyperglycemia-mediated Mt fission on cellular viability was evaluated by knockdown of Drp1. Knockdown of Drp1 resulted in decreased susceptibility to hyperglycemic damage. Conclusions We propose that: 1) Mt undergo biogenesis in response to hyperglycemia, but the increased biogenesis is insufficient to accommodate the metabolic load; 2) hyperglycemia causes an excess of Mt fission, creating small, damaged mitochondria; and 3) reduction of aberrant Mt fission increases neuronal survival and indicates an important role for the fission-fusion equilibrium in the pathogenesis of DN.

Edwards, J.L.; Quattrini, A.; Lentz, S.I.; Figueroa-Romero, C.; Cerri, F.; Backus, C.; Hong, Y.; Feldman, E.L.

2014-01-01

20

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

PubMed

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-?-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-?-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

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

21

Etoposide Induces ATM-Dependent Mitochondrial Biogenesis through AMPK Activation  

Microsoft Academic Search

BackgroundDNA damage such as double-stranded DNA breaks (DSBs) has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated). Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported

Xuan Fu; Shan Wan; Yi Lisa Lyu; Leroy F. Liu; Haiyan Qi; Sebastian D. Fugmann

2008-01-01

22

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

PubMed Central

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.

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

2012-01-01

23

Folding and Biogenesis of Mitochondrial Small Tim Proteins  

PubMed Central

Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) “small Tim” proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS.

Ceh-Pavia, Efrain; Spiller, Michael P.; Lu, Hui

2013-01-01

24

Increases in Mitochondrial Biogenesis Impair Carcinogenesis at Multiple Levels  

PubMed Central

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.

Wang, Xiao; Moraes, Carlos T.

2011-01-01

25

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

Microsoft Academic Search

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

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

2011-01-01

26

Hydroxytyrosol promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes  

Microsoft Academic Search

Hydroxytyrosol (HT) in extra-virgin olive oil is considered one of the most important polyphenolic compounds responsible for the health benefits of the Mediterranean diet for lowering incidence of cardiovascular disease, the most common and most serious complication of diabetes. We propose that HT may prevent these diseases by a stimulation of mitochondrial biogenesis that leads to enhancement of mitochondrial function

Jiejie Hao; Weili Shen; Guangli Yu; Haiqun Jia; Xuesen Li; Zhihui Feng; Ying Wang; Peter Weber; Karin Wertz; Edward Sharman; Jiankang Liu

2010-01-01

27

Coordination of Nuclear and Mitochondrial Genome Expression during Mitochondrial Biogenesis in ArabidopsisW?  

PubMed Central

Mitochondrial biogenesis and function require the regulated and coordinated expression of nuclear and mitochondrial genomes throughout plant development and in response to cellular and environmental signals. To investigate the levels at which the expression of nuclear and mitochondrially encoded proteins is coordinated, we established an Arabidopsis thaliana cell culture system to modulate mitochondrial biogenesis in response to sugar starvation and refeeding. Sucrose deprivation led to structural changes in mitochondria, a decrease in mitochondrial volume, and a reduction in the rate of cellular respiration. All these changes could be reversed by the readdition of sucrose. Analysis of the relative mRNA transcript abundance of genes encoding nuclear and mitochondrially encoded proteins revealed that there was no coordination of expression of the two genomes at the transcript level. An analysis of changes in abundance and assembly of nuclear-encoded and mitochondrially encoded subunits of complexes I to V of the mitochondrial inner membrane in organello protein synthesis and competence for protein import by isolated mitochondria suggested that coordination occurs at the level of protein-complex assembly. These results further suggest that expression of the mitochondrial genome is insensitive to the stress imposed by sugar starvation and that mitochondrial biogenesis is regulated by changes in nuclear gene expression and coordinated at the posttranslational level.

Giege, Philippe; Sweetlove, Lee J.; Cognat, Valerie; Leaver, Christopher J.

2005-01-01

28

MTERF3 Regulates Mitochondrial Ribosome Biogenesis in Invertebrates and Mammals  

PubMed Central

Regulation of mitochondrial DNA (mtDNA) expression is critical for the control of oxidative phosphorylation in response to physiological demand, and this regulation is often impaired in disease and aging. We have previously shown that mitochondrial transcription termination factor 3 (MTERF3) is a key regulator that represses mtDNA transcription in the mouse, but its molecular mode of action has remained elusive. Based on the hypothesis that key regulatory mechanisms for mtDNA expression are conserved in metazoans, we analyzed Mterf3 knockout and knockdown flies. We demonstrate here that decreased expression of MTERF3 not only leads to activation of mtDNA transcription, but also impairs assembly of the large mitochondrial ribosomal subunit. This novel function of MTERF3 in mitochondrial ribosomal biogenesis is conserved in the mouse, thus we identify a novel and unexpected role for MTERF3 in coordinating the crosstalk between transcription and translation for the regulation of mammalian mtDNA gene expression.

Metodiev, Metodi D.; Spahr, Henrik; Mourier, Arnaud; Freyer, Christoph; Ruzzenente, Benedetta; Tain, Luke; Gronke, Sebastian; Baggio, Francesca; Kukat, Christian; Kremmer, Elisabeth; Wibom, Rolf; Polosa, Paola Loguercio; Habermann, Bianca; Partridge, Linda; Park, Chan Bae; Larsson, Nils-Goran

2013-01-01

29

Staphylococcus aureus Sepsis Induces Early Renal Mitochondrial DNA Repair and Mitochondrial Biogenesis in Mice  

PubMed Central

Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection.

Bartz, Raquel R.; Fu, Ping; Suliman, Hagir B.; Crowley, Stephen D.; MacGarvey, Nancy Chou; Welty-Wolf, Karen; Piantadosi, Claude A.

2014-01-01

30

Hydroxytyrosol promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes.  

PubMed

Hydroxytyrosol (HT) in extra-virgin olive oil is considered one of the most important polyphenolic compounds responsible for the health benefits of the Mediterranean diet for lowering incidence of cardiovascular disease, the most common and most serious complication of diabetes. We propose that HT may prevent these diseases by a stimulation of mitochondrial biogenesis that leads to enhancement of mitochondrial function and cellular defense systems. In the present study, we investigated effects of HT that stimulate mitochondrial biogenesis and promote mitochondrial function in 3T3-L1 adipocytes. HT over the concentration range of 0.1-10 micromol/L stimulated the promoter transcriptional activation and protein expression of peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PPARGC1 alpha, the central factor for mitochondrial biogenesis) and its downstream targets; these included nuclear respiration factors 1 and 2 and mitochondrial transcription factor A, which leads to an increase in mitochondrial DNA (mtDNA) and in the number of mitochondria. Knockdown of Ppargc1 alpha by siRNA blocked HT's stimulating effect on Complex I expression and mtDNA copy number. The HT treatment resulted in an enhancement of mitochondrial function, including an increase in activity and protein expression of Mitochondrial Complexes I, II, III and V; increased oxygen consumption; and a decrease in free fatty acid contents in the adipocytes. The mechanistic study of the PPARGC1 alpha activation signaling pathway demonstrated that HT is an activator of 5'AMP-activated protein kinase and also up-regulates gene expression of PPAR alpha, CPT-1 and PPAR gamma. These data suggest that HT is able to promote mitochondrial function by stimulating mitochondrial biogenesis. PMID:19576748

Hao, Jiejie; Shen, Weili; Yu, Guangli; Jia, Haiqun; Li, Xuesen; Feng, Zhihui; Wang, Ying; Weber, Peter; Wertz, Karin; Sharman, Edward; Liu, Jiankang

2010-07-01

31

Hyperglycemia decreases mitochondrial function: The regulatory role of mitochondrial biogenesis  

Microsoft Academic Search

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

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

2007-01-01

32

Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle.  

PubMed

Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female rats showing greater mitochondrial mass and function compared with males. Adiponectin is an insulin-sensitizing adipokine whose expression has been related to mitochondrial function and that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this research was to elucidate the role of sex hormones in modulation of mitochondrial function, as well as its relationship with adiponectin production in rat skeletal muscle. An in vivo study with ovariectomized Wistar rats receiving or not receiving 17?-estradiol (E2) (10??g/kg per 48?h for 4 weeks) was carried out, in parallel with an assay of cultured myotubes (L6E9) treated with E2 (10?nM), progesterone (Pg; 1??M), or testosterone (1??M). E2 upregulated the markers of mitochondrial biogenesis and dynamics, and also of mitochondrial function in skeletal muscle and L6E9. Although in vivo E2 supplementation only partially restored the decreased adiponectin expression levels induced by ovariectomy, these were enhanced by E2 and Pg treatment in cultured myotubes, whereas testosterone showed no effects. Adiponectin receptor 1 expression was increased by E2 treatment, both in vivo and in vitro, but testosterone decreased it. In conclusion, our results are in agreement with the sexual dimorphism previously reported in skeletal muscle mitochondrial function and indicate E2 to be its main effector, as it enhances mitochondrial function and diminishes oxidative stress. Moreover, our data support the idea of the existence of a link between mitochondrial function and adiponectin expression in skeletal muscle, which could be modulated by sex hormones. PMID:24681828

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

2014-06-01

33

Quercetin Induces Mitochondrial Biogenesis through Activation of HO-1 in HepG2 Cells  

PubMed Central

The regeneration of mitochondria by regulated biogenesis plays an important homeostatic role in cells and tissues and furthermore may provide an adaptive mechanism in certain diseases such as sepsis. The heme oxygenase (HO-1)/carbon monoxide (CO) system is an inducible cytoprotective mechanism in mammalian cells. Natural antioxidants can provide therapeutic benefit, in part, by inducing the HO-1/CO system. This study focused on the mechanism by which the natural antioxidant quercetin can induce mitochondrial biogenesis in HepG2 cells. We found that quercetin treatment induced expression of mitochondrial biogenesis activators (PGC-1?, NRF-1, TFAM), mitochondrial DNA (mtDNA), and proteins (COX IV) in HepG2 cells. The HO inhibitor SnPP and the CO scavenger hemoglobin reversed the effects of quercetin on mitochondrial biogenesis in HepG2 cells. The stimulatory effects of quercetin on mitochondrial biogenesis could be recapitulated in vivo in liver tissue and antagonized by SnPP. Finally, quercetin conferred an anti-inflammatory effect in the liver of mice treated with LPS and prevented impairment of mitochondrial biogenesis by LPS in vivo. These salutary effects of quercetin in vivo were also antagonized by SnPP. Thus, our results suggest that quercetin enhances mitochondrial biogenesis mainly via the HO-1/CO system in vitro and in vivo. The beneficial effects of quercetin may provide a therapeutic basis in inflammatory diseases and sepsis.

Rayamajhi, Nabin; Kim, Seul-Ki; Go, Hiroe; Joe, Yeonsoo; Callaway, Zak; Kang, Jae-Gu; Ryter, Stefan W.; Chung, Hun Taeg

2013-01-01

34

Resveratrol induces hepatic mitochondrial biogenesis through the sequential activation of nitric oxide and carbon monoxide production.  

PubMed

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-1? (PGC-1?). 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-1?. 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

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; Chung, Hun Taeg

2014-06-01

35

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

SciTech Connect

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.

Kao, Li-Pin; Ovchinnikov, Dmitry; Wolvetang, Ernst, E-mail: e.wolvetang@uq.edu.au

2012-05-15

36

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

PubMed Central

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.

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

2007-01-01

37

Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans  

PubMed Central

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.

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

2007-01-01

38

Mitochondrial iron-sulfur protein biogenesis and human disease.  

PubMed

Work during the past 14 years has shown that mitochondria are the primary site for the biosynthesis of iron-sulfur (Fe/S) clusters. In fact, it is this process that renders mitochondria essential for viability of virtually all eukaryotes, because they participate in the synthesis of the Fe/S clusters of key nuclear and cytosolic proteins such as DNA polymerases, DNA helicases, and ABCE1 (Rli1), an ATPase involved in protein synthesis. As a consequence, mitochondrial function is crucial for nuclear DNA synthesis and repair, ribosomal protein synthesis, and numerous other extra-mitochondrial pathways including nucleotide metabolism and cellular iron regulation. Within mitochondria, the synthesis of Fe/S clusters and their insertion into apoproteins is assisted by 17 proteins forming the ISC (iron-sulfur cluster) assembly machinery. Biogenesis of mitochondrial Fe/S proteins can be dissected into three main steps: First, a Fe/S cluster is generated de novo on a scaffold protein. Second, the Fe/S cluster is dislocated from the scaffold and transiently bound to transfer proteins. Third, the latter components, together with specific ISC targeting factors insert the Fe/S cluster into client apoproteins. Disturbances of the first two steps impair the maturation of extra-mitochondrial Fe/S proteins and affect cellular and systemic iron homeostasis. In line with the essential function of mitochondria, genetic mutations in a number of ISC genes lead to severe neurological, hematological and metabolic diseases, often with a fatal outcome in early childhood. In this review we briefly summarize our current functional knowledge on the ISC assembly machinery, and we present a comprehensive overview of the various Fe/S protein assembly diseases. PMID:24462711

Stehling, Oliver; Wilbrecht, Claudia; Lill, Roland

2014-05-01

39

Delphinidin inhibits VEGF induced-mitochondrial biogenesis and Akt activation in endothelial cells.  

PubMed

Delphinidin, an anthocyanin present in red wine, has been reported to exert vasculoprotective properties on endothelial cells, including vasorelaxing and anti-apoptotic effects. Moreover, delphinidin treatment in a rat model of post-ischemic neovascularization has been described to exert anti-angiogenic property. Angiogenesis is an energetic process and VEGF-induced angiogenesis is associated with mitochondrial biogenesis. However, whether delphinidin induces changes in mitochondrial biogenesis has never been addressed. Effects of delphinidin were investigated in human endothelial cells at a concentration described to be anti-angiogenic in vitro (10(-2)g/l). mRNA expression of mitochondrial biogenesis factors, mitochondrial respiration, DNA content and enzyme activities were assessed after 48h of stimulation. Delphinidin increased mRNA expression of several mitochondrial biogenesis factors, including NRF1, ERR?, Tfam, Tfb2m and PolG but did not affect neither mitochondrial respiration, DNA content nor enzyme activities. In presence of delphinidin, VEGF failed to increase mitochondrial respiration, DNA content, complex IV activity and Akt activation in endothelial cells. These results suggest a possible association between inhibition of VEGF-induced mitochondrial biogenesis through Akt pathway by delphinidin and its anti-angiogenic effect, providing a novel mechanism sustaining the beneficial effect of delphinidin against pathologies associated with excessive angiogenesis such as cancers. PMID:24792670

Duluc, Lucie; Jacques, Caroline; Soleti, Raffaella; Andriantsitohaina, Ramaroson; Simard, Gilles

2014-08-01

40

Role of mitochondrial inner membrane organizing system in protein biogenesis of the mitochondrial outer membrane.  

PubMed

Mitochondria contain two membranes, the outer membrane and the inner membrane with folded cristae. The mitochondrial inner membrane organizing system (MINOS) is a large protein complex required for maintaining inner membrane architecture. MINOS interacts with both preprotein transport machineries of the outer membrane, the translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM). It is unknown, however, whether MINOS plays a role in the biogenesis of outer membrane proteins. We have dissected the interaction of MINOS with TOM and SAM and report that MINOS binds to both translocases independently. MINOS binds to the SAM complex via the conserved polypeptide transport-associated domain of Sam50. Mitochondria lacking mitofilin, the large core subunit of MINOS, are impaired in the biogenesis of ?-barrel proteins of the outer membrane, whereas mutant mitochondria lacking any of the other five MINOS subunits import ?-barrel proteins in a manner similar to wild-type mitochondria. We show that mitofilin is required at an early stage of ?-barrel biogenesis that includes the initial translocation through the TOM complex. We conclude that MINOS interacts with TOM and SAM independently and that the core subunit mitofilin is involved in biogenesis of outer membrane ?-barrel proteins. PMID:22918945

Bohnert, Maria; Wenz, Lena-Sophie; Zerbes, Ralf M; Horvath, Susanne E; Stroud, David A; von der Malsburg, Karina; Müller, Judith M; Oeljeklaus, Silke; Perschil, Inge; Warscheid, Bettina; Chacinska, Agnieszka; Veenhuis, Marten; van der Klei, Ida J; Daum, Günther; Wiedemann, Nils; Becker, Thomas; Pfanner, Nikolaus; van der Laan, Martin

2012-10-01

41

Oxidative Stress and Upregulation of Mitochondrial Biogenesis Genes in Mitochondrial DNA-Depleted HeLa Cells  

Microsoft Academic Search

The signaling mechanism through which deficitary mitochondrial function would activate nuclear genes required for mitochondrial biogenesis, has not been established. To explore the hypothesis that reactive oxygen species (ROS), a mitochondrial product, constitute part of the mitochondria-nuclei signaling pathway, we obtained HeLa cells depleted of mitochondrial DNA (?0cells) through exposure to ethidium bromide. We found evidences of oxidative stress in

Soledad Miranda; Rocio Foncea; Javier Guerrero; Federico Leighton

1999-01-01

42

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

PubMed

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 50?MH2O2 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

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

2013-08-23

43

Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1? pathway.  

PubMed

Metallothionein (MT) has been shown to inhibit cardiac oxidative stress and protect against the cardiotoxicity induced by doxorubicin (DOX), a potent and widely used chemotherapeutic agent. However, the mechanism of MT?s protective action against DOX still remains obscure. Mitochondrial biogenesis impairment has been implicated to play an important role in the etiology and progression of DOX-induced cardiotoxicity. Increasing evidence indicates an intimate link between MT-mediated cardioprotection and mitochondrial biogenesis. This study was aimed to explore the possible contribution of mitochondrial biogenesis in MT?s cardioprotective action against DOX. Adult male MT-I/II-null (MT(-/-)) and wild-type (MT(+/+)) mice were given a single dose of DOX intraperitoneally. Our results revealed that MT deficiency significantly sensitized mice to DOX-induced cardiac dysfunction, ultrastructural alterations, and mortality. DOX disrupted cardiac mitochondrial biogenesis indicated by mitochondrial DNA copy number and decreased mitochondrial number, and these effects were greater in MT(-/-) mice. Basal MT effectively protected against DOX-induced inhibition on the peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), a key regulator of mitochondrial biogenesis, and its downstream factors including mitochondrial transcription factor A. Moreover, MT was found to preserve the protein expression of manganese superoxide dismutase, a transcriptional target of PGC-1?. in vitro study showed that MT absence augmented DOX-induced increase of mitochondrial superoxide production in primary cultured cardiomyocytes. These findings suggest that MT?s cardioprotection against DOX is mediated, at least in part, by preservation of mitochondrial biogenesis involving PGC-1? pathway. PMID:24858368

Guo, Jiabin; Guo, Qian; Fang, Haiqing; Lei, Lei; Zhang, Tingfen; Zhao, Jun; Peng, Shuangqing

2014-08-15

44

Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle  

Microsoft Academic Search

We examined the transcriptional signal- ing cascade involved in the changes of mitochondrial biogenesis and mitochondrial function of skeletal mus- cle and of the exercise capacity of humans in response to long-term physical activity and chronic heart failure (CHF). Biopsy samples of vastus lateralis muscle were obtained from 18 healthy subjects with different fitness levels (assessed by maximal oxygen uptake,

Anne Garnier; Dominique Fortin; Joffrey Zoll; Benoit N'Guessan; Bertrand Mettauer; Eliane Lampert; Vladimir Veksler; Renee Ventura-Clapier

2005-01-01

45

Evidences that maternal swimming exercise improves antioxidant defenses and induces mitochondrial biogenesis in the brain of young Wistar rats.  

PubMed

Physical exercise during pregnancy has been considered beneficial to mother and child. Recent studies showed that maternal swimming improves memory in the offspring, increases hippocampal neurogenesis and levels of neurotrophic factors. The objective of this work was to investigate the effect of maternal swimming during pregnancy on redox status and mitochondrial parameters in brain structures from the offspring. Adult female Wistar rats were submitted to five swimming sessions (30 min/day) prior to mating with adult male Wistar rats, and then trained during the pregnancy (five sessions of 30-min swimming/week). The litter was sacrificed when 7 days old, when cerebellum, parietal cortex, hippocampus, and striatum were dissected. We evaluated the production of reactive species and antioxidant status, measuring the activities of superoxide-dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GPx), as well as non-enzymatic antioxidants. We also investigated a potential mitochondrial biogenesis regarding mitochondrion mass and membrane potential, through cytometric approaches. Our results showed that maternal swimming exercise promoted an increase in reactive species levels in cerebellum, parietal cortex, and hippocampus, demonstrated by an increase in dichlorofluorescein oxidation. Mitochondrial superoxide was reduced in cerebellum and parietal cortex, while nitrite levels were increased in cerebellum, parietal cortex, hippocampus, and striatum. Antioxidant status was improved in cerebellum, parietal cortex, and hippocampus. SOD activity was increased in parietal cortex, and was not altered in the remaining brain structures. CAT and GPx activities, as well as non-enzymatic antioxidant potential, were increased in cerebellum, parietal cortex, and hippocampus of rats whose mothers were exercised. Finally, we observed an increased mitochondrial mass and membrane potential, suggesting mitochondriogenesis, in cerebellum and parietal cortex of pups subjected to maternal swimming. In conclusion, maternal swimming exercise induced neurometabolic programing in the offspring that could be of benefit to the rats against future cerebral insults. PMID:23639877

Marcelino, T B; Longoni, A; Kudo, K Y; Stone, V; Rech, A; de Assis, A M; Scherer, E B S; da Cunha, M J; Wyse, A T S; Pettenuzzo, L F; Leipnitz, G; Matté, C

2013-08-29

46

Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis  

PubMed Central

Rationale: We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality. Objectives: To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients. Methods: Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1–2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery. Measurements and Main Results: Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor ? coactivator 1-? (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio. Conclusions: Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function. Clinical trial registered with clinical trials.gov (NCT00187824).

Carre, Jane E.; Orban, Jean-Christophe; Re, Lorenza; Felsmann, Karen; Iffert, Wiebke; Bauer, Michael; Suliman, Hagir B.; Piantadosi, Claude A.; Mayhew, Terry M.; Breen, Patrick; Stotz, Martin; Singer, Mervyn

2010-01-01

47

Cardioprotection by acetylcholine: a novel mechanism via mitochondrial biogenesis and function involving the PGC-1? pathway.  

PubMed

Mitochondrial biogenesis disorders appear to play an essential role in cardiac dysfunction. Acetylcholine as a potential pharmacologic agent exerts cardioprotective effects. However, its direct action on mitochondria biogenesis in acute cardiac damage due to ischemia/reperfusion remains unclear. The present study determined the involvement of mitochondrial biogenesis and function in the cardiopotection of acetylcholine in H9c2 cells subjected to hypoxia/reoxygenation (H/R). Our findings demonstrated that acetylcholine treatment on the beginning of reoxygenation improved cell viability in a concentration-dependent way. Consequently, acetylcholine inhibited the mitochondrial morphological abnormalities and caused a significant increase in mitochondrial density, mass, and mitochondrial DNA (mtDNA) copy number. Accordingly, acetylcholine enhanced ATP synthesis, membrane potentials, and activities of mitochondrial complexes in contrast to H/R alone. Furthermore, acetylcholine stimulated the transcriptional activation and protein expression of peroxisome proliferator-activated receptor co-activator 1 alpha (PGC-1?, the central factor for mitochondrial biogenesis) and its downstream targets including nuclear respiration factors and mitochondrial transcription factor A. In addition, acetylcholine activated phosphorylation of AMP-activated protein kinase (AMPK), which was located upstream of PGC-1?. Atropine (muscarinic receptor antagonist) abolished the favorable effects of acetylcholine on mitochondria. Knockdown of PGC-1? or AMPK by siRNA blocked acetylcholine-induced stimulating effects on mtDNA copy number and against cell injury. In conclusion, we suggested, acetylcholine as a mitochondrial nutrient, protected against the deficient mitochondrial biogenesis and function induced by H/R injury in a cellular model through muscarinic receptor-mediated, AMPK/PGC-1?-associated regulatory program, which may be of significance in elucidating a novel mechanism underlying acetylcholine-induced cardioprotection. PMID:23139024

Sun, Lei; Zhao, Mei; Yu, Xiao-Jiang; Wang, Hao; He, Xi; Liu, Jian-Kang; Zang, Wei-Jin

2013-06-01

48

Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers.  

PubMed

Arsenic-induced Bowen's disease (As-BD), a cutaneous carcinoma in situ, is thought to arise from gene mutation and uncontrolled proliferation. However, how mitochondria regulate the arsenic-induced cell proliferation remains unclear. The aim of this study was to clarify whether arsenic interfered with mitochondrial biogenesis and function, leading to aberrant cell proliferation in As-BD. Skin biopsy samples from patients with As-BD and controls were stained for cytochrome c oxidase (Complex IV), measured for mitochondrial DNA (mtDNA) copy number and the expression levels of mitochondrial biogenesis-related genes, including peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (mtTFA). The results showed that expression of cytochrome c oxidase, mtTFA, NRF-1, and PGC-1? was increased in As-BD compared with in healthy subjects. Treatment of primary keratinocytes with arsenic at concentrations lower than 1.0 ?mol/L induced cell proliferation, along with enhanced mitochondrial biogenesis. Furthermore, we observed that the mitochondrial oxygen consumption rate and intracellular ATP level were increased in arsenic-treated keratinocytes. Blocking of mitochondrial function by oligomycin A (Complex V inhibitor) or knockdown of mtTFA by RNA interference abrogated arsenic-induced cell proliferation without affecting cyclin D1 expression. We concluded that mtTFA up-regulation, augmented mitochondrial biogenesis, and enhanced mitochondrial functions may contribute to arsenic-induced cell proliferation. Targeting mitochondrial biogenesis may help treat arsenical cancers at the stage of cell proliferation. PMID:21514422

Lee, Chih-Hung; Wu, Shi-Bei; Hong, Chien-Hui; Liao, Wei-Ting; Wu, Ching-Ying; Chen, Gwo-Shing; Wei, Yau-Huei; Yu, Hsin-Su

2011-05-01

49

Peroxynitrite induced mitochondrial biogenesis following MnSOD knockdown in normal rat kidney (NRK) cells?  

PubMed Central

Superoxide is widely regarded as the primary reactive oxygen species (ROS) which initiates downstream oxidative stress. Increased oxidative stress contributes, in part, to many disease conditions such as cancer, atherosclerosis, ischemia/reperfusion, diabetes, aging, and neurodegeneration. Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide into hydrogen peroxide which can then be further detoxified by other antioxidant enzymes. MnSOD is critical in maintaining the normal function of mitochondria, thus its inactivation is thought to lead to compromised mitochondria. Previously, our laboratory observed increased mitochondrial biogenesis in a novel kidney-specific MnSOD knockout mouse. The current study used transient siRNA mediated MnSOD knockdown of normal rat kidney (NRK) cells as the in vitro model, and confirmed functional mitochondrial biogenesis evidenced by increased PGC1? expression, mitochondrial DNA copy numbers and integrity, electron transport chain protein CORE II, mitochondrial mass, oxygen consumption rate, and overall ATP production. Further mechanistic studies using mitoquinone (MitoQ), a mitochondria-targeted antioxidant and L-NAME, a nitric oxide synthase (NOS) inhibitor demonstrated that peroxynitrite (at low micromolar levels) induced mitochondrial biogenesis. These findings provide the first evidence that low levels of peroxynitrite can initiate a protective signaling cascade involving mitochondrial biogenesis which may help to restore mitochondrial function following transient MnSOD inactivation.

Marine, Akira; Krager, Kimberly J.; Aykin-Burns, Nukhet; MacMillan-Crow, Lee Ann

2014-01-01

50

Peroxynitrite induced mitochondrial biogenesis following MnSOD knockdown in normal rat kidney (NRK) cells.  

PubMed

Superoxide is widely regarded as the primary reactive oxygen species (ROS) which initiates downstream oxidative stress. Increased oxidative stress contributes, in part, to many disease conditions such as cancer, atherosclerosis, ischemia/reperfusion, diabetes, aging, and neurodegeneration. Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide into hydrogen peroxide which can then be further detoxified by other antioxidant enzymes. MnSOD is critical in maintaining the normal function of mitochondria, thus its inactivation is thought to lead to compromised mitochondria. Previously, our laboratory observed increased mitochondrial biogenesis in a novel kidney-specific MnSOD knockout mouse. The current study used transient siRNA mediated MnSOD knockdown of normal rat kidney (NRK) cells as the in vitro model, and confirmed functional mitochondrial biogenesis evidenced by increased PGC1? expression, mitochondrial DNA copy numbers and integrity, electron transport chain protein CORE II, mitochondrial mass, oxygen consumption rate, and overall ATP production. Further mechanistic studies using mitoquinone (MitoQ), a mitochondria-targeted antioxidant and L-NAME, a nitric oxide synthase (NOS) inhibitor demonstrated that peroxynitrite (at low micromolar levels) induced mitochondrial biogenesis. These findings provide the first evidence that low levels of peroxynitrite can initiate a protective signaling cascade involving mitochondrial biogenesis which may help to restore mitochondrial function following transient MnSOD inactivation. PMID:24563852

Marine, Akira; Krager, Kimberly J; Aykin-Burns, Nukhet; Macmillan-Crow, Lee Ann

2014-01-01

51

Curcumin prevents cerebral ischemia reperfusion injury via increase of mitochondrial biogenesis.  

PubMed

Curcumin is known to have neuroprotective properties in cerebral ischemia reperfusion (I/R) injury. However, the underlying molecular mechanisms remain largely unknown. Recently, emerging evidences suggested that increased mitochondrial biogenesis enabled preventing I/R injury. Here, we sought to determinate whether curcumin alleviates I/R damage through regulation of mitochondrial biogenesis. Sprague-Dawley rats were subjected to a 2-h period of right middle cerebral artery occlusion followed by 24 h of reperfusion. Prior to onset of occlusion, rats had been pretreated with either low (50 mg/kg, intraperitoneal injection) or high (100 mg/kg, intraperitoneal injection) dose of curcumin for 5 days. Consequently, we found that curcumin pretreatment enabled improving neurological deficit, diminishing infarct volume and increasing the number of NeuN-labeled neurons in the I/R rats. Accordingly, the index of mitochondrial biogenesis including nuclear respiratory factor-1, mitochondrial transcription factor A and mitochondrial number significantly down-regulated in I/R rats were reversed by curcumin pretreatment in a dose-dependent manner, and the mitochondrial uncoupling protein 2 presented the similar change. Taken together, our findings provided novel evidence that curcumin may exert neuroprotective effects by increasing mitochondrial biogenesis. PMID:24777807

Liu, Li; Zhang, Wenchao; Wang, Li; Li, Yu; Tan, Botao; Lu, Xi; Deng, Yushuang; Zhang, Yuping; Guo, Xiuming; Mu, Jun; Yu, Gang

2014-07-01

52

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

SciTech Connect

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.

Perez-de-Arce, Karen [Departamento de Nutricion, Diabetes y Metabolismo, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago (Chile); Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago (Chile); Foncea, Rocio [Departamento de Nutricion, Diabetes y Metabolismo, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago (Chile)]. E-mail: rfoncea@med.puc.cl; Leighton, Federico [Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago (Chile)

2005-12-16

53

Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC1  

Microsoft Academic Search

Mitochondrial number and function are altered in response to external stimuli in eukaryotes. While several transcription\\/replication factors directly regulate mitochondrial genes, the coordination of these factors into a program responsive to the environment is not understood. We show here that PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling

Zhidan Wu; Pere Puigserver; Ulf Andersson; Chenyu Zhang; Guillaume Adelmant; Vamsi Mootha; Amy Troy; Saverio Cinti; Bradford Lowell; Richard C. Scarpulla; Bruce M. Spiegelman

1999-01-01

54

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

PubMed Central

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.

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

2013-01-01

55

Complementary RNA and protein profiling identifies iron as a key regulator of mitochondrial biogenesis.  

PubMed

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

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

2013-01-31

56

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

SciTech Connect

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-1? (PGC-1?) 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.

Saxena, Saurabh [Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 (India)] [Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 (India); Shukla, Dhananjay [Department of Biotechnology, Gitam University, Gandhi Nagar, Rushikonda, Visakhapatnam-530 045 Andhra Pradesh (India)] [Department of Biotechnology, Gitam University, Gandhi Nagar, Rushikonda, Visakhapatnam-530 045 Andhra Pradesh (India); Bansal, Anju, E-mail: anjubansaldipas@gmail.com [Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 (India)] [Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 (India)

2012-11-01

57

Lipocalin 2 deficiency inhibits cell proliferation, autophagy, and mitochondrial biogenesis in mouse embryonic cells  

Microsoft Academic Search

Lipocalin 2 (LCN2) has been recently implicated as a critical player in multiple cancer tumorigeneses. However, the molecular\\u000a mechanisms for its tumorigenic role are poorly understood. Herein, we investigated the effects of LCN2 on cell proliferation,\\u000a autophagy, and mitochondrial biogenesis in MEF cells. We observed that LCN2 deficiency significantly inhibited cell proliferation\\u000a and autophagy in MEF cells. Furthermore, mitochondrial DNA

Daozhong Jin; Yuanyuan Zhang; Xiaoli Chen

2011-01-01

58

The PGC1?-dependent pathway of mitochondrial biogenesis is upregulated in type I endometrial cancer  

Microsoft Academic Search

PGC-1?-dependent pathway of mitochondrial biogenesis was investigated for the first time in type I endometrial cancer and in normal endometrium. In cancer endometrial tissue the citrate synthase activity, the mitochondrial DNA content and the TFAM level were found doubled compared to control endometrial tissue. Moreover, a 1.6- and 1.8-fold increase, respectively, of NRF-1 and PGG-1? expression was found. This study

Antonella Cormio; Flora Guerra; Gennaro Cormio; Vito Pesce; Flavio Fracasso; Vera Loizzi; Palmiro Cantatore; Luigi Selvaggi; Maria Nicola Gadaleta

2009-01-01

59

Increased mitochondrial biogenesis in muscle improves aging phenotypes in the mtDNA mutator mouse  

PubMed Central

Aging is an intricate process that increases susceptibility to sarcopenia and cardiovascular diseases. The accumulation of mitochondrial DNA (mtDNA) mutations is believed to contribute to mitochondrial dysfunction, potentially shortening lifespan. The mtDNA mutator mouse, a mouse model with a proofreading-deficient mtDNA polymerase ?, was shown to develop a premature aging phenotype, including sarcopenia, cardiomyopathy and decreased lifespan. This phenotype was associated with an accumulation of mtDNA mutations and mitochondrial dysfunction. We found that increased expression of peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), a crucial regulator of mitochondrial biogenesis and function, in the muscle of mutator mice increased mitochondrial biogenesis and function and also improved the skeletal muscle and heart phenotypes of the mice. Deep sequencing analysis of their mtDNA showed that the increased mitochondrial biogenesis did not reduce the accumulation of mtDNA mutations but rather caused a small increase. These results indicate that increased muscle PGC-1? expression is able to improve some premature aging phenotypes in the mutator mice without reverting the accumulation of mtDNA mutations.

Dillon, Lloye M.; Williams, Sion L.; Hida, Aline; Peacock, Jacqueline D.; Prolla, Tomas A.; Lincoln, Joy; Moraes, Carlos T.

2012-01-01

60

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

PubMed Central

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.

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

2014-01-01

61

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

PubMed

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

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

62

Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis  

Microsoft Academic Search

Rationale: The extent, timing, and significance of mitochondrial injury and recovery in bacterial sepsis are poorly characterized, although oxidative and nitrosative mitochondrial damage have been implicated in the development of organ failure. Objectives: To define the relationships between mitochondrial bio- genesis, oxidative metabolism, and recovery from Staphylococcus aureus sepsis. Methods: We developed a murine model of fibrin clot peritonitis, using

Douglas W. Haden; Hagir B. Suliman; Martha Sue Carraway; Karen E. Welty-Wolf; Abdelwahid S. Ali; Hiroshi Shitara; Hiromichi Yonekawa; Claude A. Piantadosi

2007-01-01

63

Exercise-Induced Bronchoconstriction  

MedlinePLUS

Share | « Back to A to Z Listing Exercise-Induced Bronchoconstriction Exercise-Induced Bronchoconstriction, (EIB), often known as exercise-induced asthma, is a narrowing of the airways causing difficulty moving air out ...

64

Order within a mosaic distribution of mitochondrial c-type cytochrome biogenesis systems?  

PubMed

Mitochondrial cytochromes c and c(1) are present in all eukaryotes that use oxygen as the terminal electron acceptor in the respiratory chain. Maturation of c-type cytochromes requires covalent attachment of the heme cofactor to the protein, and there are at least five distinct biogenesis systems that catalyze this post-translational modification in different organisms and organelles. In this study, we use biochemical data, comparative genomic and structural bioinformatics investigations to provide a holistic view of mitochondrial c-type cytochrome biogenesis and its evolution. There are three pathways for mitochondrial c-type cytochrome maturation, only one of which is present in prokaryotes. We analyze the evolutionary distribution of these biogenesis systems, which include the Ccm system (System I) and the enzyme heme lyase (System III). We conclude that heme lyase evolved once and, in many lineages, replaced the multicomponent Ccm system (present in the proto-mitochondrial endosymbiont), probably as a consequence of lateral gene transfer. We find no evidence of a System III precursor in prokaryotes, and argue that System III is incompatible with multi-heme cytochromes common to bacteria, but absent from eukaryotes. The evolution of the eukaryotic-specific protein heme lyase is strikingly unusual, given that this protein provides a function (thioether bond formation) that is also ubiquitous in prokaryotes. The absence of any known c-type cytochrome biogenesis system from the sequenced genomes of various trypanosome species indicates the presence of a third distinct mitochondrial pathway. Interestingly, this system attaches heme to mitochondrial cytochromes c that contain only one cysteine residue, rather than the usual two, within the heme-binding motif. The isolation of single-cysteine-containing mitochondrial cytochromes c from free-living kinetoplastids, Euglena and the marine flagellate Diplonema papillatum suggests that this unique form of heme attachment is restricted to, but conserved throughout, the protist phylum Euglenozoa. PMID:18393999

Allen, James W A; Jackson, Andrew P; Rigden, Daniel J; Willis, Antony C; Ferguson, Stuart J; Ginger, Michael L

2008-05-01

65

Nebivolol stimulates mitochondrial biogenesis in 3T3-L1 adipocytes  

SciTech Connect

Highlights: •Nebivolol may act as a partial agonist of ?3-adrenergic receptor (AR). •Nebivolol stimulates mitochondrial DNA replication and protein expression. •Nebivolol promotes mitochondrial synthesis via activation of eNOS by ?3-AR. -- Abstract: 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 24 h 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.

Huang, Chenglin; Chen, Dongrui; Xie, Qihai [State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology, Department of Hypertension, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025 (China)] [State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology, Department of Hypertension, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025 (China); Yang, Ying, E-mail: yangying_sh@yahoo.com [Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025 (China)] [Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025 (China); Shen, Weili, E-mail: weili_shen@hotmail.com [State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology, Department of Hypertension, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025 (China)] [State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology, Department of Hypertension, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025 (China)

2013-08-16

66

Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts  

PubMed Central

Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired.

Sitarz, Kamil S.; Elliott, Hannah R.; Karaman, Betul S.; Relton, Caroline; Chinnery, Patrick F.; Horvath, Rita

2014-01-01

67

Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts.  

PubMed

Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired. PMID:24725338

Sitarz, Kamil S; Elliott, Hannah R; Karaman, Betül S; Relton, Caroline; Chinnery, Patrick F; Horvath, Rita

2014-05-01

68

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

PubMed

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-1? 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-1? axis shows true potential as therapy; however, other effects besides mitochondrial biogenesis may be contributing to this as well. PMID:24102298

Komen, J C; Thorburn, D R

2014-04-01

69

Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis  

PubMed Central

Metabolic stimuli such as insulin and insulin like growth factor cause cellular accumulation of G protein Coupled Receptor Kinase 2 (GRK2), which in turn is able to induce insulin resistance. Here we show that in fibroblasts, GRK2 is able to increase ATP cellular content by enhancing mitochondrial biogenesis; also, it antagonizes ATP loss after hypoxia/reperfusion. Interestingly, GRK2 is able to localize in the mitochondrial outer membrane, possibly through one region within the RGS homology domain and one region within the catalytic domain. In vivo, GRK2 removal from the skeletal muscle results in reduced ATP production and impaired tolerance to ischemia. Our data show a novel sub-cellular localization of GRK2 in the mitochondria and an unexpected role in regulating mitochondrial biogenesis and ATP generation.

Fusco, Anna; Santulli, Gaetano; Sorriento, Daniela; Cipolletta, Ersilia; Garbi, Corrado; Dorn, Gerald W.; Trimarco, Bruno; Feliciello, Antonio; Iaccarino, Guido

2011-01-01

70

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

SciTech Connect

Highlights: ? First time to show that cilostazol promotes the expressions of PGC-1?. ? First time to show that cilostazol stimulates mitochondrial biogenesis in HUVECs. ? PKA/CREB pathway mediates the effect of cilostazol on PGC-1? 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 1? (PGC-1?), 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-1? could abolish cilostazol-induced mitochondrial biogenesis. Enhanced expression of p-CREB and PGC-1? induced by cilostazol could be inhibited by H-89. Moreover, the increased expression of PGC-1? 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-1? in HUVECs, which was mediated by PKA/CREB pathway.

Zuo, Luning [Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China) [Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China); Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001 (China); Li, Qiang; Sun, Bei; Xu, Zhiying [Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001 (China)] [Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001 (China); Ge, Zhiming, E-mail: zhimingge2000@hotmail.com [Department of Cardiology, Qilu Hospital, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China)] [Department of Cardiology, Qilu Hospital, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China)

2013-03-29

71

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

PubMed

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 fusion-fission 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

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

2013-12-01

72

Nitric Oxide-Dependent Mitochondrial Biogenesis Generates Ca2+ Signaling Profile of Lupus T Cells  

PubMed Central

Abnormal T cell activation and cell death underlie the pathology of systemic lupus erythematosus. Although mitochondrial hyperpolarization (MHP) represents an early and reversible checkpoint of T cell activation and apoptosis, lupus T cells exhibit persistent MHP. NO has recently been recognized as a key signal of mitochondrial biogenesis and mediator of MHP in human T lymphocytes. In this study, we show that persistent MHP was associated with increased mitochondrial mass (+47.7 ± 2.8%; p = 0.00017) and increased mitochondrial (+21.8 ± 4.1%; p = 0.016) and cytoplasmic Ca2+ content in T cells from 19 systemic lupus erythematosus patients with respect to 11 control donors (+38.0 ± 6.4%; p = 0.0023). Electron microscopy revealed that lupus lymphocytes contained 8.76 ± 1.0 mitochondria, while control donors contained 3.18 ± 0.28 mitochondria per cell (p = 0.0009). Increased mitochondrial mass in T cells was associated with 2.08 ± 0.09-fold enhanced NO production by lupus monocytes (p = 0.0023). Activation of T cells through the TCR initiates a biphasic elevation in cytosolic free Ca2+ concentration, a rapid initial peak observed within minutes, and a plateau phase lasting up to 48 h. In response to CD3/CD28 costimulation, rapid Ca2+ fluxing was enhanced while the plateau phase was diminished in lupus T cells. NO-induced mitochondrial biogenesis in normal T cells enhanced the rapid phase and reduced the plateau of Ca2+ influx upon CD3/CD28 costimulation, thus mimicking the Ca2+ signaling profile of lupus T cells. Mitochondria constitute major Ca2+ stores and NO-dependent mitochondrial biogenesis may account for altered Ca2+ handling by lupus T cells. The Journal of Immunology, 2004, 173: 3676–3683.

Nagy, Gyorgy; Barcza, Maureen; Gonchoroff, Nick; Phillips, Paul E.; Perl, Andras

2014-01-01

73

High concentration of gadolinium ion modifying isolated rice mitochondrial biogenesis.  

PubMed

Mitochondria play an important role in plant growth and development, cooperating with the endoplasmic reticulum and nucleus. Gadolinium, one of the rare earth elements, is an inhibitor of stretch-activated calcium channels located on the endoplasmic reticulum and plasma membrane and has no effect on nuclear calcium variation in plant cells. We analyzed the effects of Gd3+ on mitochondria function by monitoring mitochondrial swelling, changes of membrane fluidity, and transmembrane potential collapse and by observing mitochondrial ultrastructure. We found that high concentration of Gd3+ induces rice mitochondrial dysfunction through mitochondrial permeability transition (MPT). The protection of DTT and EDTA demonstrate that Gd3+ blocks the inner membrane ion channel through thiol chelation. PMID:24078325

Zhao, Jie; Jin, Jian-Cheng; Zhou, Zhi-Qiang; Xia, Cai-Fen; Yang, Xiao-Gang; Jiang, Feng-Lei; Dai, Jie; Liu, Yi

2013-12-01

74

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

PubMed Central

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.

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

2014-01-01

75

Loss of MED1 triggers mitochondrial biogenesis in C2C12 cells.  

PubMed

Under stress conditions transcription factors, including their coactivators, play major roles in mitochondrial biogenesis and oxidative phosphorylation. MED1 (Mediator complex subunit 1) functions as a coactivator of several transcription factors and is implicated in adipogenesis of the lipid and glucose metabolism. This suggests that MED1 may play a role in mitochondrial function. In this study, we found that both the mtDNA content and mitochondrial mass were markedly increased and cell proliferation markedly suppressed in MED1-deficient cells. Upon MED1 loss, Nrf1 and its downstream target genes involved in mitochondrial biogenesis (Tfam, Plormt, Tfb1m), were up-regulated as were those genes in the OXPHOS pathway. Moreover, the knockdown of MED1 resulted in significant changes in the profile of mitochondrial respiration, accompanied by a prominent decrease in the generation of ATP. Collectively, these observations strongly suggest that MED1 has an important affect on mitochondrial function. This further elucidates the role of MED1, particularly its role in the energy metabolism. PMID:24368311

Yu, Jialing; Xiao, Yun; Liu, Junxia; Ji, Yanchun; Liu, Hao; Xu, Jing; Jin, Xiaofen; Liu, Li; Guan, Min-Xin; Jiang, Pingping

2014-01-01

76

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

PubMed

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

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

2014-01-01

77

Tetramethylpyrazine ameliorates high glucose-induced endothelial dysfunction by increasing mitochondrial biogenesis.  

PubMed

Tetramethylpyrazine (TMP) is an active compound isolated from a Chinese herbal prescription that is widely used in traditional Chinese medicine for the treatment of inflammatory and cardiovascular diseases. We have previously reported that TMP acts as a potent antioxidant protecting endothelial cells against high glucose-induced damages. However, the molecular mechanism responsible for the antioxidant effect of TMP remains to be elucidated. In this study, we show that TMP increases nitric oxide production in endothelial cells and promotes endothelium-dependent relaxation in rate aortic rings. The antioxidant effect of TMP appears attributable to its ability to activate the mitochondrial biogenesis, as reflected in an up-regulation of complex III and amelioration of mitochondrial membrane potential. Furthermore, TMP is able to reverse high glucose-induced suppression of SIRT1 and the biogenesis-related factors, including PGC-1?, NRF1 and TFAM, suggesting a new molecular mechanism underlying the protective effect of TMP on the endothelium. PMID:24505445

Xu, Qiong; Xia, Pu; Li, Xi; Wang, Wei; Liu, Zhenqi; Gao, Xin

2014-01-01

78

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

PubMed Central

OBJECTIVE—Cannabinoid 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 METHODS—We 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 receptor–deficient (CB1?/?) and chronically SR141716-treated mice on either a standard or high-fat diet. RESULTS—SR141716 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 RNA–mediated decrease in eNOS. While high-fat diet–fed 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. CONCLUSIONS—CB1 receptor blockade increases mitochondrial biogenesis in white adipocytes by inducing the expression of eNOS. This is linked to the prevention of high-fat diet–induced fat accumulation, without concomitant changes in food intake.

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

79

Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi.  

PubMed

Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1? were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal A?1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment A?25-35, mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD. PMID:24448779

Rice, Ann C; Keeney, Paula M; Algarzae, Norah K; Ladd, Amy C; Thomas, Ravindar R; Bennett, James P

2014-01-01

80

Complementary action of the PGC1 coactivators in mitochondrial biogenesis and brown fat differentiation  

Microsoft Academic Search

Summary Mitochondria play an essential role in the ability of brown fat to generate heat, and the PGC-1 coactivators control several aspects of mitochondrial biogenesis. To investigate their specific roles in brown fat cells, we generated immortal preadipo- cyte lines from the brown adipose tissue of mice lacking PGC-1a. We could then efficiently knockdown PGC-1b expression by shRNA expression. Loss

Marc Uldry; Wenli Yang; Julie St-Pierre; Jiandie Lin; Patrick Seale; Bruce M. Spiegelman

2006-01-01

81

Triiodothyronine induces lipid oxidation and mitochondrial biogenesis in rat Harderian gland.  

PubMed

The rat Harderian gland (HG) is an orbital gland producing a copious lipid secretion. Recent studies indicate that its secretory activity is regulated by thyroid hormones. In this study, we found that both isoforms of the thyroid hormone receptor (Tr? (Thra) and Tr? (Thrb)) are expressed in rat HGs. Although Thra is expressed at a higher level, only Thrb is regulated by triiodothyronine (T3). Because T3 induces an increase in lipid metabolism in rat HGs, we investigated the effects of an animal's thyroid state on the expression levels of carnitine palmitoyltransferase-1A (Cpt1a) and carnitine palmitoyltransferase-1B (Cpt1b) and acyl-CoA oxidase (Acox1) (rate-limiting enzymes in mitochondrial and peroxisomal fatty acid oxidation respectively), as well as on the mitochondrial compartment, thereby correlating mitochondrial activity and biogenesis with morphological analysis. We found that hypothyroidism decreased the expression of Cpt1b and Acox1 mRNA, whereas the administration of T3 to hypothyroid rats increased transcript levels. Respiratory parameters and catalase protein levels provided further evidence that T3 modulates mitochondrial and peroxisomal activities. Furthermore, in hypothyroid rat HGs, the mitochondrial number and their total area decreased with respect to the controls, whereas the average area of the individual mitochondrion did not change. However, the average area of the individual mitochondrion was reduced by ?50% in hypothyroid T3-treated HGs, and the mitochondrial number and the total area of the mitochondrial compartment increased. The mitochondrial morphometric data correlated well with the molecular results. Indeed, hypothyroid status did not modify the expression of mitochondrial biogenesis genes such as Ppargc1a, Nrf1 and Tfam, whereas T3 treatment increased the expression level of these genes. PMID:23873539

Santillo, A; Burrone, L; Falvo, S; Senese, R; Lanni, A; Chieffi Baccari, G

2013-10-01

82

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

PubMed

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

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

2014-04-01

83

Glycogen synthase kinase-3 (GSK3) controls deoxyglucose-induced mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells.  

PubMed

Mitochondrial biogenesis, a mitochondrial growth and division process, is crucial for adaptation to metabolic stress. The present study demonstrated that treatment with a specific inhibitor of GSK3, SB216763, attenuated induction of mitochondrial biogenesis by a glycolysis inhibitor, 2-deoxyglucose (2-DG), without affecting this biogenesis at basal condition. Additionally, overexpression of WT-GSK3? promoted whereas GSK3?-KD attenuated 2-DG-induced mitochondrial protein expression. The mitochondrial biogenesis attenuation by GSK3 inhibitor was not due to inhibition of protein degradation. Furthermore, GSK3 inhibition further reduced transcription of mitochondrial (COXII), but not nuclear (VDAC) gene by 2-DG suggesting its participation in 2-DG-induced mitochondrial transcription. Together, our results show that GSK3 regulates mitochondrial biogenesis induced by glycolysis inhibition. PMID:24316184

Ngamsiri, Pronrumpa; Watcharasit, Piyajit; Satayavivad, Jutamaad

2014-01-01

84

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

PubMed Central

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.

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

2012-01-01

85

Dual role of mitofilin in mitochondrial membrane organization and protein biogenesis.  

PubMed

The mitochondrial inner membrane consists of two domains, inner boundary membrane and cristae membrane that are connected by crista junctions. Mitofilin/Fcj1 was reported to be involved in formation of crista junctions, however, different views exist on its function and possible partner proteins. We report that mitofilin plays a dual role. Mitofilin is part of a large inner membrane complex, and we identify five partner proteins as constituents of the mitochondrial inner membrane organizing system (MINOS) that is required for keeping cristae membranes connected to the inner boundary membrane. Additionally, mitofilin is coupled to the outer membrane and promotes protein import via the mitochondrial intermembrane space assembly pathway. Our findings indicate that mitofilin is a central component of MINOS and functions as a multifunctional regulator of mitochondrial architecture and protein biogenesis. PMID:21944719

von der Malsburg, Karina; Müller, Judith M; Bohnert, Maria; Oeljeklaus, Silke; Kwiatkowska, Paulina; Becker, Thomas; Loniewska-Lwowska, Adrianna; Wiese, Sebastian; Rao, Sanjana; Milenkovic, Dusanka; Hutu, Dana P; Zerbes, Ralf M; Schulze-Specking, Agnes; Meyer, Helmut E; Martinou, Jean-Claude; Rospert, Sabine; Rehling, Peter; Meisinger, Chris; Veenhuis, Marten; Warscheid, Bettina; van der Klei, Ida J; Pfanner, Nikolaus; Chacinska, Agnieszka; van der Laan, Martin

2011-10-18

86

Respiration and Mitochondrial Biogenesis in Germinating Embryos of Maize 1  

PubMed Central

Function of the cyanide-sensitive mitochondrial electron transport system was required for germination of the Zea mays embryo. Respiration of the standard electron transport system (rather than the alternate oxidase) began immediately upon initiation of imbibition. This respiration depended upon cytochrome c oxidase and ATPase that were conserved in an active form in the quiescent embryo rather than upon newly synthesized or assembled enzyme complexes. Immunoprecipitation of radiolabeled subunits of these enzymes showed that the initiation of mitochondrial biogenetic activities, including de novo synthesis of nuclear- and mitochondrial-encoded enzyme subunit peptides, was strongly induced after 6 hours of embryo germination. Undetectable or very low levels of transcripts for subunits 1 and 2 of the F1-ATPase and subunit 2 of cytochrome c oxidase were present in the quiescent embryo; these transcripts accumulated rapidly between 6 and 12 hours of germination and their translation products were rapidly synthesized between 6 and 24 hours. An exception was the gene for subunit 9 of the ATPase; transcripts of this mitochondrial gene were abundant in the dry embryo and rapidly accumulated further upon initiation of imbibition; they were translated actively during the first 6 hours. We isolated and sequenced a near full-length cDNA for subunit 2 (beta) of the F1-ATPase, and we compared the deduced protein sequence with related sequences of other organisms. Images Figure 2 Figure 3 Figure 5

Ehrenshaft, Marilyn; Brambl, Robert

1990-01-01

87

Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk  

PubMed Central

Background Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility. Methods Through a multi-center study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 nuclear-encoded SNPs localized to 138 genes involved in mitochondrial biogenesis (BIO, n=35), steroid hormone metabolism (HOR, n=13), and oxidative phosphorylation (OXP, n=90) pathways. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) between genotype and case status. Overall significance of each gene and pathway was evaluated using Fisher’s method to combine SNP-level evidence. At the SNP-level, we investigated whether lifetime ovulation, hormone replacement therapy (HRT), and cigarette smoking were confounders or modifiers of associations. Results Inter-individual variation involving BIO was most strongly associated with EOC risk (empirical P=0.050), especially for NRF1, MTERF, PPARGC1A, ESRRA, and CAMK2D. Several SNP-level associations strengthened after adjustment for non-genetic factors, particularly for MTERF. Statistical interactions with cigarette smoking and HRT use were observed with MTERF and CAMK2D SNPs, respectively. Overall variation within mtDNA, HOR, and OXP was not statistically significant (empirical P >0.10). Conclusion We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility. Impact A deeper understanding of the complex mechanisms implicated in mitochondrial biogenesis and oxidative stress may aid in developing strategies to reduce morbidity and mortality from EOC.

Permuth-Wey, Jennifer; Chen, Y. Ann; Tsai, Ya-Yu; Chen, Zhihua; Qu, Xiaotao; Lancaster, Johnathan M.; Stockwell, Heather; Dagne, Getachew; Iversen, Edwin; Risch, Harvey; Barnholtz-Sloan, Jill; Cunningham, Julie M.; Vierkant, Robert A.; Fridley, Brooke L.; Sutphen, Rebecca; McLaughlin, John; Narod, Steven A.; Goode, Ellen L.; Schildkraut, Joellen M.; Fenstermacher, David; Phelan, Catherine M.; Sellers, Thomas A.

2011-01-01

88

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

PubMed

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

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

2014-02-01

89

Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function.  

PubMed

Mitochondrial localization of p53 has been observed in several cell systems, but an understanding of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to the signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGFP, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (DeltaPsim) were decreased in cells expressing m53DD. Both alterations were specific for mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m53DD vs. mEGFP). The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMXRos staining, and rescue of these parameters with PK11195, imply a direct positive effect of p53 on mitochondrial biogenesis and function. PMID:11259382

Donahue, R J; Razmara, M; Hoek, J B; Knudsen, T B

2001-03-01

90

Iron–sulphur cluster biogenesis and mitochondrial iron homeostasis  

Microsoft Academic Search

Iron–sulphur clusters are important cofactors for proteins that are involved in many cellular processes, including electron transport, enzymatic catalysis and regulation. The enzymes that catalyse the formation of iron–sulphur clusters are widely conserved from bacteria to humans. Recent studies in model systems and humans reveal that iron–sulphur proteins have important roles in mitochondrial iron homeostasis and in the pathogenesis of

Tracey A. Rouault; Wing-Hang Tong

2005-01-01

91

Mitochondrial Biogenesis and Fragmentation as Regulators of Muscle Protein Degradation  

Microsoft Academic Search

Mitochondria form a dynamic network that rapidly adapts to cellular energy demand. This adaptation is particularly important\\u000a in skeletal muscle because of its high metabolic rate. Indeed, muscle energy level is one of the cellular checkpoints that\\u000a lead either to sustained protein synthesis and growth or protein breakdown and atrophy. Mitochondrial function is affected\\u000a by changes in shape, number, and

Vanina Romanello; Marco Sandri

2010-01-01

92

Glycogen synthase kinase-3 inhibition reduces ischemic cerebral damage, restores impaired mitochondrial biogenesis and prevents ROS production.  

PubMed

This study was designed to test the hypothesis that improved mitochondrial biogenesis could help reducing ischemic cerebral injury. We found that levels of proliferator-activated receptor ? coactivator 1? and nuclear respiratory factor-1, mitochondrial DNA content and other markers of mitochondrial biogenesis and function were reduced in primary mouse cortical neurons under oxygen-glucose deprivation (OGD). The glycogen synthase kinase-3 (GSK-3) inhibitor SB216763 activated an efficient mitochondrial biogenesis program in control cortical neurons and counteracted the OGD-mediated mitochondrial biogenesis impairment. This was accompanied by the activation of an antioxidant response that reduced mitochondrial reactive oxygen species generation and ischemic neuronal damage. The in vitro effects of SB216763 were mimicked by two other structurally unrelated GSK-3 inhibitors. The protective effects of SB216763 on OGD-mediated neuronal damage were abolished in the presence of diverse mitochondrial inhibitors. Finally, when systemically administered in vivo, SB216763 reduced the infarct size and recovered the loss of mitochondrial DNA in mice subjected to permanent middle cerebral artery occlusion. We conclude that GSK-3 inhibition by SB216763 might pave the way of novel promising therapies aimed at stimulating the renewal of functional mitochondria and reducing reactive oxygen species-mediated damage in ischemic stroke. PMID:21210815

Valerio, Alessandra; Bertolotti, Paola; Delbarba, Andrea; Perego, Carlo; Dossena, Marta; Ragni, Maurizio; Spano, PierFranco; Carruba, Michele O; De Simoni, Maria Grazia; Nisoli, Enzo

2011-03-01

93

GPAT2, a mitochondrial outer membrane protein, in piRNA biogenesis in germline stem cells  

PubMed Central

piRNA (PIWI-interacting RNA) is a germ cell–specific small RNA in which biogenesis PIWI (P-element wimpy testis) family proteins play crucial roles. MILI (mouse Piwi-like), one of the three mouse PIWI family members, is indispensable for piRNA production, DNA methylation of retrotransposons presumably through the piRNA, and spermatogenesis. The biogenesis of piRNA has been divided into primary and secondary processing pathways; in both of these MILI is involved in mice. To analyze the molecular function of MILI in piRNA biogenesis, we utilized germline stem (GS) cells, which are derived from testicular stem cells and possess a spermatogonial phenotype. We established MILI-null GS cell lines and their revertant, MILI-rescued GS cells, by introducing the Mili gene with Sendai virus vector. Comparison of wild-type, MILI-null, and MILI-rescued GS cells revealed that GS cells were quite useful for analyzing the molecular mechanisms of piRNA production, especially the primary processing pathway. We found that glycerol-3-phosphate acyltransferase 2 (GPAT2), a mitochondrial outer membrane protein for lysophosphatidic acid, bound to MILI using the cells and that gene knockdown of GPAT2 brought about impaired piRNA production in GS cells. GPAT2 is not only one of the MILI bound proteins but also a protein essential for primary piRNA biogenesis.

Shiromoto, Yusuke; Kuramochi-Miyagawa, Satomi; Daiba, Akito; Chuma, Shinichiro; Katanaya, Ami; Katsumata, Akiko; Nishimura, Ken; Ohtaka, Manami; Nakanishi, Mahito; Nakamura, Toshinobu; Yoshinaga, Koichi; Asada, Noriko; Nakamura, Shota; Yasunaga, Teruo; Kojima-Kita, Kanako; Itou, Daisuke; Kimura, Tohru; Nakano, Toru

2013-01-01

94

Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes  

PubMed Central

Using an siRNA-based screen, we identified the transcriptional corepressor RIP140 as a negative regulator of insulin-responsive hexose uptake and oxidative metabolism in 3T3-L1 adipocytes. Affymetrix GeneChip profiling revealed that RIP140 depletion upregulates the expression of clusters of genes in the pathways of glucose uptake, glycolysis, TCA cycle, fatty acid oxidation, mitochondrial biogenesis, and oxidative phosphorylation in these cells. Conversely, we show that reexpression of RIP140 in mouse embryonic fibroblasts derived from RIP140-null mice downregulates expression of many of these same genes. Consistent with these microarray data, RIP140 gene silencing in cultured adipocytes increased both conversion of [14C]glucose to CO2 and mitochondrial oxygen consumption. RIP140-null mice, previously reported to resist weight gain on a high-fat diet, are shown here to display enhanced glucose tolerance and enhanced responsiveness to insulin compared with matched wild-type mice upon high-fat feeding. Mechanistically, RIP140 was found to require the nuclear receptor ERR? to regulate hexose uptake and mitochondrial proteins SDHB and CoxVb, although it likely acts through other nuclear receptors as well. We conclude that RIP140 is a major suppressor of adipocyte oxidative metabolism and mitochondrial biogenesis, as well as a negative regulator of whole-body glucose tolerance and energy expenditure in mice.

Powelka, Aimee M.; Seth, Asha; Virbasius, Joseph V.; Kiskinis, Evangelos; Nicoloro, Sarah M.; Guilherme, Adilson; Tang, Xiaoqing; Straubhaar, Juerg; Cherniack, Andrew D.; Parker, Malcolm G.; Czech, Michael P.

2005-01-01

95

The PGC-1alpha-dependent pathway of mitochondrial biogenesis is upregulated in type I endometrial cancer.  

PubMed

PGC-1alpha-dependent pathway of mitochondrial biogenesis was investigated for the first time in type I endometrial cancer and in normal endometrium. In cancer endometrial tissue the citrate synthase activity, the mitochondrial DNA content and the TFAM level were found doubled compared to control endometrial tissue. Moreover, a 1.6- and 1.8-fold increase, respectively, of NRF-1 and PGG-1alpha expression was found. This study demonstrates, for the first time, that the increased mitochondrial biogenesis in type I endometrial cancer is associated to the upregulation of PGC-1alpha signalling pathway. PMID:19861117

Cormio, Antonella; Guerra, Flora; Cormio, Gennaro; Pesce, Vito; Fracasso, Flavio; Loizzi, Vera; Cantatore, Palmiro; Selvaggi, Luigi; Gadaleta, Maria Nicola

2009-12-25

96

Mitochondrial transcription factor A regulated ionizing radiation-induced mitochondrial biogenesis in human lung adenocarcinoma A549 cells.  

PubMed

Mitochondrial transcription factor A (TFAM), the first well-characterized transcription factor from vertebrate mitochondria, is closely related to mitochondrial DNA (mtDNA) maintenance and repair. Recent evidence has shown that the ratio of mtDNA to nuclearDNA (nDNA) is increased in both human cells and murine tissues after ionizing radiation (IR). However, the underlying mechanism has not as yet been clearly identified. In the present study, we demonstrated that in human lung adenocarcinoma A549 cells, expression of TFAM was upregulated, together with the increase of the relative mtDNA copy number and cytochrome c oxidase (COX) activity after ?-particle irradiation. Furthermore, short hairpin RNA (shRNA)-mediated TFAM knockdown inhibited the enhancement of the relative mtDNA copy number and COX activity caused by ?-particles. Taken together, our data suggested that TFAM plays a crucial role in regulating mtDNA amplification and mitochondrial biogenesis under IR conditions. PMID:23645454

Yu, Jing; Wang, Qisen; Chen, Ni; Sun, Yuxiang; Wang, Xiaofei; Wu, Lijun; Chen, Shaopeng; Yuan, Hang; Xu, An; Wang, Jun

2013-11-01

97

Silybin exerts antioxidant effects and induces mitochondrial biogenesis in liver of rat with secondary biliary cirrhosis.  

PubMed

The accumulation of toxic hydrophobic bile acids in hepatocytes, observed during chronic cholestasis, induces substantial modification in the redox state and in mitochondrial functions. Recent reports have suggested a significant role of impaired lipid metabolism in the progression of chronic cholestasis. In this work we report that changes observed in the expression of the lipogenic enzymes acetyl-CoA carboxylase and fatty acid synthase were associated with a decrease in the activity of citrate carrier (CIC), a protein of the inner mitochondrial membrane closely related to hepatic lipogenesis. We also verified that the impairment of citrate transport was dependent on modification of the phospholipid composition of the mitochondrial membrane and on cardiolipin oxidation. Silybin, an extract of silymarin with antioxidant and anti-inflammatory properties, prevented mitochondrial reactive oxygen species (ROS) production, cardiolipin oxidation, and CIC failure in cirrhotic livers but did not affect the expression of lipogenic enzymes. Moreover, supplementation of silybin was also associated with mitochondrial biogenesis. In conclusion, we demonstrate that chronic cholestasis induces cardiolipin oxidation that in turn impairs mitochondrial function and further promotes ROS production. The capacity of silybin to limit mitochondrial failure is part of its hepatoprotective property. PMID:24819445

Serviddio, Gaetano; Bellanti, Francesco; Stanca, Eleonora; Lunetti, Paola; Blonda, Maria; Tamborra, Rosanna; Siculella, Luisa; Vendemiale, Gianluigi; Capobianco, Loredana; Giudetti, Anna Maria

2014-08-01

98

Ras proteins control mitochondrial biogenesis and function in Saccharomyces cerevisiae.  

PubMed

The evolutionarily conserved Ras proteins function as a point of convergence for different signaling pathways in eukaryotes and have been implicated in both aging and cancer development. In Saccharomyces cerevisiae the plasma membrane proteins Ras1 and Ras2 are sensing the nutritional status of the environments, e.g., the abundance and quality of available carbon sources. The cAMP-protein kinase A pathway is the most explored signaling pathway controlled by Ras proteins; it affects a large number of genes, some of which are important to defend the cell against oxidative stress. In addition, recent analysis has shown that the Ras system of yeast is involved in the development of mitochondria and in regulating their activity. As a sensor of environmental status and an effector of mitochondrial activity, Ras serves as a Rosetta stone of cellular energy transduction. This review summarizes the physical and functional involvement of Ras proteins and Ras-dependent signaling pathways in mitochondrial function in S. cerevisiae. Since mitochondria produce harmful reactive oxygen species as an inevitable byproduct and are partly under control of Ras, illuminating these regulatory interactions may improve our understanding of both cancer and aging. PMID:15058183

Hlavatá, L; Nyström, T

2003-01-01

99

High-Fat Diet-Induced Mitochondrial Biogenesis Is Regulated by Mitochondrial-Derived Reactive Oxygen Species Activation of CaMKII.  

PubMed

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

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

100

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

PubMed

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 1? (PGC-1?) 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 (10mg/kgb.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-1? was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1? 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-1? 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. PMID:24084166

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

2013-12-01

101

Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism.  

PubMed

Endurance exercise training increases cardiac energy metabolism through poorly understood mechanisms. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) in cardiomyocytes contributes to cardiac adaptation. Here we demonstrate that the NO donor diethylenetriamine-NO (DETA-NO) activated mitochondrial biogenesis and function, as assessed by upregulated peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?), nuclear respiratory factor 1, and mitochondrial transcription factor A (Tfam) expression, and by increased mitochondrial DNA content and citrate synthase activity in primary mouse cardiomyocytes. DETA-NO also induced mitochondrial biogenesis and function and enhanced both basal and insulin-stimulated glucose uptake in HL-1 cardiomyocytes. The DETA-NO-mediated effects were suppressed by either PGC-1? or Tfam small-interference RNA in HL-1 cardiomyocytes. Wild-type and eNOS(-/-) mice were subjected to 6 wk graduated swim training. We found that eNOS expression, mitochondrial biogenesis, mitochondrial volume density and number, and both basal and insulin-stimulated glucose uptake were increased in left ventricles of swim-trained wild-type mice. On the contrary, the genetic deletion of eNOS prevented all these adaptive phenomena. Our findings demonstrate that exercise training promotes eNOS-dependent mitochondrial biogenesis in heart, which behaves as an essential step in cardiac glucose transport. PMID:24381004

Vettor, Roberto; Valerio, Alessandra; Ragni, Maurizio; Trevellin, Elisabetta; Granzotto, Marnie; Olivieri, Massimiliano; Tedesco, Laura; Ruocco, Chiara; Fossati, Andrea; Fabris, Roberto; Serra, Roberto; Carruba, Michele O; Nisoli, Enzo

2014-03-01

102

PPAR? is an essential transcriptional regulator for mitochondrial protection and biogenesis in adult heart  

PubMed Central

Rationale PPARs (?, ? and ?/?) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPAR? deficiency in mice leads to depressed myocardial fatty acid oxidation (FAO), bioenergetics and premature death with lipotoxic cardiomyopathy. Objective To explore the essential role of PPAR? in the adult heart. Methods and Results We investigating the consequences of inducible short-term PPAR? knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPAR? knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2), leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPAR? coactivator-1 were substantially decreased in the short-term PPAR? deficient heart, concomitant with decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPAR? knockout hearts. Consequently, PPAR? deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy. Conclusions PPAR? is an essential regulator of cardiac mitochondrial protection and biogenesis and PPAR? activation can be a potential therapeutic target for cardiac disorders.

Wang, Peiyong; Liu, Jian; Li, Yuquan; Wu, Sijie; Luo, Jinwen; Yang, Huan; Subbiah, Ramasamy; Chatham, John; Zhelyabovska, Olga; Yang, Qinglin

2010-01-01

103

Nitric Oxide in Skeletal Muscle: Role on Mitochondrial Biogenesis and Function  

PubMed Central

Nitric oxide (NO) has been implicated in several cellular processes as a signaling molecule and also as a source of reactive nitrogen species (RNS). NO is produced by three isoenzymes called nitric oxide synthases (NOS), all present in skeletal muscle. While neuronal NOS (nNOS) and endothelial NOS (eNOS) are isoforms constitutively expressed, inducible NOS (iNOS) is mainly expressed during inflammatory responses. Recent studies have demonstrated that NO is also involved in the mitochondrial biogenesis pathway, having PGC-1? as the main signaling molecule. Increased NO synthesis has been demonstrated in the sarcolemma of skeletal muscle fiber and NO can also reversibly inhibit cytochrome c oxidase (Complex IV of the respiratory chain). Investigation on cultured skeletal myotubes treated with NO donors, NO precursors or NOS inhibitors have also showed a bimodal effect of NO that depends on the concentration used. The present review will discuss the new insights on NO roles on mitochondrial biogenesis and function in skeletal muscle. We will also focus on potential therapeutic strategies based on NO precursors or analogs to treat patients with myopathies and mitochondrial deficiency.

Tengan, Celia Harumi; Rodrigues, Gabriela Silva; Godinho, Rosely Oliveira

2012-01-01

104

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

PubMed

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

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

2014-01-01

105

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

PubMed Central

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.

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

2013-01-01

106

Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice.  

PubMed

Androgen reduces fat mass, although the underlying mechanisms are unknown. Here, we examined the effect of testosterone on heat production and mitochondrial biogenesis. Testosterone-treated mice exhibited elevated heat production. Treatment with testosterone increased the expression level of peroxisome proliferator-activated receptor-? coactivator-1? (PGC1?), ATP5B and Cox4 in skeletal muscle, but not that in brown adipose tissue and liver. mRNA levels of genes involved in mitochondrial biogenesis were elevated in skeletal muscle isolated from testosterone-treated male mice, but were down-regulated in androgen receptor deficient mice. These results demonstrated that the testosterone-induced increase in energy expenditure is derived from elevated mitochondrial biogenesis in skeletal muscle. PMID:24726723

Usui, Taro; Kajita, Kazuo; Kajita, Toshiko; Mori, Ichiro; Hanamoto, Takayuki; Ikeda, Takahide; Okada, Hideyuki; Taguchi, Koichiro; Kitada, Yoshihiko; Morita, Hiroyuki; Sasaki, Tsutomu; Kitamura, Tadahiro; Sato, Takashi; Kojima, Itaru; Ishizuka, Tatsuo

2014-05-21

107

Physical Exercise Regulates p53 Activity Targeting SCO2 and Increases Mitochondrial COX Biogenesis in Cardiac Muscle with Age  

PubMed Central

The purpose of this study was to outline the timelines of mitochondrial function, oxidative stress and cytochrome c oxidase complex (COX) biogenesis in cardiac muscle with age, and to evaluate whether and how these age-related changes were attenuated by exercise. ICR/CD-1 mice were treated with pifithrin-? (PFT?), sacrificed and studied at different ages; ICR/CD-1 mice at younger or older ages were randomized to endurance treadmill running and sedentary conditions. The results showed that mRNA expression of p53 and its protein levels in mitochondria increased with age in cardiac muscle, accompanied by increased mitochondrial oxidative stress, reduced expression of COX subunits and assembly proteins, and decreased expression of most markers in mitochondrial biogenesis. Most of these age-related changes including p53 activity targeting cytochrome oxidase deficient homolog 2 (SCO2), p53 translocation to mitochondria and COX biogenesis were attenuated by exercise in older mice. PFT?, an inhibitor blocking p53 translocation to mitochondria, increased COX biogenesis in older mice, but not in young mice. Our data suggest that physical exercise attenuates age-related changes in mitochondrial COX biogenesis and p53 activity targeting SCO2 and mitochondria, and thereby induces antisenescent and protective effects in cardiac muscle.

Qi, Zhengtang; He, Jie; Su, Yuhui; He, Qiang; Liu, Jingxia; Yu, Lu; Al-Attas, Omar; Hussain, Tajamul; Ding, Shuzhe; Ji, Liu; Qian, Min

2011-01-01

108

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

PubMed

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

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

2014-01-01

109

Biphasic response of mitochondrial biogenesis to oxidative stress in visceral fat of diet-induced obesity mice.  

PubMed

Abstract Aims: Studies in skeletal muscle demonstrate a strong association of mitochondrial dysfunction with insulin resistance (IR). However, there is still a paucity of knowledge regarding the alteration of mitochondria in adipose tissue (AT) in the pathogenesis of IR in obesity. We investigated the mitochondrial biogenesis in visceral fat (VF) and subcutaneous fat (SF) in C57BL/6J mice fed a high-fat high-sucrose diet for 12 months. Results: Impairment of glucose tolerance and insulin sensitivity developed after 1 month of the diet and was associated with a prompt increase of VF. The VF adipocytes were larger than those in the SF and had increased expressions of HIF-1? and p-NF?B p65. However, the alteration of mitochondrial biogenesis did not occur in the early stage when increased intracellular reactive oxygen species (ROS), mitochondrial oxygen consumption rate, and mitochondrial ROS emerged at the 1st, 2nd and 2nd month, respectively. Until the 6th month, the VF had markedly increased mitochondrial DNA content and expression of PGC-1?, Tfam, ATP5A, and MnSOD. This increase of mitochondrial biogenesis was followed by a generalized decrease at the 12th month and the mitochondrial morphology altered markedly. In the late stage, although mitochondrial ROS decreased, the increased expression of 8-OHdG in VF continued. Innovation and Conclusion: These data suggest that IR and ROS production occur before the biphasic changes of mitochondrial biogenesis in AT, and the VF plays a more crucial role. Antioxid. Redox Signal. 20, 2572-2588. PMID:24111683

Wang, Pei-Wen; Kuo, Hsiao-Mei; Huang, Hung-Tu; Chang, Alice Yw; Weng, Shao-Wen; Tai, Ming-Hong; Chuang, Jiin-Haur; Chen, I-Ya; Huang, Shun-Chen; Lin, Tsu-Kung; Liou, Chia-Wei

2014-06-01

110

C7orf30 is necessary for biogenesis of the large subunit of the mitochondrial ribosome  

PubMed Central

Defects of the translation apparatus in human mitochondria are known to cause disease, yet details of how protein synthesis is regulated in this organelle remain to be unveiled. Here, we characterize a novel human protein, C7orf30 that contributes critically to mitochondrial translation and specifically associates with the large subunit of the mitochondrial ribosome (mt-LSU). Inactivation of C7orf30 in human cells by RNA interference results in respiratory incompetence owing to reduced mitochondrial translation rates without any appreciable effects on the steady-state levels of mitochondrial mRNAs and rRNAs. Ineffective translation in C7orf30-depleted cells or cells overexpressing a dominant-negative mutant of the protein results from aberrant assembly of mt-LSU and consequently reduced formation of the monosome. These findings lead us to propose that C7orf30 is a human assembly and/or stability factor involved in the biogenesis of the large subunit of the mitochondrial ribosome.

Rorbach, Joanna; Gammage, Payam A.; Minczuk, Michal

2012-01-01

111

Acetate supplementation increases brain phosphocreatine and reduces AMP levels with no effect on mitochondrial biogenesis  

PubMed Central

Acetate supplementation in rats increases plasma acetate and brain acetyl-CoA levels. Although acetate is used as a marker to study glial energy metabolism, the effect that acetate supplementation has on normal brain energy stores has not been quantified. To determine the effect(s) that an increase in acetyl-CoA levels has on brain energy metabolism, we measured brain nucleotide, phosphagen and glycogen levels, and quantified cardiolipin content and mitochondrial number in rats subjected to acetate supplementation. Acetate supplementation was induced with glyceryl triacetate (GTA) by oral gavage (6 g/Kg body weight). Rats used for biochemical analysis were euthanized using head-focused microwave irradiation at 2, and 4 hr following treatment to immediately stop metabolism. We found that acetate did not alter brain ATP, ADP, NAD, GTP levels, or the energy charge ratio [ECR, (ATP + ½ ADP) / (ATP + ADP + AMP)] when compared to controls. However, after 4 hr of treatment brain phosphocreatine levels were significantly elevated with a concomitant reduction in AMP levels with no change in glycogen levels. In parallel studies where rats were treated with GTA for 28 days, we found that acetate did not alter brain glycogen and mitochondrial biogenesis as determined by measuring brain cardiolipin content, the fatty acid composition of cardiolipin and using quantitative ultra-structural analysis to determine mitochondrial density/unit area of cytoplasm in hippocampal CA3 neurons. Collectively, these data suggest that an increase in brain acetyl-CoA levels by acetate supplementation does increase brain energy stores however it has no effect on brain glycogen and neuronal mitochondrial biogenesis.

Bhatt, Dhaval P.; Houdek, Heidi M.; Watt, John A.; Rosenberger, Thad A.

2013-01-01

112

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

PubMed Central

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.

2014-01-01

113

Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis.  

PubMed

Acute kidney injury (AKI) is a disease with mitochondrial dysfunction and a newly established risk factor for the development of chronic kidney disease (CKD) and fibrosis. We examined mitochondrial homeostasis in the folic acid (FA)-induced AKI model that develops early fibrosis over a rapid time course. Mice given a single dose of FA had elevated serum creatinine (3-fold) and urine glucose (2.2-fold) 1 and 2 d after injection that resolved by 4d. In contrast, peroxisome proliferator gamma coactivator 1? (PGC-1?) and mitochondrial transcription factor A (TFAM), critical transcriptional regulators of mitochondrial biogenesis (MB), were down-regulated ?80% 1d after FA injection and remained depressed through 14 d. Multiple electron transport chain and ATP synthesis genes were also down-regulated from 1 to 14 d after FA, including NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUF?8), ATP synthase subunit ? (ATPS-?), and cytochrome C oxidase subunit I (COXI). Mitochondrial DNA copy number was reduced ?50% from 2 to 14 d after FA injection. Protein levels of early fibrosis markers ?-smooth muscle actin and transforming growth factor ?1 were elevated at 6 and 14 d after FA. Picrosirius red staining and collagen 1A2 (COL1A2) IHC revealed staining for mature collagen deposition at 14 d. We propose that mitochondrial dysfunction induced by AKI is a persistent cellular injury that promotes progression to fibrosis and CKD, and that this model can be used to test mitochondrial therapeutics that limit progression to fibrosis and CKD. PMID:24275386

Stallons, L Jay; Whitaker, Ryan M; Schnellmann, Rick G

2014-01-30

114

Mitochondrial dysfunction and biogenesis: do ICU patients die from mitochondrial failure?  

PubMed Central

Mitochondrial functions include production of energy, activation of programmed cell death, and a number of cell specific tasks, e.g., cell signaling, control of Ca2+ metabolism, and synthesis of a number of important biomolecules. As proper mitochondrial function is critical for normal performance and survival of cells, mitochondrial dysfunction often leads to pathological conditions resulting in various human diseases. Recently mitochondrial dysfunction has been linked to multiple organ failure (MOF) often leading to the death of critical care patients. However, there are two main reasons why this insight did not generate an adequate resonance in clinical settings. First, most data regarding mitochondrial dysfunction in organs susceptible to failure in critical care diseases (liver, kidney, heart, lung, intestine, brain) were collected using animal models. Second, there is no clear therapeutic strategy how acquired mitochondrial dysfunction can be improved. Only the benefit of such therapies will confirm the critical role of mitochondrial dysfunction in clinical settings. Here we summarized data on mitochondrial dysfunction obtained in diverse experimental systems, which are related to conditions seen in intensive care unit (ICU) patients. Particular attention is given to mechanisms that cause cell death and organ dysfunction and to prospective therapeutic strategies, directed to recover mitochondrial function. Collectively the data discussed in this review suggest that appropriate diagnosis and specific treatment of mitochondrial dysfunction in ICU patients may significantly improve the clinical outcome.

2011-01-01

115

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

PubMed

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-1?), 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-1? 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-1? and NRF-1. PMID:24931672

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

2014-07-18

116

Nuclear recruitment of neuronal nitric-oxide synthase by ?-syntrophin is crucial for the induction of mitochondrial biogenesis.  

PubMed

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

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

2014-01-01

117

Age-associated declines in mitochondrial biogenesis and protein quality control factors are minimized by exercise training  

PubMed Central

A decline in mitochondrial biogenesis and mitochondrial protein quality control in skeletal muscle is a common finding in aging, but exercise training has been suggested as a possible cure. In this report, we tested the hypothesis that moderate-intensity exercise training could prevent the age-associated deterioration in mitochondrial biogenesis in the gastrocnemius muscle of Wistar rats. Exercise training, consisting of treadmill running at 60% of the initial V?o2max, reversed or attenuated significant age-associated (detrimental) declines in mitochondrial mass (succinate dehydrogenase, citrate synthase, cytochrome-c oxidase-4, mtDNA), SIRT1 activity, AMPK, pAMPK, and peroxisome proliferator-activated receptor gamma coactivator 1-?, UCP3, and the Lon protease. Exercise training also decreased the gap between young and old animals in other measured parameters, including nuclear respiratory factor 1, mitochondrial transcription factor A, fission-1, mitofusin-1, and polynucleotide phosphorylase levels. We conclude that exercise training can help minimize detrimental skeletal muscle aging deficits by improving mitochondrial protein quality control and biogenesis.

Koltai, Erika; Hart, Nikolett; Taylor, Albert W.; Goto, Sataro; Ngo, Jenny K.; Davies, Kelvin J. A.

2012-01-01

118

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

PubMed Central

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.

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

119

Induction of mitochondrial biogenesis protects against caspase-dependent and caspase-independent apoptosis in L6 myoblasts.  

PubMed

Apoptotic signaling plays an important role in skeletal muscle degradation, atrophy, and dysfunction. Mitochondria are central executers of apoptosis by directly participating in caspase-dependent and caspase-independent cell death signaling. Given the important apoptotic role of mitochondria, altering mitochondrial content could influence apoptosis. Therefore, we examined the direct effect of modest, but physiological increases in mitochondrial biogenesis and content on skeletal muscle apoptosis using a cell culture approach. Treatment of L6 myoblasts with SNAP or AICAR (5h/day for 5days) significantly increased PGC-1, AIF, cytochrome c, and MnSOD protein content as well as MitoTracker staining. Following induction of mitochondrial biogenesis, L6 myoblasts displayed decreased sensitivity to apoptotic cell death as well as reduced caspase-3 and caspase-9 activation following exposure to staurosporine (STS) and C2-ceramide. L6 myoblasts with higher mitochondrial content also exhibited reduced apoptosis and AIF release following exposure to hydrogen peroxide (H2O2). Analysis of several key apoptosis regulatory proteins (ARC, Bax, Bcl-2, XIAP), antioxidant proteins (catalase, MnSOD, CuZnSOD), and reactive oxygen species (ROS) measures (DCF and MitoSOX fluorescence) revealed that these mechanisms were not responsible for the observed cellular protection. However, myoblasts with higher mitochondrial content were less sensitive to Ca(2+)-induced mitochondrial permeability transition pore formation (mPTP) and mitochondrial membrane depolarization. Collectively, these data demonstrate that increased mitochondrial content at physiological levels provides protection against apoptotic cell death by decreasing caspase-dependent and caspase-independent signaling through influencing mitochondrial Ca(2+)-mediated apoptotic events. Therefore, increasing mitochondrial biogenesis/content may represent a potential therapeutic approach in skeletal muscle disorders displaying increased apoptosis. PMID:23643731

Dam, Aaron D; Mitchell, Andrew S; Quadrilatero, Joe

2013-12-01

120

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

PubMed Central

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.

2014-01-01

121

Peroxiredoxin 3 Is a Key Molecule Regulating Adipocyte Oxidative Stress, Mitochondrial Biogenesis, and Adipokine Expression  

PubMed Central

Abstract Aims: Increased oxidative stress and mitochondrial dysfunction in obese adipocytes contribute to adipokine dysregulation, inflammation, and insulin resistance. Results: Through an advanced proteomic analysis, we found that peroxiredoxin 3 (Prx3), a thioredoxin-dependent mitochondrial peroxidase, is highly expressed in 3T3-L1 adipocytes compared to preadipocytes. Interestingly, in obese db/db mice and human subjects, adipose Prx3 levels were significantly decreased, indicating its association with obesity. We therefore employed Prx3 knockout (KO) mice and transfected 3T3-L1 cells to examine the role of endogenous Prx3 in adipocyte metabolism. Prx3 KO mice had increased fat mass compared to wild-type due to adipocyte hypertrophy. Increased adipogenic transcription factors and lipogenic gene expression during differentiation of adipose tissue-derived stem cells from Prx3-deficient mice confirmed that these adipocytes are likely to accumulate fat. Mitochondrial protein carbonylation in Prx3 KO adipose tissue and mitochondrial superoxide level in Prx3 knockdown 3T3-L1 cells were increased showing aberrant regulation of oxidative stress. Proteomic analysis and gene expression analysis of Prx3 KO mice adipocytes also showed defect in mitochondria biogenesis along with enzymes involved in glucose/lipid metabolism and oxidative phosphorylation. In addition, expression level of adiponectin was downregulated and plasminogen activator inhibitor-1 was upregulated in Prx3 KO adipocytes. Impaired glucose tolerance and insulin resistance further implied metabolic dysregulation in Prx3 KO mice. Innovation and Conclusion: These data suggest that endogenous Prx3 may play an essential role in maintaining normal characteristics of adipocytes and that defect in Prx3 alters mitochondrial redox state and function, and adipokine expression in adipocytes leading to metabolic alteration. Antioxid. Redox Signal. 16, 229–243.

Huh, Joo Young; Kim, Yunghee; Jeong, Jaeho; Park, Jehyun; Kim, Inok; Huh, Kyu Ha; Kim, Yu Seun; Woo, Hyun Ae; Rhee, Sue Goo

2012-01-01

122

Rev-erb-? modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy.  

PubMed

The nuclear receptor Rev-erb-? modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-? is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-? deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1? signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-?, Nr1d1. In complementary experiments, Rev-erb-? overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-? in vivo increased exercise capacity. This study identifies Rev-erb-? as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function. PMID:23852339

Woldt, Estelle; Sebti, Yasmine; Solt, Laura A; Duhem, Christian; Lancel, Steve; Eeckhoute, Jérôme; Hesselink, Matthijs K C; Paquet, Charlotte; Delhaye, Stéphane; Shin, Youseung; Kamenecka, Theodore M; Schaart, Gert; Lefebvre, Philippe; Nevière, Rémi; Burris, Thomas P; Schrauwen, Patrick; Staels, Bart; Duez, Hélène

2013-08-01

123

G protein coupled receptor kinase 2 interacting protein 1 (GIT1) is a novel regulator of mitochondrial biogenesis in heart.  

PubMed

G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multi-function scaffold protein. However, little is known about its physiological role in the heart. Here we sought to identify the cardiac function of GIT1. Global GIT1 knockout (KO) mice were generated and exhibited significant cardiac hypertrophy that progressed to heart failure. Electron microscopy revealed that the hearts of GIT1 KO mice demonstrated significant morphological abnormities in mitochondria, including decreased mitochondrial volume density, cristae density and increased vacuoles. Moreover, mitochondrial biogenesis-related gene peroxisome proliferator-activated receptor ? (PPAR?) co-activator-1? (PGC-1?), PGC-1?, mitochondrial transcription factor A (Tfam) expression, and total mitochondrial DNA were remarkably decreased in hearts of GIT1 KO mice. These animals also had impaired mitochondrial function, as evidenced by reduced ATP production and dissipated mitochondrial membrane potential (?(m)) in adult cardiomyocytes. Concordant with these mitochondrial observations, GIT1 KO mice showed enhanced cardiomyocyte apoptosis and cardiac dysfunction. In conclusion, our findings identify GIT1 as a new regulator of mitochondrial biogenesis and function, which is necessary for postnatal cardiac maturation. PMID:21756914

Pang, Jinjiang; Xu, Xiangbin; Getman, Michael R; Shi, Xi; Belmonte, Stephen L; Michaloski, Heidi; Mohan, Amy; Blaxall, Burns C; Berk, Bradford C

2011-11-01

124

Exercise Training Induces Mitochondrial Biogenesis and Glucose Uptake in Subcutaneous Adipose Tissue Through eNOS-Dependent Mechanisms.  

PubMed

Insulin resistance and obesity are associated with a reduction of mitochondrial content in various tissues of mammals. Moreover, a reduced nitric oxide (NO) bioavailability impairs several cellular functions, including mitochondrial biogenesis and insulin-stimulated glucose uptake, two important mechanisms of body adaptation in response to physical exercise. Although these mechanisms have been thoroughly investigated in skeletal muscle and heart, few studies have focused on the effects of exercise on mitochondria and glucose metabolism in adipose tissue. In this study, we compared the in vivo effects of chronic exercise in subcutaneous adipose tissue of wild-type (WT) and endothelial NO synthase (eNOS) knockout (eNOS(-/-)) mice after a swim training period. We then investigated the in vitro effects of NO on mouse 3T3-L1 and human subcutaneous adipose tissue-derived adipocytes after a chronic treatment with an NO donor: diethylenetriamine-NO (DETA-NO). We observed that swim training increases mitochondrial biogenesis, mitochondrial DNA content, and glucose uptake in subcutaneous adipose tissue of WT but not eNOS(-/-) mice. Furthermore, we observed that DETA-NO promotes mitochondrial biogenesis and elongation, glucose uptake, and GLUT4 translocation in cultured murine and human adipocytes. These results point to the crucial role of the eNOS-derived NO in the metabolic adaptation of subcutaneous adipose tissue to exercise training. PMID:24622799

Trevellin, Elisabetta; Scorzeto, Michele; Olivieri, Massimiliano; Granzotto, Marnie; Valerio, Alessandra; Tedesco, Laura; Fabris, Roberto; Serra, Roberto; Quarta, Marco; Reggiani, Carlo; Nisoli, Enzo; Vettor, Roberto

2014-08-01

125

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

PubMed Central

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.

Becker, Thomas; Horvath, Susanne E.; Bottinger, Lena; Gebert, Natalia; Daum, Gunther; Pfanner, Nikolaus

2013-01-01

126

Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation  

PubMed Central

Background Mitochondrial dysfunction has been linked to neuronal death and a wide array of neurodegenerative diseases. Previously, we have shown sex differences in mitochondria-mediated cell death pathways following hypoxia-ischemia. However, the role of mitochondrial biogenesis in hypoxic-ischemic brain injury between male vs. female has not been studied yet. Results Primary cerebellar granule neurons (CGNs), isolated from P7 male and female mice (CD-1) segregated based on visual inspection of sex, were exposed to 2 h of oxygen glucose deprivation (OGD) followed by 6–24 h of reoxygenation (Reox). Mitochondrial membrane potential (??m) and cellular ATP levels were reduced significantly in XX CGNs as compared to XY CGNs. Mitochondrial DNA (mtDNA) content was increased (>2-fold) at 2 h OGD in XY CGNs and remained increased up to 24 h of Reox compared to XX neurons and normoxia controls. The expression of mitochondrial transcription factor A (Tfam), the nuclear respiratory factor-1 (NRF-1) and the peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), a master regulator of mitochondrial biogenesis, were up-regulated (2-fold, ***p?mitochondrial proteins HSP60 and COXIV were increased in XY neurons only. Supportively, a balanced stimulation of fusion (Mfn 1and Mfn 2) and fission (Fis 1 and Drp 1) genes and enhanced formation of donut-shaped mitochondria were observed in XY CGNs vs. XX neurons (**p?mitochondrial biogenesis and morphological changes in a sex-specific way, influencing neuronal injury/survival differently in both sexes.

2014-01-01

127

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

PubMed Central

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 µmol·L?1, whereas LA was most effective at 100 µmol·L?1. At 10 µmol·L?1, lipoamide, but not LA, stimulated mRNA expressions of PPAR-?, PPAR-? and CPT-1?. The potency of lipoamide was 10–100-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.

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

2011-01-01

128

Sphingosine 1-phosphate (S1P) promotes mitochondrial biogenesis in Hep G2 cells by activating Peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?).  

PubMed

Sphingosine 1-phosphate (S1P), a potent bioactive phospholipid, has been reported to regulate a broad spectrum of biological processes. However, little is known regarding S1P's effects on mitochondrial function. In this study, we investigated the S1P's effects on the Peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) signaling pathway and mitochondrial biogenesis in Hep G2 cells. Our results indicate that administration of S1P leads to a significant upregulation of mitochondrial DNA replication and transcription, increased mitochondrial mass, and elevated adenosine triphosphate synthesis. In addition, we found that treatment with S1P stimulates expression of PGC-1?, a master regulator of mitochondrial biogenesis, as well as its downstream targets: nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Moreover, our data demonstrate that S1P's effects on PGC-1? and mitochondrial biogenesis are mediated by the protein kinase A/cAMP response element-binding protein (PKA/CREB) pathway. Importantly, we also revealed that S1P's effects on mitochondrial biogenesis are dependent on its type 2 receptor (S1P2), though not on either its type 1 (S1P1) or type 3 (S1P3) receptors. Based on these observations, we concluded that S1P activates the PKA/CREB pathway through S1P2, which then promotes expression of PGC-1?/NRF1/TFAM and subsequent mitochondrial biogenesis in Hep G2 cells. PMID:24293320

Shen, Zhixin; Liu, Chong; Liu, Pingping; Zhao, Jiamin; Xu, Wanpeng

2014-07-01

129

Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice.  

PubMed

Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival in eukaryotes. Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in endothelial nitric oxide synthase null mutant mice. These data reveal an important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals. PMID:20889128

D'Antona, Giuseppe; Ragni, Maurizio; Cardile, Annalisa; Tedesco, Laura; Dossena, Marta; Bruttini, Flavia; Caliaro, Francesca; Corsetti, Giovanni; Bottinelli, Roberto; Carruba, Michele O; Valerio, Alessandra; Nisoli, Enzo

2010-10-01

130

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

PubMed Central

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

Rogers, Ryan P.; Rogina, Blanka

2014-01-01

131

Exercise-induced anaphylaxis  

Microsoft Academic Search

Exercise-induced anaphylaxis has been recognized with increasing frequency since its original description in 1980. Recent\\u000a studies suggest food-induced reactions may occur frequently in this syndrome, which is a mast cell-dependent phenomenon. In\\u000a this article, the clinical manifestations of exercise-induced anaphylaxis are reviewed, and food related factors contributing\\u000a to the disorder are considered.

Mariana C. Castells; Richard F. Horan; Albert L. Sheffer

2003-01-01

132

Altered mitochondrial biogenesis and its fusion gene expression is involved in the high-altitude adaptation of rat lung.  

PubMed

Intermittent hypobaric hypoxia-induced preconditioning (IHH-PC) of rat favored the adaption of lungs to severe HH conditions, possibly through stabilization of mitochondrial function. This is based on the data generated on regulatory coordination of nuclear DNA-encoded mitochondrial biogenesis; dynamics, and mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (mtOXPHOS) genes expression. At 16th day after start of IHH-PC (equivalent to 5000m, 6h/d, 2w of treatment), rats were exposed to severe HH stimulation at 9142m for 6h. The IHH-PC significantly counteracted the HH-induced effect of increased lung: water content; tissue damage; and oxidant injury. Further, IHH-PC significantly increased the mitochondrial number, mtDNA content and mtOXPHOS complex activity in the lung tissues. This observation is due to an increased expression of genes involved in mitochondrial biogenesis (PGC-1?, ERR?, NRF1, NRF2 and TFAM), fusion (Mfn1 and Mfn2) and mtOXPHOS. Thus, the regulatory pathway formed by PGC-1?/ERR?/Mfn2 axes is required for the mitochondrial adaptation provoked by IHH-PC regimen to counteract subsequent HH stress. PMID:24361501

Chitra, Loganathan; Boopathy, Rathanam

2014-02-01

133

Reduced adiponectin signaling due to weight gain results in nonalcoholic steatohepatitis through impaired mitochondrial biogenesis.  

PubMed

Obesity and adiponectin depletion have been associated with the occurrence of nonalcoholic fatty liver disease (NAFLD). The goal of this study was to identify the relationship between weight gain, adiponectin signaling, and development of nonalcoholic steatohepatitis (NASH) in an obese, diabetic mouse model. Leptin-receptor deficient (Lepr(db/db) ) and C57BL/6 mice were administered a diet high in unsaturated fat (HF) (61%) or normal chow for 5 or 10 weeks. Liver histology was evaluated using steatosis, inflammation, and ballooning scores. Serum, adipose tissue, and liver were analyzed for changes in metabolic parameters, messenger RNA (mRNA), and protein levels. Lepr(db/db) HF mice developed marked obesity, hepatic steatosis, and more than 50% progressed to NASH at each timepoint. Serum adiponectin level demonstrated a strong inverse relationship with body mass (r?=?-0.82; P?mitochondrial biogenesis and ?-oxidation (Cox4, Nrf1, Pgc1?, Pgc1? and Tfam). In contrast, recombinant adiponectin administration up-regulated the expression of mitochondrial genes in AML-12 hepatocytes, with or without lipid-loading. Conclusion: Lepr(db/db) mice fed a diet high in unsaturated fat develop weight gain and NASH through adiponectin depletion, which is associated with adipose tissue inflammation and hepatic mitochondrial dysfunction. We propose that this murine model of NASH may provide novel insights into the mechanism for development of human NASH. (Hepatology 2014;60:133-145). PMID:24464605

Handa, Priya; Maliken, Bryan D; Nelson, James E; Morgan-Stevenson, Vicki; Messner, Donald J; Dhillon, Barjinderjit K; Klintworth, Heather M; Beauchamp, Mary; Yeh, Matthew M; Elfers, Clinton T; Roth, Christian L; Kowdley, Kris V

2014-07-01

134

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

PubMed Central

There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17?-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 ER? and ER? 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.

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

2009-01-01

135

Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway.  

PubMed

Adaptation of cardiomyocytes to chronic hypoxia in cyanotic patients remains unclear. Mitochondrial biogenesis is enhanced in myocardium from cyanotic patients, which is possibly an adaptive response. Erythropoietin (EPO) in blood and its receptor (EPOR) on cardiomyocytes are upregulated by chronic hypoxia, suggesting that EPO-EPOR interaction is increased, which is inferred to positively regulate mitochondrial biogenesis through protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signalling pathway. H9c2 cardiomyocytes were exposed to hypoxia (1% O(2)) for 1 week and treated with different doses of recombinant human erythropoietin (rhEPO). Mitochondrial number, mitochondrial DNA (mtDNA) copy number and peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1?) mRNA expression increased in a dose-dependent manner induced by rhEPO. Akt and eNOS were significantly phosphorylated by rhEPO. Both blocking Akt with Wortmannin and silencing eNOS expression with shRNA plasmid decreased the mtDNA copy number and PGC-1? mRNA expression induced by rhEPO. Blocking Akt was associated with the decreased phosphorylation of Akt and eNOS. RNA interference led to a reduction in the total and phosphorylated proteins of eNOS. Thus EPO enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia, at least partly through Akt/eNOS signalling, which might be an adaptive mechanism of cardiomyocytes associated with the increased EPO-EPOR interaction in patients with cyanotic congenital heart disease (CCHD). PMID:24436050

Qin, Chuan; Zhou, Shengkai; Xiao, Yingbin; Chen, Lin

2014-03-01

136

Role of phosphatidylethanolamine in the biogenesis of mitochondrial outer membrane proteins.  

PubMed

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

Becker, Thomas; Horvath, Susanne E; Böttinger, Lena; Gebert, Natalia; Daum, Günther; Pfanner, Nikolaus

2013-06-01

137

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

(-)-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, PGC1?, 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

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

138

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

SciTech Connect

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.

Wu, C.-W. [Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China); Ping, Y.-H. [Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China); Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (China); Brain Research Center, University System of Taiwan, Taiwan (China); Yen, J.-C. [Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China); Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (China); Brain Research Center, University System of Taiwan, Taiwan (China); Chang, C.-Y. [Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China); Wang, S.-F. [Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China); Yeh, C.-L. [Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China); Chi, C.-W. [Department a nd Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China); Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan 112 (China); Lee, H.-C. [Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112 (China) and Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (China) and Brain Research Center, University System of Taiwan, Taiwan (China)]. E-mail: hclee2@ym.edu.tw

2007-05-01

139

Exercise-Induced Bronchoconstriction Quiz  

MedlinePLUS

... t have asthma or exercise-induced bronchoconstriction. True False False: Even mild symptoms of exercise-induced bronchoconstriction may ... should be kept out of gym class. True False False: If appropriately evaluated and treated, the vast ...

140

Assessment of newly synthesized mitochondrial DNA using BrdU labeling in primary neurons from Alzheimer's disease mice: Implications for impaired mitochondrial biogenesis and synaptic damage.  

PubMed

The purpose of our study was to assess mitochondrial biogenesis and distribution in murine primary neurons. Using 5-bromo-2-deoxyuridine (BrdU) incorporation and primary neurons, we studied the mitochondrial biogenesis and mitochondrial distribution in hippocampal neurons from amyloid beta precursor protein (A?PP) transgenic mice and wild-type (WT) neurons treated with oxidative stressors, rotenone and H(2)O(2). We found that after 20h of labeling, BrdU incorporation was specific to porin-positive mitochondria. The proportion of mitochondrial area labeled with BrdU was 40.3±6.3% at 20h. The number of mitochondria with newly synthesized DNA was higher in A?PP neuronal cell bodies than in the cell bodies of WT neurons (A?PP, 45.23±2.67 BrdU-positive/cell body; WT, 32.92±2.49 BrdU-positive/cell body; p=0.005). In neurites, the number of BrdU-positive mitochondria decreased in A?PP cultures compared to WT neurons (A?PP, 0.105±0.008 BrdU-positive/?m neurite; WT, 0.220±0.036 BrdU-positive/?m neurite; p=0.010). Further, BrdU in the cell body increased when neurons were treated with low doses of H(2)O(2) (49.6±2.7 BrdU-positive/cell body, p=0.0002 compared to untreated cells), while the neurites showed decreased BrdU staining (0.122±0.010 BrdU-positive/?m neurite, p=0.005 compared to the untreated). BrdU labeling was increased in the cell body under rotenone treatment. Additionally, under rotenone treatment, the content of BrdU labeling decreased in neurites. These findings suggest that A? and mitochondrial toxins enhance mitochondrial fragmentation in the cell body, and may cause impaired axonal transport of mitochondria leading to synaptic degeneration. PMID:21549836

Calkins, Marcus J; Reddy, P Hemachandra

2011-09-01

141

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

PubMed Central

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 longevity—decreased 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 interventions—calorie 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.

2013-01-01

142

Regulation of Mitochondrial Biogenesis by Lipoprotein Lipase in Muscle of Insulin-Resistant Offspring of Parents With Type 2 Diabetes  

PubMed Central

Recent studies reveal a strong relationship between reduced mitochondrial content and insulin resistance in human skeletal muscle, although the underlying factors responsible for this association remain unknown. To address this question, we analyzed muscle biopsy samples from young, lean, insulin resistant (IR) offspring of parents with type 2 diabetes and control subjects by microarray analyses and found significant differences in expression of ?512 probe pairs. We then screened these genes for their potential involvement in the regulation of mitochondrial biogenesis using RNA interference and found that mRNA and protein expression of lipoprotein lipase (LPL) in skeletal muscle was significantly decreased in the IR offspring and was associated with decreased mitochondrial density. Furthermore, we show that LPL knockdown in muscle cells decreased mitochondrial content by effectively decreasing fatty acid delivery and subsequent activation of peroxisome proliferator–activated receptor (PPAR)-?. Taken together, these data suggest that decreased mitochondrial content in muscle of IR offspring may be due in part to reductions in LPL expression in skeletal muscle resulting in decreased PPAR-? activation.

Morino, Katsutaro; Petersen, Kitt Falk; Sono, Saki; Choi, Cheol Soo; Samuel, Varman T.; Lin, Aiping; Gallo, Amy; Zhao, Hongyu; Kashiwagi, Atsunori; Goldberg, Ira J.; Wang, Hong; Eckel, Robert H.; Maegawa, Hiroshi; Shulman, Gerald I.

2012-01-01

143

Promise of Neurorestoration and Mitochondrial Biogenesis in Parkinson's Disease with Multi Target Drugs: An Alternative to Stem Cell Therapy  

PubMed Central

There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1? (peroxisome proliferator-activated receptor ? coactivator-1?), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis.

Oh, Young J.

2013-01-01

144

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

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.

Baxter, Kristin Kathleen; Uittenbogaard, Martine [Department of Anatomy and Regenerative Biology, George Washington University Medical Center, Washington, DC (United States)] [Department of Anatomy and Regenerative Biology, George Washington University Medical Center, Washington, DC (United States); Chiaramello, Anne, E-mail: achiaram@gwu.edu [Department of Anatomy and Regenerative Biology, George Washington University Medical Center, Washington, DC (United States)] [Department of Anatomy and Regenerative Biology, George Washington University Medical Center, Washington, DC (United States)

2012-10-15

145

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

PubMed Central

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 compartments—a glycolytic tumor stroma, which surrounds oxidative epithelial cancer cells—that 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.

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

146

Drosophila cyclin D/Cdk4 regulates mitochondrial biogenesis and aging and sensitizes animals to hypoxic stress.  

PubMed

Drosophila cyclinD (CycD) is the single fly ortholog of the mammalian cyclin D1 and promotes both cell cycle progression and cellular growth. However, little is known about how CycD promotes cell growth. We show here that CycD/Cdk4 hyperactivity leads to increased mitochondrial biogenesis (mitobiogenesis), mitochondrial mass, NRF-1 activity (Tfam transcript levels) and metabolic activity in Drosophila, whereas loss of CycD/Cdk4 activity has the opposite effects. Surprisingly, both CycD/Cdk4 addition and loss of function increase mitochondrial superoxide production and decrease lifespan, indicating that an imbalance in mitobiogenesis may lead to oxidative stress and aging. In addition, we provide multiple lines of evidence indicating that CycD/Cdk4 activity affects the hypoxic status of cells and sensitizes animals to hypoxia. Both mitochondrial and hypoxia-related effects can be detected at the global transcriptional level. We propose that mitobiogenesis and the hypoxic stress response have an antagonistic relationship, and that CycD/Cdk4 levels regulate mitobiogenesis contemporaneous to the cell cycle, such that only when cells are sufficiently oxygenated can they proliferate. PMID:22293404

Icreverzi, Amalia; de la Cruz, Aida Flor; Van Voorhies, Wayne A; Edgar, Bruce A

2012-02-01

147

Mitochondrial Gene Therapy Improves Respiration, Biogenesis, and Transcription in G11778A Leber's Hereditary Optic Neuropathy and T8993G Leigh's Syndrome Cells  

PubMed Central

Abstract Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ?1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future.

Bergquist, Kristen; Young, Kisha; Gnaiger, Erich; Rao, Raj R.

2012-01-01

148

Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells.  

PubMed

Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ?1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future. PMID:22390282

Iyer, Shilpa; Bergquist, Kristen; Young, Kisha; Gnaiger, Erich; Rao, Raj R; Bennett, James P

2012-06-01

149

The disulfide relay system of mitochondria is required for the biogenesis of mitochondrial Ccs1 and Sod1.  

PubMed

Cells protect themselves against oxygen stress and reactive oxygen species. An important enzyme in this process is superoxide dismutase, Sod1, which converts superoxide radicals into water and hydrogen peroxide. The biogenesis of functional Sod1 is dependent on its copper chaperone, Ccs1, which introduces a disulfide bond and a copper ion into Sod1. Ccs1 and Sod1 are present in the cytosol but are also found in the mitochondrial intermembrane space (IMS), the compartment between the outer and the inner membrane of mitochondria. Ccs1 mediates mitochondrial localization of Sod1. Here, we report on the biogenesis of the fractions of Ccs1 and Sod1 present in mitochondria of Saccharomyces cerevisiae. The IMS of mitochondria harbors a disulfide relay system consisting of the import receptor Mia40 and the thiol oxidase Erv1, which drives the import of substrates with conserved cysteine residues arranged in typical twin Cx(3)C and twin Cx(9)C motifs. We show that depletion of Mia40 results in decreased levels of Ccs1 and Sod1. On the other hand, overexpression of Mia40 increased the mitochondrial fraction of both proteins. In addition, the import rates of Ccs1 were enhanced by increased levels of Mia40 and reduced upon depletion of Mia40. Mia40 forms mixed disulfides with Ccs1, suggesting a role of Mia40 for the generation of disulfide bonds in Ccs1. We suggest that the disulfide relay system transfers disulfide bonds via Mia40 to Ccs1, which then shuttles disulfide bonds to Sod1. In conclusion, the disulfide relay system is crucial for the import of Ccs1, thereby affecting the transport of Sod1, and it can control the distribution of Ccs1 and Sod1 between the IMS of mitochondria and the cytosol. PMID:19010334

Reddehase, Silvia; Grumbt, Barbara; Neupert, Walter; Hell, Kai

2009-01-16

150

Training-induced acceleration of O(2) uptake on-kinetics precedes muscle mitochondrial biogenesis in humans.  

PubMed

The effects of 5 weeks of moderate-intensity endurance training on pulmonary oxygen uptake kinetics (V(O(2)) on-kinetics) were studied in 15 healthy men (mean ± SD: age 22.7 ± 1.8 years, body weight 76.4 ± 8.9 kg and maximal V(O(2)) 46.0 ± 3.7 ml kg(-1) min(-1)). Training caused a significant acceleration (P = 0.003) of V(O(2)) on-kinetics during moderate-intensity cycling (time constant of the 'primary' component 30.0 ± 6.6 versus 22.8 ± 5.6 s before and after training, respectively) and a significant decrease (P = 0.04) in the amplitude of the primary component (837 ± 351 versus 801 ± 330 ml min(-1)). No changes in myosin heavy chain distribution, muscle fibre capillarization, level of peroxisome proliferator-activated receptor ? coactivator 1? and other markers of mitochondrial biogenesis (mitochondrial DNA copy number, cytochrome c and cytochrome oxidase subunit I contents) in the vastus lateralis were found after training. A significant downregulation in the content of the sarcoplasmic reticulum ATPase 2 (SERCA2; P = 0.03) and a tendency towards a decrease in SERCA1 (P = 0.055) was found after training. The decrease in SERCA1 was positively correlated (P = 0.05) with the training-induced decrease in the gain of the V(O(2)) on-kinetics (?V(O(2)) at steady state/?power output). In the early stage of training, the acceleration in V(O(2)) on-kinetics during moderate-intensity cycling can occur without enhanced mitochondrial biogenesis or changes in muscle myosin heavy chain distribution and in muscle fibre capillarization. The training-induced decrease of the O(2) cost of cycling could be caused by the downregulation of SERCA pumps. PMID:23204290

Zoladz, Jerzy A; Grassi, Bruno; Majerczak, Joanna; Szkutnik, Zbigniew; Korosty?ski, Micha?; Karasi?ski, Janusz; Kilarski, Wincenty; Korzeniewski, Bernard

2013-04-01

151

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

PubMed

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 ? coactivator-1?. 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-? coactivator-1?, 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

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

152

Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function  

Microsoft Academic Search

Mitochondrial localization of p53 has been observed in several cell systems, but an under- standing of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Con- structs were generated to express mitochondrial tar- geted enhanced green fluorescent

RONALD J. DONAHUE; MARJANEH RAZMARA; JAN B. HOEK; THOMAS B. KNUDSEN

2001-01-01

153

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

PubMed Central

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.

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

2013-01-01

154

Interferon-stimulated gene ISG12b1 inhibits adipogenic differentiation and mitochondrial biogenesis in 3T3-L1 cells.  

PubMed

Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-gamma (PPARgamma), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARgamma and PPARalpha agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated diseases. PMID:18948406

Li, Bing; Shin, Jonghyun; Lee, Kichoon

2009-03-01

155

Assessment of Newly Synthesized Mitochondrial DNA Using BrdU Labeling in Primary Neurons from Alzheimer's Disease Mice: Implications for Impaired Mitochondrial Biogenesis and Synaptic Damage  

PubMed Central

The purpose our study was to assess mitochondrial biogenesis and distribution in murine primary neurons. Using 5-bromo-2-deoxyuridie (BrdU) incorporation and primary neurons, we studied the mitochondrial biogenesis and mitochondrial distribution in hippocampal neurons from amyloid beta precursor protein (A?PP) transgenic mice and wild-type (WT) neurons treated with oxidative stressors, rotenone and H2O2. We found that after 20 hr of labeling, BrdU incorporation was specific to porin-positive mitochondria. The proportion of mitochondrial area that labeled with BrdU was 40.3 ± 6.3% at 20 hr. The number of mitochondria with newly synthesized DNA was higher in A?PP neuronal cell bodies than in the cell bodies of WT neurons (A?PP, 45.23 ± 2.67 BrdU-positive/cell body; WT, 32.92 ± 2.49 BrdU-positive/cell body; p = 0.005). In neurites, the number of BrdU-positive mitochondria decreased in A?PP cultures compared to WT neurons (A?PP, 0.105 ± 0.008 BrdU-positive/?m neurite; WT, 0.220 ± 0.036 BrdU-positive?/??m neurite; p = 0.010). Further, BrdU in the cell body increased when neurons were treated with low doses of H2O2 (49.6 ± 2.7 BrdU-positive/cell body, p = 0.0002 compared to untreated cells), while the neurites showed decreased BrdU staining (0.122 ± 0.010 BrdU-positive/?m neurite, p = 0.005 compared to the untreated). BrdU labeling was increased in the cell body under rotenone treatment. Additionally, under rotenone treatment, the content of BrdU labeling decreased in neurites. These findings suggest that A? and mitochondrial toxins enhance mitochondrial fragmentation in cell body, and may cause impaired axonal transport of mitochondria leading to synaptic degeneration.

Calkins, Marcus J.; Reddy, P. Hemachandra

2011-01-01

156

Exercise induced hypoglycaemic hyperinsulinism  

PubMed Central

BACKGROUND—Hyperinsulinism in childhood is often caused by genetic defects involving the regulation of insulin secretion leading to recurrent episodes of hypoglycaemia. We report two patients with exercise induced hypoglycaemia.?METHODS—Standardised short exercise tests with frequent blood glucose and plasma insulin measurements were performed in the patients and young healthy controls.?RESULTS—Short term exercise resulted in insulin induced hypoglycaemia 15 to 50 minutes after the end of exercise. A massive burst of insulin secretion was observed within a few minutes of the start of exercise in both patients. By contrast glucose and insulin concentrations remained unchanged in healthy controls.?CONCLUSIONS—Hyperinsulinaemic hypoglycaemia after moderate physical exercise represents a rarely described phenotype of hyperinsulinism with an as yet unknown defect in the regulation of insulin secretion. It should be suspected in individuals with recurrent exercise related syncope or disturbance of consciousness.??

Meissner, T; Otonkoski, T; Feneberg, R; Beinbrech, B; Apostolidou, S; Sipila, I; Schaefer, F; Mayatepek, E

2001-01-01

157

Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone.  

PubMed

The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator-activated receptor (PPAR) gamma agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet-fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/+ and standard-fat diet-fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1beta, PGC-1alpha, estrogen-related receptor alpha, and PPARalpha, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria. PMID:17456854

Rong, James X; Qiu, Yang; Hansen, Michael K; Zhu, Lei; Zhang, Vivian; Xie, Mi; Okamoto, Yuji; Mattie, Michael D; Higashiyama, Hiroyuki; Asano, Satoshi; Strum, Jay C; Ryan, Terence E

2007-07-01

158

An analogue of resveratrol HS-1793 exhibits anticancer activity against MCF-7 cells via inhibition of mitochondrial biogenesis gene expression.  

PubMed

Resveratrol is a phytoalexin and polyphenol derived from grapes, berries, and peanuts. It has been shown to mediate death of a wide variety of cancer cells. Although resveratrol is considered an important potential chemotherapeutic agent, it is required at high doses to achieve a biologically or physiologically significant effect, which may be impractical for treating cancer. Thus, a more stable and potent derivative of resveratrol, with more effective tumoricidal activity, must be developed. A novel resveratrol analog, HS-1793, has recently been synthesized and was determined to exhibit a greater decrease in cancer cell viability than resveratrol. However, the underlying mechanism of HS-1793-induced cancer cell death remains unknown. We thus investigated the mechanism by which HS-1793 induces cell death and assessed whether this occurs through a mitochondrial-mediated mechanism. Using the MCF-7 breast cancer cell line, we determined that HS-1793 treatment significantly increased cell death at a relatively low dose compared with resveratrol. HS-1793 treatment more significantly decreased mitochondrial membrane potential, cellular ATP concentration, and cellular oxygen consumption rate than resveratrol treatment. At the molecular level, HS-1793 treatment down-regulated the expression of major mitochondrial biogenesis-regulating proteins, including mitochondrial transcriptional factor A (TFAM), Tu translation elongation factor (TUFM), and single-stranded DNA-binding protein. We conclude that HS- 1793 acts by regulating the expression of TFAM and TUFM, leading to a block in normal mitochondrial function, which sensitizes cancer cells to cell death. We therefore propose that HS-1793 can be a useful chemosensitization agent, which together with other such agents can efficiently target cancer cells. PMID:23104437

Jeong, Seung Hun; Song, In Sung; Kim, Hyoung Kyu; Lee, Sung Ryul; Song, Suhee; Suh, Hongsuk; Yoon, Young Geol; Yoo, Young Hyun; Kim, Nari; Rhee, Byoung Doo; Ko, Kyung Soo; Han, Jin

2012-10-01

159

An Analogue of Resveratrol HS-1793 Exhibits Anticancer Activity Against MCF-7 Cells Via Inhibition of Mitochondrial Biogenesis Gene Expression  

PubMed Central

Resveratrol is a phytoalexin and polyphenol derived from grapes, berries, and peanuts. It has been shown to mediate death of a wide variety of cancer cells. Although resveratrol is considered an important potential chemotherapeutic agent, it is required at high doses to achieve a biologically or physiologically significant effect, which may be impractical for treating cancer. Thus, a more stable and potent derivative of resveratrol, with more effective tumoricidal activity, must be developed. A novel resveratrol analog, HS-1793, has recently been synthesized and was determined to exhibit a greater decrease in cancer cell viability than resveratrol. However, the underlying mechanism of HS-1793-induced cancer cell death remains unknown. We thus investigated the mechanism by which HS-1793 induces cell death and assessed whether this occurs through a mitochondrial-mediated mechanism. Using the MCF-7 breast cancer cell line, we determined that HS-1793 treatment significantly increased cell death at a relatively low dose compared with resveratrol. HS-1793 treatment more significantly decreased mitochondrial membrane potential, cellular ATP concentration, and cellular oxygen consumption rate than resveratrol treatment. At the molecular level, HS-1793 treatment down-regulated the expression of major mitochondrial biogenesis-regulating proteins, including mitochondrial transcriptional factor A (TFAM), Tu translation elongation factor (TUFM), and single-stranded DNA-binding protein. We conclude that HS-1793 acts by regulating the expression of TFAM and TUFM, leading to a block in normal mitochondrial function, which sensitizes cancer cells to cell death. We therefore propose that HS-1793 can be a useful chemosensitization agent, which together with other such agents can efficiently target cancer cells.

Jeong, Seung Hun; Song, In Sung; Kim, Hyoung Kyu; Lee, Sung Ryul; Song, Suhee; Suh, Hongsuk; Yoon, Young Geol; Yoo, Young Hyun; Kim, Nari; Rhee, Byoung Doo; Ko, Kyung Soo; Han, Jin

2012-01-01

160

Elevated PGC-1? Activity Sustains Mitochondrial Biogenesis and Muscle Function without Extending Survival in a Mouse Model of Inherited ALS  

PubMed Central

SUMMARY The transcriptional coactivator PGC-1? induces multiple effects on muscle, including increased mitochondrial mass and activity. Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, adult-onset neurodegenerative disorder characterized by selective loss of motor neurons and skeletal muscle degeneration. An early event is thought to be denervation-induced muscle atrophy accompanied by alterations in mitochondrial activity and morphology within muscle. We now report that elevation of PGC-1? levels in muscles of mice that develop fatal paralysis from an ALS-causing SOD1 mutant elevates PGC-1?-dependent pathways throughout disease course. Mitochondrial biogenesis and activity are maintained through end-stage disease, accompanied by retention of muscle function, delayed muscle atrophy, and significantly improved muscle endurance even at late disease stages. However, survival was not extended. Therefore, muscle is not a primary target of mutant SOD1-mediated toxicity, but drugs increasing PGC-1? activity in muscle represent an attractive therapy for maintaining muscle function during progression of ALS.

Da Cruz, Sandrine; Parone, Philippe A.; Lopes, Vanda S.; Lillo, Concepcion; McAlonis-Downes, Melissa; Lee, Sandra K.; Vetto, Anne P.; Petrosyan, Susanna; Marsala, Martin; Murphy, Anne N.; Williams, David S.; Spiegelman, Bruce M.; Cleveland, Don W.

2013-01-01

161

Rosiglitazone Induces Mitochondrial Biogenesis in Differentiated Murine 3T3-L1 and C3H/10T1/2 Adipocytes  

PubMed Central

Growing evidence indicates that PPAR? agonists, including rosiglitazone (RSG), induce adipose mitochondrial biogenesis. By systematically analyzing mitochondrial gene expression in two common murine adipocyte models, the current study aimed to further establish the direct role of RSG and capture temporal changes in gene transcription. Microarray profiling revealed that in fully differentiated 3T3-L1 and C3H/10T1/2 adipocytes treated with RSG or DMSO vehicle for 1, 2, 4, 7, 24, and 48?hrs, RSG overwhelmingly increased mitochondrial gene transcripts time dependently. The timing of the increases was consistent with the cascade of organelle biogenesis, that is, initiated by induction of transcription factor(s), followed by increases in the biosynthesis machinery, and then by increases in functional components. The transcriptional increases were further validated by increased mitochondrial staining, citrate synthase activity, and O2 consumption, and were found to be associated with increased adiponectin secretion. The work provided further insight on the mechanism of PPAR?-induced mitochondrial biogenesis in differentiated adipocytes.

Rong, James X.; Klein, Jean-Louis D.; Qiu, Yang; Xie, Mi; Johnson, Jennifer H.; Waters, K. Michelle; Zhang, Vivian; Kashatus, Jennifer A.; Remlinger, Katja S.; Bing, Nan; Crosby, Renae M.; Jackson, Tymissha K.; Witherspoon, Sam M.; Moore, John T.; Ryan, Terence E.; Neill, Sue D.; Strum, Jay C.

2011-01-01

162

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

PubMed

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-1?, 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

Saleem, Ayesha; Hood, David A

2013-07-15

163

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

PubMed Central

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 ?,?-carotene 9’,10’-oxygenase 2, and induced activation and nuclear enrichment of retinal AMP-activated protein kinase ?2 (AMPK?2). Furthermore, wolfberry attenuated hypoxia and mitochondrial stress as demonstrated by declined expression of hypoxia-inducible factor-1?, 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 ? co-activator 1 ?, 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.

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

164

Insulin therapy modulates mitochondrial dynamics and biogenesis, autophagy and tau protein phosphorylation in the brain of type 1 diabetic rats.  

PubMed

The main purpose of this study was to examine whether streptozotocin (STZ)-induced type 1 diabetes (T1D) and insulin (INS) treatment affect mitochondrial function, fission/fusion and biogenesis, autophagy and tau protein phosphorylation in cerebral cortex from diabetic rats treated or not with INS. No significant alterations were observed in mitochondrial function as well as pyruvate levels, despite the significant increase in glucose levels observed in INS-treated diabetic rats. A significant increase in DRP1 protein phosphorylated at Ser616 residue was observed in the brain cortex of STZ rats. Also an increase in NRF2 protein levels and in the number of copies of mtDNA were observed in STZ diabetic rats, these alterations being normalized by INS. A slight decrease in LC3-II levels was observed in INS-treated rats when compared to STZ diabetic animals. An increase in tau protein phosphorylation at Ser396 residue was observed in STZ diabetic rats while INS treatment partially reversed that effect. Accordingly, a modest reduction in the activation of GSK3? and a significant increase in the activity of phosphatase 2A were found in INS-treated rats when compared to STZ diabetic animals. No significant alterations were observed in caspases 9 and 3 activity and synaptophysin and PSD95 levels. Altogether our results show that mitochondrial alterations induced by T1D seem to involve compensation mechanisms since no significant changes in mitochondrial function and synaptic integrity were observed in diabetic animals. In addition, INS treatment is able to normalize the alterations induced by T1D supporting the importance of INS signaling in the brain. PMID:24747740

Santos, R X; Correia, S C; Alves, M G; Oliveira, P F; Cardoso, S; Carvalho, C; Duarte, A I; Santos, M S; Moreira, P I

2014-07-01

165

Exercise-Induced Asthma  

Microsoft Academic Search

\\u000a \\u000a Key Points  \\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a Exercise-induced asthma (EIA) occurs in 90% of individuals with asthma.\\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a The prevalence of EIA among athletes ranges between 3 and 11%.\\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a EIA is characterized by transient airway obstruction occurring after strenuous exertion.\\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a Pathophysiological mechanisms that could possibly explain the phenomenon of EIA include respiratory, heat or water loss (or\\u000a both), hyperventilation leading to the

Rahmat Afrasiabi

166

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

PubMed

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

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

2014-08-01

167

Sciadopitysin alleviates methylglyoxal-mediated glycation in osteoblastic MC3T3-E1 cells by enhancing glyoxalase system and mitochondrial biogenesis.  

PubMed

Methylglyoxal (MG) is a precursor of advanced glycation end products, which contribute to diabetic complications, including bone defects. In the present study, the effect of sciadopitysin on MG-induced cytotoxicity was investigated using osteoblastic MC3T3-E1 cells. Pretreatment of MC3T3-E1 cells with sciadopitysin prevented the MG-induced cell death and protein adducts formation. Sciadopitysin restored the MG-induced change in glyoxalase activity almost to the control level and increased glutathione levels. In addition, sciadopitysin decreased MG-induced formation of intracellular reactive oxygen species (ROS), mitochondrial superoxide, and cardiolipin peroxidation. These findings suggest that sciadopitysin provides a protective action against MG-induced glycation by increasing MG detoxification system and by reducing oxidative stress. Pretreatment with sciadopitysin prior to MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential (MMP) dissipation and adenosine triphosphate (ATP) loss. The nitric oxide (NO) level was decreased by MG treatment, but it was significantly increased by sciadopitysin, suggesting that sciadopitysin may induce NO-dependent mitochondrial biogenesis. Furthermore, sciadopitysin treatment increased the levels of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1?), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM). These findings indicate that sciadopitysin might exert its therapeutic effects via upregulation of mitochondrial biogenesis. Therefore, sciadopitysin may prevent the development of diabetic osteopathy. PMID:24628445

Choi, E M; Suh, K S; Rhee, S Y; Kim, Y S

2014-07-01

168

Biogenesis of mitochondria: the mitochondrial gene (aap1) coding for mitochondrial ATPase subunit 8 in Saccharomyces cerevisiae.  

PubMed Central

A mitochondrial gene (denoted aap1) in Saccharomyces cerevisiae has been characterized by nucleotide sequence analysis of a region of mtDNA between the oxi3 and oli2 genes. The reading frame of the aap1 gene specifies a hydrophobic polypeptide containing 48 amino acids. The functional nature of this reading frame was established by sequence analysis of a series of mit- mutants and revertants. Evidence is presented that the aap1 gene codes for a mitochondrially synthesized polypeptide associated with the mitochondrial ATPase complex. This polypeptide (denoted subunit 8) is a proteolipid whose size has been previously assumed to be 10 kilodaltons based on its mobility on SDS-polyacrylamide gels, but the sequence of the aap1 gene predicts a molecular weight of 5,815 for this protein.

Macreadie, I G; Novitski, C E; Maxwell, R J; John, U; Ooi, B G; McMullen, G L; Lukins, H B; Linnane, A W; Nagley, P

1983-01-01

169

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

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.

Tiranti, V.; Rossi, G.; DiDonato, S. [Istituto Nazionale Neurologico, Carlo Besta (Italy)] [and others] [Istituto Nazionale Neurologico, Carlo Besta (Italy); and others

1995-01-20

170

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

PubMed Central

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.

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

2012-01-01

171

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

PubMed

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). [(18)F]-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. PMID:22362892

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

2012-06-01

172

Estradiol Stimulates Transcription of Nuclear Respiratory Factor1 and Increases Mitochondrial Biogenesis  

Microsoft Academic Search

Estrogen has direct and indirect effects on mito- chondrial activity, but the mechanisms mediating these effects remain unclear. Others reported that long-term estradiol (E2) treatment increased nu- clear respiratory factor-1 (NRF-1) protein in cere- bral blood vessels of ovariectomized rats. NRF-1 is a transcription factor that regulates the expression of nuclear-encoded mitochondrial genes, e.g. mi- tochondrial transcription factor A (TFAM),

Kathleen A. Mattingly; Margarita M. Ivanova; Krista A. Riggs; Nalinie S. Wickramasinghe; Margaret J. Barch; Carolyn M. Klinge

2007-01-01

173

The transcriptional cascade associated with creatine kinase down-regulation and mitochondrial biogenesis in mice sarcoma  

Microsoft Academic Search

The tissue-specific expressions of creatine kinase (CK) isoforms are regulated by the coordinated action of various transcription\\u000a factors. The myogenic differentiation factor D (MyoD) family of proteins and the myocyte-specific enhancer binding factor\\u000a 2 family of transcription factors are important in regulating the muscle-specific expression of cytosolic muscle-type CK (MCK)\\u000a and mitochondrial CKs. As reported in some related studies, TNF-?

Soumen Bera; Manju Ray

2009-01-01

174

Sam50 functions in mitochondrial intermembrane space bridging and biogenesis of respiratory complexes.  

PubMed

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 ?-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

Ott, Christine; Ross, Katharina; Straub, Sebastian; Thiede, Bernd; Götz, Monika; Goosmann, Christian; Krischke, Markus; Mueller, Martin J; Krohne, Georg; Rudel, Thomas; Kozjak-Pavlovic, Vera

2012-03-01

175

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

PubMed Central

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 ?-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).

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

2012-01-01

176

Adolescents and Exercise Induced Asthma  

ERIC Educational Resources Information Center

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.)

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

2008-01-01

177

Mitochondrial biogenesis during fungal spore germination: effects of the antilipogenic antibiotic cerulenin upon Botryodiplodia spores.  

PubMed Central

Germination of spores of the fungus Botryodiplodia theobromae was inhibited by the antilipogenic antibiotic cerulenin. The spores remained viable in the presence of the antibiotic, however, and after prolonged incubation they were able to overcome the inhibition. Cerulenin inhibition of germination was reversed by Tween 40 and Tween 60 (derivatives of palmitate and stearate, respectively), but not by representatives of a range of free fatty acids or their soaps. Cerulenin abolished incorporation of [14C]acetate into sterols and triglycerides and reduced its incorporation into fatty acids by 69%. Cyanide-sensitive oxygen consumption by spores incubated in the presence of cerulenin was greatly reduced throughout germination, and the activity of cytochrome c oxidase was no more than 13% of the activity in untreated spores, even after prolonged incubation. However, low-temperature difference spectra of mitochondrial extracts showed that the cerulenin-treated spores accumulated a threefold excess of cytochrome a, whereas the cellular concentrations of cytochroms c and b were identical to those of untreated spores. Cerulenin treatment sharply reduced the rates of whole spore protein and RNA synthesis. Cerulenin had no effects upon mitochondrial morphology which could be discerned with an electron microscope.

Brambl, R; Wenzler, H; Josephson, M

1978-01-01

178

The Impact of Aging on Mitochondrial Function and Biogenesis Pathways in Skeletal Muscle of Sedentary High- and Low-Functioning Elderly Individuals  

PubMed Central

Summary Age-related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high- and low-functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low-functioning elderly (LFE) participants when compared to young and high-functioning elderly (HFE) participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in COX activity. Levels of key metabolic regulators, SIRT3 and PGC-1? were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects, however no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery (PIM) components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways, and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.

Joseph, Anna-Maria; Adhihetty, Peter J.; Buford, Thomas W.; Wohlgemuth, Stephanie E.; Lees, Hazel A.; Nguyen, Linda M.-D.; Aranda, Juan M.; Sandesara, Bhanu D.; Pahor, Marco; Manini, Todd M.; Marzetti, Emanuele; Leeuwenburgh, Christiaan

2012-01-01

179

Maturation of the unusual single-cysteine (XXXCH) mitochondrial c-type cytochromes found in trypanosomatids must occur through a novel biogenesis pathway  

PubMed Central

The c-type cytochromes are characterized by the covalent attachment of haem to the polypeptide via thioether bonds formed from haem vinyl groups and, normally, the thiols of two cysteines in a CXXCH motif. Intriguingly, the mitochondrial cytochromes c and c1 from two euglenids and the Trypanosomatidae contain only a single cysteine within the haem-binding motif (XXXCH). There are three known distinct pathways by which c-type cytochromes are matured post-translationally in different organisms. The absence of genes encoding any of these c-type cytochrome biogenesis machineries is established here by analysis of six trypanosomatid genomes, and correlates with the presence of single-cysteine cytochromes c and c1. In contrast, we have identified a comprehensive catalogue of proteins required for a typical mitochondrial oxidative phosphorylation apparatus. Neither spontaneous nor catalysed maturation of the single-cysteine Trypanosoma brucei cytochrome c occurred in Escherichia coli. However, a CXXCH variant was matured by the E. coli cytochrome c maturation machinery, confirming the proposed requirement of the latter for two cysteines in the haem-binding motif and indicating that T. brucei cytochrome c can accommodate a second cysteine in a CXXCH motif. The single-cysteine haem attachment conserved in cytochromes c and c1 of the trypanosomatids is suggested to be related to their cytochrome c maturation machinery, and the environment in the mitochondrial intermembrane space. Our genomic and biochemical studies provide very persuasive evidence that the trypanosomatid mitochondrial cytochromes c are matured by a novel biogenesis system.

Allen, James W. A.; Ginger, Michael L.; Ferguson, Stuart J.

2004-01-01

180

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

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.

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

2014-01-01

181

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

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.

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

182

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

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.

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

2012-01-01

183

Activation of the Human Mitochondrial Transcription Factor A Gene by Nuclear Respiratory Factors: A Potential Regulatory Link Between Nuclear and Mitochondrial Gene Expression in Organelle Biogenesis  

Microsoft Academic Search

Mitochondrial transcription factor A (mtTFA), the product of a nuclear gene, stimulates transcription from the two divergent mitochondrial promoters and is likely the principal activator of mitochondrial gene expression in vertebrates. Here we establish that the proximal promoter of the human mtTFA gene is highly dependent upon recognition sites for the nuclear respiratory factors, NRF-1 and NRF-2, for activity. These

Joseph V. Virbasius; Richard C. Scarpulla

1994-01-01

184

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

PubMed

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

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

2012-01-15

185

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

PubMed Central

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.

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

2012-01-01

186

Exercise-induced Pulmonary Hypertension  

PubMed Central

Exercise stresses the pulmonary circulation through increases in cardiac output (Q.) and left atrial pressure. Invasive as well as noninvasive studies in healthy volunteers show that the slope of mean pulmonary artery pressure (mPAP)–flow relationships ranges from 0.5 to 3 mm Hg?min?L?1. The upper limit of normal mPAP at exercise thus approximates 30 mm Hg at a Q. of less than 10 L?min?1 or a total pulmonary vascular resistance at exercise of less than 3 Wood units. Left atrial pressure increases at exercise with an average upstream transmission to PAP in a close to one-for-one mm Hg fashion. Multipoint PAP–flow relationships are usually described by a linear approximation, but present with a slight curvilinearity, which is explained by resistive vessel distensibility. When mPAP is expressed as a function of oxygen uptake or workload, plateau patterns may be observed in patients with systolic heart failure who cannot further increase Q. at the highest levels of exercise. Exercise has to be dynamic to avoid the increase in systemic vascular resistance and abrupt changes in intrathoracic pressure that occur with resistive exercise and can lead to unpredictable effects on the pulmonary circulation. Postexercise measurements are unreliable because of the rapid return of pulmonary vascular pressures and flows to the baseline resting state. Recent studies suggest that exercise-induced increase in PAP to a mean higher than 30 mm Hg may be associated with dyspnea-fatigue symptomatology.

Vanderpool, Rebecca; Dhakal, Bishnu P.; Saggar, Rajeev; Saggar, Rajan; Vachiery, Jean-Luc; Lewis, Gregory D.

2013-01-01

187

Posttranslational modification of mitochondrial transcription factor A in impaired mitochondria biogenesis: implications in diabetic retinopathy and metabolic memory phenomenon.  

PubMed

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 assessed, 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

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

2014-04-01

188

Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease  

PubMed Central

Increasing evidence suggests that the accumulation of amyloid beta (A?) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of A? in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized A? precursor protein transgenic (A?PP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of A?-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric A?. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from A?PP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in A?PP primary neurons. We also found an increased accumulation of oligomeric A? and increased apoptotic neuronal death in the primary neurons from the A?PP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric A?, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in A?PP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from A? toxicity.

Calkins, Marcus J.; Manczak, Maria; Mao, Peizhong; Shirendeb, Ulziibat; Reddy, P. Hemachandra

2011-01-01

189

Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease.  

PubMed

Increasing evidence suggests that the accumulation of amyloid beta (A?) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of A? in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized A? precursor protein transgenic (A?PP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of A?-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric A?. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from A?PP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in A?PP primary neurons. We also found an increased accumulation of oligomeric A? and increased apoptotic neuronal death in the primary neurons from the A?PP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric A?, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in A?PP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from A? toxicity. PMID:21873260

Calkins, Marcus J; Manczak, Maria; Mao, Peizhong; Shirendeb, Ulziibat; Reddy, P Hemachandra

2011-12-01

190

Chitooligosaccharide Induces Mitochondrial Biogenesis and Increases Exercise Endurance through the Activation of Sirt1 and AMPK in Rats  

Microsoft Academic Search

By catabolizing glucose and lipids, mitochondria produce ATPs to meet energy demands. When the number and activity of mitochondria are not sufficient, the human body becomes easily fatigued due to the lack of ATP, thus the control of the quantity and function of mitochondria is important to optimize energy balance. By increasing mitochondrial capacity? it may be possible to enhance

Hyun Woo Jeong; Si Young Cho; Shinae Kim; Eui Seok Shin; Jae Man Kim; Min Jeong Song; Pil Joon Park; Jong Hee Sohn; Hyon Park; Dae-Bang Seo; Wan Gi Kim; Sang-Jun Lee

2012-01-01

191

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

PubMed

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-? 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-?-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-? 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

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

2012-02-01

192

Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis.  

PubMed

The nuclear respiratory factor-1 (NRF1) gene is activated by lipopolysaccharide (LPS), which might reflect TLR4-mediated mitigation of cellular inflammatory damage via initiation of mitochondrial biogenesis. To test this hypothesis, we examined NRF1 promoter regulation by NF?B, and identified interspecies-conserved ?B-responsive promoter and intronic elements in the NRF1 locus. In mice, activation of Nrf1 and its downstream target, Tfam, by Escherichia coli was contingent on NF?B, and in LPS-treated hepatocytes, NF?B served as an NRF1 enhancer element in conjunction with NF?B promoter binding. Unexpectedly, optimal NRF1 promoter activity after LPS also required binding by the energy-state-dependent transcription factor CREB. EMSA and ChIP assays confirmed p65 and CREB binding to the NRF1 promoter and p65 binding to intron 1. Functionality for both transcription factors was validated by gene-knockdown studies. LPS regulation of NRF1 led to mtDNA-encoded gene expression and expansion of mtDNA copy number. In cells expressing plasmid constructs containing the NRF-1 promoter and GFP, LPS-dependent reporter activity was abolished by cis-acting ?B-element mutations, and nuclear accumulation of NF?B and CREB demonstrated dependence on mitochondrial H(2)O(2). These findings indicate that TLR4-dependent NF?B and CREB activation co-regulate the NRF1 promoter with NF?B intronic enhancement and redox-regulated nuclear translocation, leading to downstream target-gene expression, and identify NRF-1 as an early-phase component of the host antibacterial defenses. PMID:20587593

Suliman, Hagir B; Sweeney, Timothy E; Withers, Crystal M; Piantadosi, Claude A

2010-08-01

193

Acetyl-L-carnitine activates the peroxisome proliferator-activated receptor-? coactivators PGC-1?/PGC-1?-dependent signaling cascade of mitochondrial biogenesis and decreases the oxidized peroxiredoxins content in old rat liver.  

PubMed

The behavior of the peroxisome proliferator-activated receptor-? coactivators PGC-1?/PGC-?-dependent mitochondrial biogenesis signaling pathway, as well as the level of some antioxidant enzymes and proteins involved in mitochondrial dynamics in the liver of old rats before and after 2 months of acetyl-L-carnitine (ALCAR) supplementation, was tested. The results reveal that ALCAR treatment is able to reverse the age-associated decline of PGC-1?, PGC-1?, nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 1 (ND1), and cytochrome c oxidase subunit IV (COX IV) protein levels, of mitochondrial DNA (mtDNA) content, and of citrate synthase activity. Moreover, it partially reverses the mitochondrial superoxide dismutase 2 (SOD2) decline and reduces the cellular content of oxidized peroxiredoxins. These data demonstrate that ALCAR treatment is able to promote in the old rat liver a new mitochondrial population that can contribute to the cellular oxidative stress reduction. Furthermore, a remarkable decline of Drp1 and of Mfn2 proteins is reported here for the first time, suggesting a reduced mitochondrial dynamics in aging liver with no effect of ALCAR treatment. PMID:22533417

Pesce, Vito; Nicassio, Luigi; Fracasso, Flavio; Musicco, Clara; Cantatore, Palmiro; Gadaleta, Maria Nicola

2012-04-01

194

Increased 8-hydroxy-2'-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1, anti-oxidant enzymes, mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus.  

PubMed

We measured plasma levels of the oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) and leucocyte mRNA expression levels of the genes encoding the 8-OHdG repair enzyme human 8-oxoguanine DNA glycosylase 1 (hOGG1), the anti-oxidant enzymes copper/zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase-1 (GPx-1), GPx-4, glutathione reductase (GR) and glutathione synthetase (GS), the mitochondrial biogenesis-related proteins mtDNA-encoded ND 1 polypeptide (ND1), ND6, ATPase 6, mitochondrial transcription factor A (Tfam), nuclear respiratory factor 1(NRF-1), pyruvate dehydrogenase E1 component alpha subunit (PDHA1), pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1) and hypoxia inducible factor-1? (HIF-1?) and the glycolytic enzymes hexokinase-II (HK-II), glucose 6-phosphate isomerase (GPI), phosphofructokinase (PFK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase A (LDHa). We analysed their relevance to oxidative damage in 85 systemic lupus erythematosus (SLE) patients, four complicated SLE patients undergoing rituximab treatment and 45 healthy individuals. SLE patients had higher plasma 8-OHdG levels (P?mitochondrial biogenesis-related proteins (P?mitochondrial biogenesis-related proteins (P?mitochondrial biogenesis and glucose metabolism may be implicated in SLE deterioration, and this impairment might be improved by targeted biological therapy. PMID:24345202

Lee, H-T; Lin, C-S; Lee, C-S; Tsai, C-Y; Wei, Y-H

2014-04-01

195

Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1?  

PubMed Central

Previous investigations show that intracerebroventricular administration of a potent inhibitor of fatty acid synthase, C75, increases the level of its substrate, malonyl-CoA, in the hypothalamus. The “malonyl-CoA signal” is rapidly transmitted to skeletal muscle by the sympathetic nervous system, increasing fatty acid oxidation, uncoupling protein-3 (UCP3) expression, and thus, energy expenditure. Here, we show that intracerebroventricular or intraperitoneal administration of C75 increases the number of mitochondria in white and red (soleus) skeletal muscle. Consistent with signal transmission from the hypothalamus by the sympathetic nervous system, centrally administered C75 rapidly (?2 h) up-regulated the expression (in skeletal muscle) of the ?-adrenergic signaling molecules, i.e., norepinephrine, ?3-adrenergic receptor, and cAMP; the transcriptional regulators peroxisomal proliferator activator regulator ? coactivator 1? (PGC-1?) and estrogen receptor-related receptor ? (ERR?); and the expression of key oxidative mitochondrial enzymes, including pyruvate dehydrogenase kinase, medium-chain length fatty acyl-CoA dehydrogenase, ubiquinone–cytochrome c reductase, cytochrome oxidase, as well as ATP synthase and UCP3. The role of PGC-1? in mediating these responses in muscle was assessed with C2C12 myocytes in cell culture. Consistent with the in vivo response, adenovirus-directed expression of PGC-1? in C2C12 muscle cells provoked the phosphorylation/inactivation and reduced expression of acetyl-CoA carboxylase 2, causing a reduction of the malonyl-CoA concentration. These effects, coupled with an increased carnitine palmitoyltransferase 1b, led to increased fatty acid oxidation. PGC-1? also increased the expression of ERR?, PPAR?, and enzymes that support mitochondrial fatty acid oxidation, ATP synthesis, and thermogenesis, apparently mediated by an increased expression of UCP3.

Cha, Seung-Hun; Rodgers, Joseph T.; Puigserver, Pere; Chohnan, Shigeru; Lane, M. Daniel

2006-01-01

196

Biogenesis of mitochondria: DNA sequence analysis of mit- mutations in the mitochondrial oli2 gene coding for mitochondrial ATPase subunit 6 in Saccharomyces cerevisiae.  

PubMed Central

A series of yeast mitochondrial mit- mutants with defects in the oli2 gene, coding for subunit 6 of the mitochondrial ATPase complex, has been analyzed at the DNA sequence level. Fifteen of sixteen primary mit- mutants were shown to contain frameshift or nonsense mutations predicting truncated subunit 6 polypeptides, in various strains ranging from about 20% to 95% of the wild-type length of 259 amino acids. In only one strain could the defect in subunit 6 function be assigned to amino acid substitution in an otherwise full-length subunit 6. Many mutants carried multiple base substitutions or insertions/deletions, presumably arising from the manganese chloride mutagenesis treatment. Revertants from three of the mit- mutants were analyzed: all contained full-length subunit 6 proteins with one or more amino acid substitutions. The preponderance of truncated proteins as opposed to substituted full-length proteins in oli2 mit- mutants is suggested to reflect the ability of subunit 6 to accommodate amino acid substitutions at many locations, with little or no change in its functional properties in the membrane FO-sector of the ATPase complex.

John, U P; Willson, T A; Linnane, A W; Nagley, P

1986-01-01

197

Aspirin may promote mitochondrial biogenesis via the production of hydrogen peroxide and the induction of Sirtuin1/PGC-1? genes  

PubMed Central

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-1? (PGC-1?), 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-1? profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases.

Kamble, Pratibha; Selvarajan, Krithika; Narasimhulu, Chandrakala Aluganti; Nandave, Mukesh; Parthasarathy, Sampath

2013-01-01

198

Aspirin may promote mitochondrial biogenesis via the production of hydrogen peroxide and the induction of Sirtuin1/PGC-1? genes.  

PubMed

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 (H(2)O(2)), 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-1? (PGC-1?), 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 H(2)O(2), 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 O(2)(-.) and H(2)O(2). As Sirt1 and PGC-1? profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases. PMID:23228932

Kamble, Pratibha; Selvarajan, Krithika; Aluganti Narasimhulu, Chandrakala; Nandave, Mukesh; Parthasarathy, Sampath

2013-01-15

199

Acrosome biogenesis  

PubMed Central

The acrosome is a unique membranous organelle located over the anterior part of the sperm nucleus that is highly conserved throughout evolution. This acidic vacuole contains a number of hydrolytic enzymes that, when secreted, help the sperm penetrate the egg's coats. Although acrosome biogenesis is an important aspect of spermiogenesis, the molecular mechanism(s) that regulates this event remains unknown. Active trafficking from the Golgi apparatus is involved in acrosome formation, but experimental evidence indicates that trafficking of vesicles out of the Golgi also occurs during acrosomogenesis. Unfortunately, this second aspect of acrosome biogenesis remains poorly studied. In this article, we briefly discuss how the biosynthetic and endocytic pathways, assisted by a network of microtubules, tethering factors, motor proteins and small GTPases, relate and connect to give rise to the sperm-specific vacuole, with a particular emphasis placed on the endosomal compartment. It is hoped that this information will be useful to engage more studies on acrosome biogenesis by focusing attention towards suggested directions.

Paiardi, Chiara

2011-01-01

200

Expression of mitochondrial genes and of the transcription factors involved in the biogenesis of mitochondria Tfam, NRF-1 and NRF-2, in rat liver, testis and brain  

Microsoft Academic Search

Mitochondrial function requires genes encoded in both mitochondrial and nuclear genomes. Tfam, the activator of mammalian mitochondrial transcription, is encoded in the nucleus and its expression has been shown in in vitro studies to be controlled by nuclear respiratory factors NRF-1 and NRF-2. In order to understand the physiological dependence of mitochondrial gene expression, we have analyzed in rat liver,

Héctor Escrivá; Angeles Rodríguez-Peña; Carmen G. Vallejo

1999-01-01

201

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

PubMed

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

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

2014-05-01

202

Imitators of exercise-induced bronchoconstriction  

PubMed Central

Exercise-induced bronchoconstriction (EIB) is described by transient narrowing of the airways after exercise. It occurs in approximately 10% of the general population, while athletes may show a higher prevalence, especially in cold weather and ice rink athletes. Diagnosis of EIB is often made on the basis of self-reported symptoms without objective lung function tests, however, the presence of EIB can not be accurately determined on the basis of symptoms and may be under-, over-, or misdiagnosed. The goal of this review is to describe other clinical entities that mimic asthma or EIB symptoms and can be confused with EIB.

2009-01-01

203

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

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

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

2013-10-25

204

Exercise-induced asthma: nutritional management.  

PubMed

Exercise-induced asthma (EIA) refers to the transient narrowing of the airways following strenuous exercise in asthmatic and otherwise healthy individuals. Despite the heterogeneous treatment options for patients with EIA, there remains a substantial burden of unaddressed disease, even with optimal treatment. Epidemiological studies indicate that patients frequently resort to complementary and alternative therapies while being treated for asthma and other chronic health conditions. There is now convincing evidence that many dietary factors such as increased omega-3 polyunsaturated fatty acids, antioxidant intake and caffeine, and a sodium-restricted diet can reduce the severity of EIA. It is important that these dietary therapies be safe, effective, and likely to be used by individuals with EIA. This review will critically examine whether dietary modification represents a beneficial intervention for asthmatic individuals with EIA. PMID:23531894

Mickleborough, Timothy D; Head, Sally K; Lindley, Martin R

2011-07-01

205

Montelukast sodium for exercise-induced asthma.  

PubMed

Exercise is the most common trigger of bronchospasm in children with asthma. Exercise-induced bronchoconstriction (EIB) occurs in up to 90% of individuals with asthma who are not under antiinflammatory treatment and in about 40% of those with allergic rhinitis. EIB may be an overwhelming problem in childhood and adolescence, when physical activity is a prominent component of daily life. The importance for those with asthma to maintain regular physical activity is recognized by asthma guidelines, which include the recommendation of full participation in sporting activities in their goals for the management of asthma. Cysteinyl leukotrienes, which are derivatives of the 5-lipoxygenase pathway of arachidonic acid metabolism, are important mediators of airway allergic inflammation and have a role in the pathogenetic mechanism of EIB. Montelukast sodium (Singulair, Merck & Co.) is a selective and orally active leukotriene receptor antagonist with demonstrated activity for treating asthma and allergic rhinitis. The effect of this drug in the prevention of EIB has been evaluated in a variety of studies in adults as well as in children. Both single-dose and regular-treatment studies showed that montelukast provides effective protection against EIB. Furthermore, chronic treatment with montelukast does not induce tolerance to the bronchoprotective effect over time. This aspect is particularly relevant for children, who tend to be active at frequent and irregular intervals throughout the day, and who therefore may benefit from around-the-clock pharmacologic protection. PMID:19180262

de Benedictis, Fernando Maria; Vaccher, Silvia; de Benedictis, Diletta

2008-11-01

206

Schizosaccharomyces pombe homologs of the Saccharomyces cerevisiae mitochondrial proteins Cbp6 and Mss51 function at a post-translational step of respiratory complex biogenesis  

PubMed Central

Complexes III and IV of the mitochondrial respiratory chain contain a few key subunits encoded by the mitochondrial genome. In Saccharomyces cerevisiae, fifteen mRNA-specific translational activators control mitochondrial translation, of which five are conserved in Schizosaccharomyces pombe. These include homologs of Cbp3, Cbp6 and Mss51 that participate in translation and the post-translational steps leading to the assembly of respiratory complexes III and IV. In this study we show that in contrast to budding yeast, Cbp3, Cbp6 and Mss51 from S. pombe are not required for the translation of mitochondrial mRNAs, but fulfill post-translational functions, thus probably accounting for their conservation.

Kuhl, Inge; Fox, Thomas D.; Bonnefoy, Nathalie

2012-01-01

207

Bone Stress Injuries Causing Exercise-Induced Knee Pain  

Microsoft Academic Search

Background:No comprehensive studies of bone stress injuries in the knee based on magnetic resonance imaging findings have been published.Purpose:Assess the incidence, location, nature, and patterns of bone stress injuries in the knee in military conscripts with exercise-induced knee pain.Study Design:Case series; Level of evidence, 4.Methods:During a period of 70 months, 1330 patients with exercise-induced knee pain underwent magnetic resonance imaging

Maria H. Niva; Martti J. Kiuru; Riina Haataja; Harri K. Pihlajamäki

2006-01-01

208

Seasonal Factors Influencing Exercise-Induced Asthma  

PubMed Central

Purpose Exercise-induced bronchoconstriction (EIB) in patients with asthma occurs more frequently in winter than in summer. The concentration of house dust mite (HDM) allergens in beds also shows seasonal variation. This study examined the relationship between seasonal differences in the prevalence of EIB and sensitization to HDMs in patients with asthma. Methods The medical records of 74 young adult male patients with asthma-like symptoms who underwent bronchial challenge with methacholine, 4.5% saline and exercise, and allergen skin prick tests, were reviewed. The subjects were divided into summer (n=27), spring/fall (n=26) and winter (n=21) groups according to the season during which they underwent testing. Results The positive responses to exercise differed according to season (48.1% in summer, 73.1% in spring/fall, and 90.5% in winter; P<0.01). In addition, the prevalence of positive responses to HDM (70.4%, 88.5%, and 95.2%, respectively; P<0.05) and pollen skin tests (37.0%, 19.2%, and 0%, respectively; P<0.01) also showed significant seasonal differences. Severe responses to 4.5% saline showed a similar trend, although it was not statistically significant (44.4%, 50.0%, and 71.4%, respectively; P=0.07). Skin test reactivity to HDMs was significantly related to maximal fall in forced expiratory volume in one second (FEV1) following exercise (r=0.302, P<0.01) and the index of airway hyperresponsiveness (AHR) to 4.5% saline (r=-0.232, P<0.05), but not methacholine (r=-0.125, P>0.05). Conclusions Positive skin test reactions to HDMs and EIB occurred in winter, spring/fall, and summer in decreasing order of frequency. Seasonal variation in the prevalence of EIB may be related to seasonal variation in sensitization to HDMs, accompanied by differences in indirect, but not direct, AHR.

Ki, Won-Joo; Kim, Tae-Ock; Han, Eui-Ryoung; Seo, Il-Kook

2012-01-01

209

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

PubMed

? 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

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

2013-09-15

210

Human mitochondrial ferritin improves respiratory function in yeast mutants deficient in iron-sulfur cluster biogenesis, but is not a functional homologue of yeast frataxin  

PubMed Central

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 Mössbauer 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.

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

211

Resveratrol attenuates exercise-induced adaptive responses in rats selectively bred for low running performance.  

PubMed

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

Hart, Nikolett; Sarga, Linda; Csende, Zsolt; Koch, Lauren G; Britton, Steven L; Davies, Kelvin J A; Radak, Zsolt

2014-01-01

212

Resveratrol Attenuates Exercise-Induced Adaptive Responses in Rats Selectively Bred for Low Running Performance  

PubMed Central

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.

Hart, Nikolett; Sarga, Linda; Csende, Zsolt; Koch, Lauren G.; Britton, Steven L.; Davies, Kelvin J.A.; Radak, Zsolt

2014-01-01

213

Surgical management of a patient with exercise-induced esotropia.  

PubMed

Exercise-induced esotropia is a rare form of strabismus characterized by paroxysms of esotropia and diplopia only during exercise. This report describes a 15-year-old boy who presented with a 1-year history of exercise-induced esotropia. He has been asymptomatic after recession of a single medial rectus muscle. It is hypothesized that the esotropia was attributable to a malfunction in the muscle tension-control circuit and that altering the small signal gain with surgery resulted in improvement. PMID:23158550

Abrams, Michael S

2012-12-01

214

Exercise-induced orgasm and pleasure among women  

Microsoft Academic Search

Orgasm is typically considered to be a sexual experience. However, orgasms occurring during physical exercise have been occasionally documented. The primary objective of the current study was to understand more about women's experience with exercise-induced orgasm (EIO) including the types of exercise that women have noted have led to EIO and associations with self-reported sexual experiences. A secondary purpose was

Debby Herbenick; J. Dennis Fortenberry

2011-01-01

215

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...

216

Hyperthermia increases exercise-induced oxidative stress.  

PubMed

The purpose of this investigation was to examine oxidative markers after exercise in a hyperthermic environment (35 degrees C, 70 % RH) (Hot) versus a neutral environment (25 degrees C, 40 % RH) (Con). Hyperthermia may exacerbate oxidative stress by uncoupling the mitochondrial respiratory chain or by inhibiting antioxidant defense mechanisms, but this has not been assessed in vivo. Six male subjects performed low-intensity exercise (50 % VO(2max)) on a treadmill in Hot until a core temperature of 39.5 degrees C was reached, and for an equivalent time in Con. Blood samples were drawn before and immediately after exercise and at 8 min and 15 min following exercise. Samples were analyzed for F2 isoprostanes (FIP), lipid hydroperoxides (LPO), and lactate. A 2 x 4 repeated measures ANOVA was used to test for treatment, time, and interaction effects for FIP, LPO, and lactate. Differences in VO(2) were tested with Student's t-test. Significance was set at p < 0.05. Oxygen consumption was not significantly different between Hot and Con. The pattern of change of FIP and lactate in Hot was significant versus exercise in Con. LPO was significantly elevated over time in both Hot and Con, but the pattern of change was not significantly different. Ending core temperatures and heart rates were significantly elevated in Hot versus Con. These data indicate that hyperthermia increases oxidative stress and selectively affects specific lipid markers, independent of oxygen consumption. PMID:15776334

McAnulty, S R; McAnulty, L; Pascoe, D D; Gropper, S S; Keith, R E; Morrow, J D; Gladden, L B

2005-04-01

217

Unraveling the complexities of SIRT1-mediated mitochondrial regulation in skeletal muscle  

PubMed Central

SIRT1 is a purported central regulator of skeletal muscle mitochondrial biogenesis. Herein we discuss our recent work utilizing conditional mouse models, which highlight the complexities of SIRT1 biology in vivo, and question its role in regulating mitochondrial function and mitochondrial adaptions to endurance exercise. Further, we discuss the possible contribution of proposed SIRT1 substrates to muscle mitochondrial biogenesis.

Philp, Andrew; Schenk, Simon

2013-01-01

218

Role of Twin Cys-Xaa9-Cys Motif Cysteines in Mitochondrial Import of the Cytochrome c Oxidase Biogenesis Factor Cmc1*  

PubMed Central

The Mia40 import pathway facilitates the import and oxidative folding of cysteine-rich protein substrates into the mitochondrial intermembrane space. Here we describe the in vitro and in organello oxidative folding of Cmc1, a twin CX9C-containing substrate, which contains an unpaired cysteine. In vitro, Cmc1 can be oxidized by the import receptor Mia40 alone when in excess or at a lower rate by only the sulfhydryl oxidase Erv1. However, physiological and efficient Cmc1 oxidation requires Erv1 and Mia40. Cmc1 forms a stable intermediate with Mia40 and is released from this interaction in the presence of Erv1. The three proteins are shown to form a ternary complex in mitochondria. Our results suggest that this mechanism facilitates efficient formation of multiple disulfides and prevents the formation of non-native disulfide bonds.

Bourens, Myriam; Dabir, Deepa V.; Tienson, Heather L.; Sorokina, Irina; Koehler, Carla M.; Barrientos, Antoni

2012-01-01

219

Mitochondrial Autophagy  

PubMed Central

Efficient and functional mitochondrial networks are essential for myocardial contraction and cardiomyocyte survival. Mitochondrial autophagy (mitophagy) refers to selective sequestration of mitochondria by autophagosomes, which subsequently deliver them to lysosomes for destruction. This process is essential for myocardial homeostasis and adaptation to stress. Elimination of damaged mitochondria protects against cell death, as well as stimulates mitochondrial biogenesis. Mitophagy is a tightly controlled and highly selective process. It is modulated by mitochondrial fission and fusion proteins, BCL-2 family proteins, and the PINK1/Parkin pathway. Recent studies have provided evidence that miRNAs can regulate mitophagy by controlling the expression of essential proteins involved in the process. Disruption of autophagy leads to rapid accumulation of dysfunctional mitochondria, and diseases associated with impaired autophagy produce severe cardiomyopathies. Thus, autophagy and mitophagy pathways hold promise as new therapeutic targets for clinical cardiac care.

Thomas, Robert L.; Gustafsson, Asa B.

2014-01-01

220

Exercise-induced arterial adaptations in elite judo athletes  

Microsoft Academic Search

The purpose of this study was to examine exercise-induced arterial adaptations in elite Judo male and female athletes. 27 male Judo athletes (age 24.06 ± 2 years), 11 female Judoka (age 24.27 ± 1 years), 27 sedentary healthy men (age 24.01 ± 2 years) and 11 women (age 24.21 ± 1 years) participated in the current study. The examined vessels

Panagiotis Karagounis; Maria Maridaki; Xenofon Papaharalampous; Giorgos Prionas; Panagiotis Baltopoulos

221

Exercise-Induced Deep Vein Thrombosis of the Upper Extremity  

Microsoft Academic Search

Upper-extremity deep venous thrombosis (UEDVT) is an increasingly important clinical problem in children. These events are classified as primary or secondary, with the latter being the most common and usually associated with the presence of a central venous line. Among primary UEDVT, the so-called Paget-Schroetter syndrome, effort-related or exercise-induced upper-extremity thrombotic event represents an extremely rare finding that has never

Leonardo R. Brandão; Suzan Williams; Walter H. A. Kahr; Clodagh Ryan; Michael Temple; Anthony K.C. Chan

2006-01-01

222

Effect of exercise-induced hyperthermia on serum iron concentration  

Microsoft Academic Search

Serum iron levels have been shown to decline both with fever and with strenuous exercise, leading to the supposition that\\u000a the decrease might be the result of a rise in core body temperature. To evaluate this hypothesis, the serum iron response\\u000a to an exercise-induced 1.5?C rise in core body temperature was measured. To increase core temperature, five females and two

Michael J. Buono; Michelle T. Barrack; Fabienne Bouton-Sander; Patricia Bradley; Kristina A. Majer Cottonaro

2005-01-01

223

Metabolic response to light exercise after exercise-induced rhabdomyolysis  

Microsoft Academic Search

.   Inherent compromises in substrate metabolism, or impaired perfusion of muscle may contribute to the occurrence of exercise-induced\\u000a rhabdomyolysis. In this study, the lactate response of the elbow flexor muscles to light exercise was examined in eight subjects\\u000a (five males, three females) who previously demonstrated rhabdomyolysis with extreme swelling (ES; n=4) or no swelling (NS; n=4) of the upper arm

Stephen P. Sayers; Priscilla Clarkson; Jehangir J. Patel

2002-01-01

224

SIRT3 Deacetylates ATP Synthase F1 Complex Proteins in Response to Nutrient- and Exercise-Induced Stress.  

PubMed

Abstract Aims: Adenosine triphosphate (ATP) synthase uses chemiosmotic energy across the inner mitochondrial membrane to convert adenosine diphosphate and orthophosphate into ATP, whereas genetic deletion of Sirt3 decreases mitochondrial ATP levels. Here, we investigate the mechanistic connection between SIRT3 and energy homeostasis. Results: By using both in vitro and in vivo experiments, we demonstrate that ATP synthase F1 proteins alpha, beta, gamma, and Oligomycin sensitivity-conferring protein (OSCP) contain SIRT3-specific reversible acetyl-lysines that are evolutionarily conserved and bind to SIRT3. OSCP was further investigated and lysine 139 is a nutrient-sensitive SIRT3-dependent deacetylation target. Site directed mutants demonstrate that OSCP(K139) directs, at least in part, mitochondrial ATP production and mice lacking Sirt3 exhibit decreased ATP muscle levels, increased ATP synthase protein acetylation, and an exercise-induced stress-deficient phenotype. Innovation: This work connects the aging and nutrient response, via SIRT3 direction of the mitochondrial acetylome, to the regulation of mitochondrial energy homeostasis under nutrient-stress conditions by deacetylating ATP synthase proteins. Conclusion: Our data suggest that acetylome signaling contributes to mitochondrial energy homeostasis by SIRT3-mediated deacetylation of ATP synthase proteins. Antioxid. Redox Signal. 21, 551-564. PMID:24252090

Vassilopoulos, Athanassios; Pennington, J Daniel; Andresson, Thorkell; Rees, David M; Bosley, Allen D; Fearnley, Ian M; Ham, Amy; Flynn, Charles Robb; Hill, Salisha; Rose, Kristie Lindsey; Kim, Hyun-Seok; Deng, Chu-Xia; Walker, John E; Gius, David

2014-08-01

225

Exercise-induced asthma and cardiovascular fitness in asthmatic children.  

PubMed Central

BACKGROUND: The role of physical training in the management of children with exercise-induced asthma is controversial. A study was undertaken to determine whether a relationship could be found between the occurrence of exercise-induced asthma and the degree of cardiovascular fitness in asthmatic children. METHODS: Twenty eight children aged 6-13 with mild to moderate asthma and dyspnoea during or after physical exercise were tested. All patients had a basal forced expiratory volume in one second (FEV1) of > 80% predicted. Twelve patients were taking corticosteroid maintenance medication by inhalation and 16 were not. Two exercise tests were performed on a treadmill to assess peak oxygen consumption rate (VO2max) and the percentage decrease in FEV1 after exercise. RESULTS: There was no correlation between the VO2max and the percentage decrease in FEV1. Patients not taking steroids showed a greater fall in FEV1 than those receiving corticosteroid medication (mean fall in FEV1 28.7% versus 6.6%). Four of the 12 children treated with steroids and two of the 16 children not taking steroids had a level of cardiovascular fitness lower than the 5th percentile for healthy Dutch children. CONCLUSION: Normal cardiovascular fitness does not prevent exercise-induced asthma.

Thio, B. J.; Nagelkerke, A. F.; Ketel, A. G.; van Keeken, B. L.; Dankert-Roelse, J. E.

1996-01-01

226

Exercise-induced pulmonary perfusion redistribution in heaves.  

PubMed

This study aimed to compare exercise-induced pulmonary perfusion redistribution in healthy vs. 'heavey' horses using scintigraphy, a minimally invasive technique. Six healthy (A) and 5 'heavey' horses in remission (B(I)) and during clinical signs of disease (B(II)) were investigated. Dimensions of the exercising pulmonary perfusion (QE) images were expressed in percent of the resting perfusion (QR) images. Computed QE to QR ratios (QE/QR) images enabled the definition of the region more perfused at exercise than at rest (R1). In all groups, exercise induced a major enlargement of the Q image but a larger increase of the lung height was found in 'heavey' horses. Compared to A, 'heavey' horses showed a larger R1 region with a significantly higher QE/QR. Location of R1 pointed out the dorsal lung region as a major site of pulmonary perfusion redistribution for all groups. This work demonstrated (1) the feasibility of using scintigraphy for studying exercise-induced pulmonary perfusion redistribution; (2) perfusion redistribution to the dorsal lung with exercise and (3) an intensified redistribution in 'heavey' horses, either clinically affected or not. PMID:12405737

Harmegnies, N F; Duvivier, D H; Vandenput, S N; Art, T; Lekeux, P M; Votion, D M

2002-09-01

227

Biogenesis of telomerase ribonucleoproteins  

PubMed Central

Telomerase adds simple-sequence repeats to the ends of linear chromosomes to counteract the loss of end sequence inherent in conventional DNA replication. Catalytic activity for repeat synthesis results from the cooperation of the telomerase reverse transcriptase protein (TERT) and the template-containing telomerase RNA (TER). TERs vary widely in sequence and structure but share a set of motifs required for TERT binding and catalytic activity. Species-specific TER motifs play essential roles in RNP biogenesis, stability, trafficking, and regulation. Remarkably, the biogenesis pathways that generate mature TER differ across eukaryotes. Furthermore, the cellular processes that direct the assembly of a biologically functional telomerase holoenzyme and its engagement with telomeres are evolutionarily varied and regulated. This review highlights the diversity of strategies for telomerase RNP biogenesis, RNP assembly, and telomere recruitment among ciliates, yeasts, and vertebrates and suggests common themes in these pathways and their regulation.

Egan, Emily D.; Collins, Kathleen

2012-01-01

228

Mitochondrial Turnover in the Heart  

PubMed Central

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.

Gustafsson, Asa B.

2010-01-01

229

A bifunctional protein regulates mitochondrial protein synthesis  

PubMed Central

Mitochondrial gene expression is predominantly regulated at the post-transcriptional level and mitochondrial ribonucleic acid (RNA)-binding proteins play a key role in RNA metabolism and protein synthesis. The AU-binding homolog of enoyl-coenzyme A (CoA) hydratase (AUH) is a bifunctional protein with RNA-binding activity and a role in leucine catabolism. AUH has a mitochondrial targeting sequence, however, its role in mitochondrial function has not been investigated. Here, we found that AUH localizes to the inner mitochondrial membrane and matrix where it associates with mitochondrial ribosomes and regulates protein synthesis. Decrease or overexpression of the AUH protein in cells causes defects in mitochondrial translation that lead to changes in mitochondrial morphology, decreased mitochondrial RNA stability, biogenesis and respiratory function. Because of its role in leucine metabolism, we investigated the importance of the catalytic activity of AUH and found that it affects the regulation of mitochondrial translation and biogenesis in response to leucine.

Richman, Tara R.; Davies, Stefan M.K.; Shearwood, Anne-Marie J.; Ermer, Judith A.; Scott, Louis H.; Hibbs, Moira E.; Rackham, Oliver; Filipovska, Aleksandra

2014-01-01

230

Sedentary aging increases resting and exercise-induced intramuscular free radical formation  

PubMed Central

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 ± 6 yr) and six aged (71 ± 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 ± 62%) and during exercise (+143 ± 40%), and this was further complemented by a greater increase in ?-phenyl-tert-butylnitrone adducts identified as a combination of lipid-derived alkoxyl-alkyl radicals (+295 ± 96% and +298 ± 120%). Lipid hydroperoxides were also elevated at rest (0.190 ± 0.169 vs. 0.148 ± 0.071 nmol/mg total protein) and during exercise (0.567 ± 0.259 vs. 0.320 ± 0.263 nmol/mg total protein) despite a more marked depletion of ascorbate and uptake of ?/?-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.

McEneny, Jane; Mathieu-Costello, Odile; Henry, Robert R.; James, Philip E.; McCord, Joe M.; Pietri, Sylvia; Young, Ian S.; Richardson, Russell S.

2010-01-01

231

Molecular Genetics of Mitochondrial Disorders  

ERIC Educational Resources Information Center

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…

Wong, Lee-Jun C.

2010-01-01

232

Exercise-induced hand tremor: a possible test for beta 2-adrenoceptor selectivity in man?  

PubMed Central

The effects of intravenous doses of propranolol, sotalol, timolol, atenolol and placebo on exercise-induced tachycardia and exercise-induced increases in hand tremor were assessed in four healthy volunteers. All active drugs produced significant reductions in exercise-induced tachycardia. Exercise caused consistent significant increases in hand tremor which were blocked by the three non-cardioselective drugs but not by atenolol or placebo. The blockade of exercise-induced hand tremor is suggested as a possible test for the assessment of the selectivity of beta-adrenoceptor blockade in man.

Abila, B; Wilson, J F; Marshall, R W; Richens, A

1986-01-01

233

AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation  

Microsoft Academic Search

The AMP-activated protein kinase agonist AICAR mimics a low intracellular energy state and inhibits the proliferation of cancer cells by different mechanisms, which may depend on the bioenergetic signature of these cells. AICAR can also stimulate mitochondrial biogenesis in myoblasts, neurons and HeLa cells. Yet, whether the reactivation of oxidative phosphorylation biogenesis by AICAR contributes to the growth arrest of

Caroline Jose; Etienne Hébert-Chatelain; Nadège Bellance; Anaïs Larendra; Melser Su; Karine Nouette-Gaulain; Rodrigue Rossignol

2011-01-01

234

The influence of exercise-induced fatigue on cognitive function.  

PubMed

Although anecdotal reports suggest that information processing and decision making is impaired immediately following prolonged periods of physical activity, results obtained from laboratory studies of exercise-induced fatigue have been inconsistent. Fatigue effects may be task specific and related to the time of post-exercise testing. The present study examined the effects on adults' performance of two cognitive tasks that differed in processing demands over an 80-min period of fatigue. Thirty young adult men and women were randomly assigned to either an exercise group and completed a 60-min bout of cycle ergometry at 90% ventilatory threshold or a control group and rested for 60 min. Following interventions, each participant completed a simple and complex version of a visual perceptual discrimination test, a 40-min memory-based vigilance test and a repetition of the visual perceptual discrimination tests. Those who exercised evidenced significant decrements in performance on complex perceptual-discrimination tasks compared to participants who rested. The response time of exercisers during a memory-demanding vigilance test were significantly slower than those of participants who rested; however, detection performance did not differ between groups neither was there a decrease in target detection across the vigil. The effects of exercise-induced fatigue may be task specific, with greater effects on perceptual tasks, which involve relatively automatic processing, compared to effortful memory-based tasks. PMID:22494399

Moore, Robert D; Romine, Mathew W; O'connor, Patrick J; Tomporowski, Phillip D

2012-05-01

235

Effect of simulated weightlessness on exercise-induced anaerobic threshold  

NASA Technical Reports Server (NTRS)

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.

Convertino, V. A.; Karst, G. M.; Kirby, C. R.; Goldwater, D. J.

1986-01-01

236

Exercise-induced bronchoconstriction and atopy in Tunisian athletes  

PubMed Central

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.

Sallaoui, Ridha; Chamari, Karim; Mossa, Abbas; Tabka, Zouhair; Chtara, Moktar; Feki, Youssef; Amri, Mohamed

2009-01-01

237

Laser acupuncture in children and adolescents with exercise induced asthma  

PubMed Central

Background: Laser acupuncture, a painless technique, is a widely used alternative treatment method for childhood asthma, although its efficacy has not been proved in controlled clinical studies. Methods: A double blind, placebo controlled, crossover study was performed to investigate the possible protective effect of a single laser acupuncture treatment on cold dry air hyperventilation induced bronchoconstriction in 44 children and adolescents of mean age 11.9 years (range 7.5–16.7) with exercise induced asthma. Laser acupuncture was performed on real and placebo points in random order on two consecutive days. Lung function was measured before laser acupuncture, immediately after laser acupuncture (just before cold dry air challenge (CACh)), and 3 and 15 minutes after CACh. CACh consisted of a 4 minute isocapnic hyperventilation of –10°C absolute dry air. Results: Comparison of real acupuncture with placebo acupuncture showed no significant differences in the mean maximum CACh induced decrease in forced expiratory volume in 1 second (27.2 (18.2)% v 23.8 (16.2)%) and maximal expiratory flow at 25% remaining vital capacity (51.6 (20.8)% v 44.4 (22.3)%). Conclusions: A single laser acupuncture treatment offers no protection against exercise induced bronchoconstriction in paediatric and adolescent patients.

Gruber, W; Eber, E; Malle-Scheid, D; Pfleger, A; Weinhandl, E; Dorfer, L; Zach, M

2002-01-01

238

Increase of mitochondrial DNA content and transcripts in early bovine embryogenesis associated with upregulation of mtTFA and NRF1 transcription factors  

Microsoft Academic Search

BACKGROUND: Recent work has shown that mitochondrial biogenesis and mitochondrial functions are critical determinants of embryonic development. However, the expression of the factors controlling mitochondrial biogenesis in early embryogenesis has received little attention so far. METHODS: We used real-time quantitative PCR to quantify mitochondrial DNA (mtDNA) in bovine oocytes and in various stages of in vitro produced embryos. To investigate

Pascale May-Panloup; Xavier Vignon; Marie-Françoise Chrétien; Yvan Heyman; Manoel Tamassia; Yves Malthièry; Pascal Reynier

2005-01-01

239

Number matters: control of mammalian mitochondrial DNA copy number  

Microsoft Academic Search

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

Laura L. Clay Montier; Janice J. Deng; Yidong Bai

2009-01-01

240

Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency  

ERIC Educational Resources Information Center

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…

Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

2010-01-01

241

An unusual example of exercise-induced asthma  

PubMed Central

A patient with exercise-induced asthma is described in whom the post-exercise fall in F.E.V.1 was not prevented by the inhalation of isoprenaline immediately before exercise but was almost completely prevented by subcutaneous atropine given 40 minutes before exercise. A large fall in F.E.V.1 similar to the fall after exercise occurred after carbon dioxide-induced hyperventilation and voluntary hyperventilation performed at rest. Only a slight fall in F.E.V.1 occurred when atropine was given before voluntary hyperventilation was performed. It is postulated that the post-exercise fall in F.E.V.1 in this patient is due to hyperventilation reflexly causing bronchial constriction.

Crompton, G. K.

1968-01-01

242

Dietary strategies to recover from exercise-induced muscle damage.  

PubMed

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

Sousa, Mónica; Teixeira, Vítor H; Soares, José

2014-03-01

243

Does deep water running reduce exercise-induced breast discomfort?  

PubMed Central

Aim To establish whether exercise?induced vertical breast displacement and discomfort in women with large breasts were reduced during deep water running compared to treadmill running. Methods Sixteen women (mean age ?=?32 years, range 19–43 years; mean mass ?=?74.1?kg, range 61–114?kg; mean height ?=?1.7?m, range 1.61–1.74?m), who were professionally sized to wear a C+ bra cup, were recruited as representative of women with large breasts. After extensive familiarisation, vertical breast motion of the participants was quantified as they ran at a self?selected stride rate on a treadmill and in 2.4?m deep water. Immediately after running, the subjects rated their breast discomfort and breast pain (visual analogue scale) and their perceived exertion (Borg scale). Breast discomfort, breast pain, perceived exertion, vertical breast displacement and vertical breast velocity were compared between the two experimental conditions. Results Exercise?induced breast discomfort was significantly less and perceived exertion was significantly greater during deep water running relative to treadmill running. Although there was no significant between?condition difference in vertical breast displacement, mean peak vertical breast velocity was significantly (p<0.05) less during deep water (upward mean (SD): 29.7 (14.0)?cm.s?1; downward: 31.1 (17.0)?cm.s?1) compared to treadmill running (upward mean (SD): 81.4 (21.7)?cm.s?1; downward: 100.0 (25.0)?cm.s?1). Conclusion Deep water running was perceived as a more strenuous but comfortable exercise mode for women with large breasts. Increased comfort was attributed to reduced vertical breast velocity rather than reduced vertical breast displacement.

McGhee, Deirdre E; Steele, Julie R; Power, Bruce M

2007-01-01

244

The role of muscle mass in exercise-induced hyperemia.  

PubMed

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

Garten, Ryan S; Groot, H Jonathan; Rossman, Matthew J; Gifford, Jayson R; Richardson, Russell S

2014-05-01

245

Sex differences in exercise-induced cardiac hypertrophy.  

PubMed

Physiological cardiac hypertrophy (PCH), induced by intensive exercise or pregnancy, differs substantially from the pathological form of myocardial hypertrophy, accruing after aortic stenosis or chronic arterial hypertension. In contrast to pathological forms of cardiac hypertrophy, exercise-induced increase of left ventricular mass is related to cardiac myocytes enlargement, with no apparent sign of fibrosis or apoptosis, and does usually not result in cardiac failure. Recently published results obtained from various animal studies documented clear sex-specific regulation of exercise-induced cardiac hypertrophy in rodents, with a pronounced hypertrophic response to training load observed in female animals when compared to male littermate. In addition to increased cardiac hypertrophic response, females exhibited augmented lipolytic activity measured in adipose tissue in response to exercise, resulting in increased plasma free fatty acid levels, measured after training. Importantly, sex-specific differences in adipose tissue lipolysis and systemic fat metabolism induced by intensive training were also confirmed in human studies, performed on athletes and healthy volunteers. Since development of PCH during the physical training is accompanied by enhanced fatty acid oxidation and reduced glucose uptake, intensive lipolytic activity, measured in female adipose tissue could explain, at least in part, sex-specific differences observed in hypertrophic response to exercising. Given that sex hormones, such as estrogens and testosterone, in addition to their role in the regulation of adipose tissue metabolism, were also reported to modulate development of pathological myocardial hypertrophy, one may expect also a putative contribution of sex hormones in processes regulating the development and progression of PCH. PMID:23417601

Foryst-Ludwig, Anna; Kintscher, Ulrich

2013-05-01

246

Role of transcription factors in mtDNA biogenesis mediated by thyroid hormones  

Microsoft Academic Search

Exogenous thyroid hormones are regulators of cellular metabolism that involves, along with other cell structures, mitochondria.\\u000a Mechanisms of the influence of thyroid hormones on the biogenesis of mtDNA are not fully understood due to their pleiotropic\\u000a nature. Different ways of regulation of mitochondrial biogenesis by thyroid hormones are discussed in literature, but thyroid\\u000a receptors, localized in both the nucleus and

M. V. Patrushev; V. E. Patrusheva

2011-01-01

247

Biogenesis and Assembly of Eukaryotic Cytochrome c Oxidase Catalytic Core  

PubMed Central

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.

Soto, Ileana C.; Fontanesi, Flavia; Liu, Jingjing; Barrientos, Antoni

2011-01-01

248

Mitochondrial DNA transcription regulation and nucleoid organization  

Microsoft Academic Search

Mitochondrial biogenesis is a complex process depending on both nuclear and mitochondrial DNA (mtDNA) transcription regulation\\u000a to tightly coordinate mitochondrial levels and the cell’s energy demand. The energy requirements for a cell to support its\\u000a metabolic function can change in response to varying physiological conditions, such as, proliferation and differentiation.\\u000a Therefore, mitochondrial transcription regulation is constantly being modulated in order

Adriana P. Rebelo; Lloye M. Dillon; Carlos T. Moraes

249

BRL10833 in inhibiting exercise-induced bronchoconstriction in asthmatic children.  

PubMed

A double-blind controlled exercise challenge study has been performed in 16 asthmatic chlidren to show the effectiveness of BRL10833 in inhibiting exercise-induced bronchoconstriction. The children attended the respiratory laboratory on four occasions within the space of two weeks; on each occassion a routine 6-min exercise test was performed. At the first visit no drugs were given before the exercise test and all the children demonstrated abnormal exercise-induced bronchoconstriction as measured by peak expiratory flow rate (PEFR), forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC). On the other three occasions the children were given sodium cromoglycate, BRL10833 or placebo medications before the exercise test. After sodium cromoglycate administration four children showed complete blocking and four showed partial blocking of exercise-induced bronchoconstriction. After BRL10833 four children showed complete blocking and six showed partial blocking of exercise induced bronchoconstriction. Placebo administration produced complete blocking of exercise-induced bronchoconstriction in three and partial blocking in two children. The results indicated that BRL10833 was almost as effective as sodium cromoglycate in inhibiting exercise-induced bronchoconstriction and placebo, although less effective than the two preparations, did afford protection from exercise-induced bronchoconstriction in some of the children. PMID:100129

Lenney, W; Milner, A D; Tyler, R M

1978-07-01

250

Peroxisome Biogenesis and Function  

PubMed Central

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.

Kaur, Navneet; Reumann, Sigrun; Hu, Jianping

2009-01-01

251

BIOGENESIS OF MITOCHONDRIA  

PubMed Central

Growth under conditions of oxygen restriction results in a generalized decrease in the definition of the mitochondrial membranes, a decrease in the mitochondrial cytochromes, and a decrease in citric acid cycle enzymes of the obligate aerobic yeast Candida parapsilosis. Addition of unsaturated fatty acids and ergosterol to cultures exposed to limited oxygen results in improved definition of the mitochondrial membranes and an increase in the total mitochondrial cytochrome content of the cells. Euflavine completely inhibits mitochondrial protein synthesis in vitro. Its in vivo effect is to cause the formation of giant mitochondrial profiles with apparently intact outer membranes and modified internal membranes; the cristae (in-folds) appear only as apparently disorganized remnants while the remainder of the inner membrane seems intact. Cytochromes a, a3, b, and c1 are not synthesized by the cells in the presence of euflavine. Ethidium appears to have effects identical to those of euflavine, whereas chloramphenicol, lincomycin, and erythromycin have similar effects in principle but they are less marked. The effects of all the inhibitors are freely reversible after removal of the drugs. The results are discussed in terms of a functionally three-membrane model of the mitochondrion. In addition, the phylogenetic implications of the observed differences between this organism and the facultative anaerobic yeasts are considered.

Kellerman, G. M.; Biggs, D. R.; Linnane, Anthony W.

1969-01-01

252

Proventil HFA prevents exercise-induced bronchoconstriction in children.  

PubMed

Short-acting inhaled beta2-agonists used just prior to exercise are an effective method for preventing exercise-induced bronchoconstriction (EIB) in children. This was a randomized, single-blind, placebo-controlled, four-period crossover study that compared the effectiveness of albuterol formulated in hydrofluoroalkane-134a (HFA) to albuterol formulated in chlorofluorocarbons (CFCs) and to placebo in protecting asthmatic children age 6-11 from EIB. Patients self-administered either HFA albuterol, two different CFC albuterol products, or placebo 30 min prior to exercise challenge. Spirometry was performed predose and 5, 10, 15, 30, 45, 60, 75, and 90 min after the exercise challenge was completed. The smallest percent change from the predose forced expiratory volume in 1 sec (FEV1) after exercise challenge was similar for the three active treatments, and each of the active treatments was significantly better than placebo. Each active treatment had significantly fewer patients unprotected from EIB (unprotected defined as having >20% fall in FEV1 after exercise challenge) than placebo. Changes in heart rate, blood pressure and electrocardiogram (ECG) intervals were similar for the three active treatments following exercise. HFA albuterol is as effective as albuterol products formulated in CFCs and more effective than placebo in protecting asthmatic children from EIB. PMID:10609622

Colice, G L; Klinger, N M; Ekholm, B P; Dockhorn, R J

1999-12-01

253

Environmental temperature and exercise-induced blood oxidative stress.  

PubMed

Previous research findings indicate that environmental temperature can influence exercise-induced oxidative-stress responses, although the response to variable temperatures is unknown. The purpose of this study was to investigate the effect of warm, cold, and "neutral," or room, environmental temperatures on the blood oxidative stress associated with exercise and recovery. Participants (N = 12, age 27 ± 5 yr, VO2max = 56.7 ± 5.8 ml · kg-1 · min-1, maximal cycle power output = 300 ± 39 W) completed 3 exercise sessions consisting of a 1-hr ride at 60% Wmax, at 40% relative humidity in warm (33 °C), cold (7 °C), and room-temperature environments (20 °C) in a randomized crossover fashion. Rectal core temperature was monitored continually as participants remained in the respective trial temperature throughout a 3-hr recovery. Blood was collected preexercise and immediately, 1 hr, and 3 hr postexercise and analyzed for oxidative-stress markers including ferric-reducing ability of plasma (FRAP), Trolox-equivalent antioxidant capacity (TEAC), lipid hydroperoxides, and protein carbonyls. Core temperature was significantly elevated by all exercise trials, but recovery core temperatures reflected the given environment. FRAP (p < .001), TEAC (p < .001), and lipid hydroperoxides (p < .001) were elevated after warm exercise while protein carbonyls were not altered (p > .05). These findings indicate that moderate-intensity exercise and associated recovery in a warm environment elicits a blood oxidative-stress response not observed at comparable exercise performed at lower temperatures. PMID:23532145

Quindry, John; Miller, Lindsey; McGinnis, Graham; Kliszczewiscz, Brian; Slivka, Dustin; Dumke, Charles; Cuddy, John; Ruby, Brent

2013-04-01

254

Exercise-Induced Muscle Damage and Running Economy in Humans  

PubMed Central

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 (~15–30 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.

Assumpcao, Claudio de Oliveira; Lima, Leonardo Coelho Rabello; Oliveira, Felipe Bruno Dias; Greco, Camila Coelho; Denadai, Benedito Sergio

2013-01-01

255

Prevalence of exercise induced asthma in female school students.  

PubMed

The prevalence of exercise induced asthma (EIA) in Iran is not known. In the present study the prevalence of EIA among female students of guidance school in the city of Mashhad was evaluated. A total of 1690 female students aged 12-14 years in ten randomly selected schools in north east of Iran (Mashhad) completed an asthma symptoms- specific questionnaire. One hundred forty four randomly selected students including 49 symptomatic and 95 asymptomatic cases participated in a 6 minutes free run test (until reaching 70-75% of MHR (maximum heart rate) for evaluating EIA. Pulmonary function tests (PFT) were measured before (baseline), immediately, 5 minutes and 15 minutes after exercise. The prevalence of asthma symptoms among the studied students was 12.54%. There was not significant difference in any of PFT values between asymptomatic and symptomatic students. The results of exercise test showed that totally 61.22% of symptomatic students responded to exercise test (their post-exercise PFT values decline more than 15%) while only 16.82% of asymptomatic students were responders to exercise (p<0.001). However, in both asymptomatic and symptomatic responder students, all PFT values declined significantly after exercise compared to baseline values (p<0.05 to p<0.001) and there was not any significant difference between two groups.The results showed that although higher number of symptomatic students showed EIA, some asymptomatic students also sowed EIA. PMID:22184270

Marefati, Hamid; Nikbine, Helimeh; Boskabady, Mohammad Hossein

2011-12-01

256

Lycium barbarum Polysaccharides Reduce Exercise-Induced Oxidative Stress  

PubMed Central

The purpose of the present study was to investigate the effects of Lycium barbarum polysaccharides (LBP) on exercise-induced oxidative stress in rats. Rats were divided into four groups, i.e., one control group and three LBP treated groups. The animals received an oral administration of physiological saline or LBP (100, 200 and 400 mg/kg body weight) for 28 days. On the day of the exercise test, rats were required to run to exhaustion on the treadmill. Body weight, endurance time, malondialdehyde (MDA), super oxide dismutase (SOD) and glutathione peroxidase (GPX) level of rats were measured. The results showed that the body weight of rats in LBP treated groups were not significantly different from that in the normal control group before and after the experiment (P > 0.05). After exhaustive exercise, the mean endurance time of treadmill running to exhaustion of rats in LBP treated groups were significantly prolonged compared with that in the normal control group. MDA levels of rats in LBP treated groups were significantly decreased compared with that in the normal control group (P < 0.05). SOD and GPX levels of rats in LBP treated groups were significantly increased compared with that in the normal control group (P < 0.05). Together, these results indicate that LBP was effective in preventing oxidative stress after exhaustive exercise.

Shan, Xiaozhong; Zhou, Junlai; Ma, Tao; Chai, Qiongxia

2011-01-01

257

[Advances of studies on acupuncture and moxibustion for exercise-induced fatigue].  

PubMed

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

Zhang, Yan-hong; Liu, Jun; Li, Xiao-feng; Jia, Chun-sheng

2010-03-01

258

The Effects of Exercise-induced Fatigue on Acetylcholinesterase Expression and Activity at Rat Neuromuscular Junctions  

PubMed Central

Acetylcholinesterase is the enzyme that terminates neurotransmission by hydrolyzing the acetylcholine released by the motoneurons at the neuromuscular junctions. Although acetylcholinesterase has been studied for almost a century, the underlying relationship between exercise-induced fatigue and acetylcholinesterase activity at the synaptic cleft is not clear. The purpose of this study was to assess the effects of exercise-induced fatigue on the expression and activity of acetylcholinesterase at the neuromuscular junctions. The expression and activity of acetylcholinesterase at the gastrocnemius neuromuscular junctions was decreased transiently by exercise-induced fatigue and then gradually increased over 24 hr. The expression of acetylcholinesterase in the 24 hr recovery group returned to the level of the control (non-exercised) group, but the activity of acetylcholinesterase remained significantly lower. These data suggest that the decrease of acetylcholinesterase expression and activity may be involved in the production and/or maintenance of exercise-induced fatigue.

Wen, Guo; Hui, Wang; Dan, Chen; Xiao-Qiong, Wu; Jian-Bin, Tong; Chang-Qi, Li; De-Liang, Lei; Wei-Jun, Cai; Zhi-Yuan, Li; Xue-Gang, Luo

2009-01-01

259

Nutritional modulation of exercise-induced immunodepression in athletes: a systematic review and meta-analysis  

Microsoft Academic Search

Background:Heavy exercise induces marked immunodepression that is multifactorial in origin. Nutrition can modulate normal immune function.Objective:To assess the efficacy of nutritional supplements in exercise-induced immunodepression in athletes.Design:Systematic review.Review methods:Randomised and\\/or controlled trials of athletes undertaking nutritional supplements to minimise the immunodepression after exercise were retrieved. The primary outcome measure was incidence of upper respiratory tract (URT) illness symptoms after exercise,

A Moreira; R A Kekkonen; L Delgado; J Fonseca; R Korpela; T Haahtela

2007-01-01

260

Renal hypouricemia: Prevention of exercise-induced acute renal failure and a review of the literature  

Microsoft Academic Search

Isolated renal hypouricemia from defective uric acid reabsorption and\\/or secretion is a well-described entity, with a prevalence of 0.12% to 0.20% in Japan. It is rarely associated with exercise-induced acute renal failure (ARF). The etiology of ARF is debated. Prevention of ARF in renal hypouricemia has not been previously addressed. A 29-year-old Pakistani man had recurrent exercise-induced ARF. He was

Jane Y. Yeun; James A. Hasbargen

1995-01-01

261

Effects of cold water immersion on the symptoms of exercise-induced muscle damage  

Microsoft Academic Search

Cryotherapy is an effective treatment for acute sports injury to soft tissue, although the effect of cryotherapy on exercise-induced muscle damage is unclear. The aim of this study was to assess the effects of cold water immersion on the symptoms of exercise-induced muscle damage following strenuous eccentric exercise. After performing a bout of damage-inducing eccentric exercise (eight sets of five

ROGER ESTON; DANIEL PETERS

1999-01-01

262

Relationship between serum creatine kinase activity following exercise-induced muscle damage and muscle fibre composition  

Microsoft Academic Search

In this study, we examined the relationship between serum creatine kinase activity following exercise-induced muscle damage and muscle fibre composition. Seventeen untrained males volunteered and underwent a [Vdot]O2max test, Wingate test, and an exercise-induced muscle damage protocol. Muscle soreness and blood samples were recorded before, immediately after, and 24, 48, 72, and 96 h after exercise. Biopsy samples from the vastus

Meir Magal; Charles L. Dumke; Zea G. Urbiztondo; Michael J. Cavill; N. Travis Triplett; John C. Quindry; Jeff M. McBride; Yoram Epstein

2010-01-01

263

Mitochondrial Therapeutics for Cardioprotection  

PubMed Central

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.

Carreira, Raquel S.; Lee, Pamela; Gottlieb, Roberta A.

2013-01-01

264

Exercise-induced silent myocardial ischemia in patients with vasospastic angina  

SciTech Connect

To clarify the incidence and clinical characteristics of exercise-induced myocardial ischemia in patients with vasospastic angina, we performed exercise thallium computed tomography in 25 patients who had no significant coronary artery stenosis greater than 70%. Coronary artery spasm was documented by coronary angiography in all patients. Eleven patients (44%) developed exercise-induced perfusion defects, but only four of them had anginal pain (36%). Diltiazem (90 mg, administered orally) prevented the development of exercise-induced perfusion defects in all patients. Multivessel coronary spasm was documented by coronary angiography in 11 patients, and nine of them (82%) showed exercise-induced perfusion defects (p less than 0.05). From this study it can be concluded: (1) Exercise-induced myocardial ischemia was demonstrated in 44% of patients who had vasospastic angina without fixed coronary stenosis, and 64% of them were asymptomatic. (2) Patients with multivessel spasm had a greater prevalence of exercise-induced myocardial ischemia than those with single-vessel spasm.

Aoki, M.; Koyanagi, S.; Sakai, K.; Irie, T.; Takeshita, A.; Nakamura, M.; Nakagaki, O. (Kyushu Univ., Fukuoka (Japan))

1990-03-01

265

Importing Mitochondrial Proteins: Machineries and Mechanisms  

PubMed Central

Most mitochondrial proteins are synthesized on cytosolic ribosomes and must be imported across one or both mitochondrial membranes. There is an amazingly versatile set of machineries and mechanisms, and at least four different pathways, for the importing and sorting of mitochondrial precursor proteins. The translocases that catalyze these processes are highly dynamic machines driven by the membrane potential, ATP, or redox reactions, and they cooperate with molecular chaperones and assembly complexes to direct mitochondrial proteins to their correct destinations. Here, we discuss recent insights into the importing and sorting of mitochondrial proteins and their contributions to mitochondrial biogenesis.

Chacinska, Agnieszka; Koehler, Carla M.; Milenkovic, Dusanka; Lithgow, Trevor; Pfanner, Nikolaus

2014-01-01

266

Exercise-induced oxidative stress and hypoxic exercise recovery.  

PubMed

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

Ballmann, Christopher; McGinnis, Graham; Peters, Bridget; Slivka, Dustin; Cuddy, John; Hailes, Walter; Dumke, Charles; Ruby, Brent; Quindry, John

2014-04-01

267

Undiagnosed exercise-induced bronchoconstriction in ski-mountaineers.  

PubMed

Because the practise conditions put the ski-mountaineering athletes potentially at risk for exercise-induced bronchoconstriction (EIB), this study was conducted to estimate the prevalence of EIB in this population. Thirty-one highly-trained ski-mountaineers with racing experience participating in the race were evaluated. EIB was determined after a European race at high altitude and frigid conditions. Pre-race investigations included pulmonary function measurements and a questionnaire enquiring about i) training habits, ii) respiratory history during training and/or competition. Pulmonary function was also tested after the race. None of the athletes reported a basal airway obstruction. Two groups were determined after post-race airway response: i) EIB (+) group exhibiting a fall in FEV (1) > or = 10 % (n = 15) and ii) EIB (-) without fall in FEV (1) or fall < 10 % (n = 16). Neither training habits nor baseline lung function were associated with the post-race airway response. Six of the 31 ski-mountaineers had a previous physician-made diagnosis of asthma and/or EIB, nevertheless 23 of our athletes complained about at least one characteristic symptom of asthma during practise. Four of our 15 EIB (+) had a previous physician-made diagnosis of asthma/EIB indicating that 73 % of EIB (+) athletes were undiagnosed for EIB. The proportion of allergic athletes was not significantly different between EIB (+) and EIB (-). This study showed that approximatively half of highly-trained ski-mountaineers with racing experience can develop EIB after a race and that 73 % of them are unaware of the problem. PMID:15776341

Durand, F; Kippelen, P; Ceugniet, F; Gomez, V R; Desnot, P; Poulain, M; Préfaut, C

2005-04-01

268

Airway immunopathology of asthma with exercise-induced bronchoconstriction  

PubMed Central

Background: Exercise-induced bronchoconstriction (EIB) is a common cause of symptoms in a subgroup of asthmatic subjects. The pathobiology that makes this group of asthmatic subjects susceptible to bronchoconstriction after a brief period of exercise remains poorly understood. Objective: We sought to determine whether there are differences in lower airway inflammation and production of cytokines and eicosanoids between asthmatic subjects with and without EIB. Methods: Two distinct groups of asthmatic subjects based on a priori definitions were identified, one with moderate-to-severe EIB and the other without significant bronchoconstriction after exercise challenge. Both groups met the definition of asthma on the basis of bronchodilator response, bronchial hyperresponsiveness, or both. A comparative immunopathology study was conducted by using induced sputum to identify differences in lower airway inflammation and production of cytokines and eicosanoids. Results: The groups had similar baseline lung function and bronchodilator response and did not have any asthma exacerbations within the prior year. The concentration of columnar epithelial cells was markedly higher in the group with EIB (1.4 × 105 vs 2.9 × 104 cells/mL, P = .01). The concentration of eosinophils was higher in the group with EIB (3.6 × 104 vs 4.9 × 103 cells/mL P = .04). Cysteinyl leukotrienes (CysLTs; 727.7 vs 151.9 pg/mL, P = .01) and the ratio of CysLTs to prostaglandin E2 (1.85 vs 1.04, P = .002) in the airways were higher in the group with EIB. Conclusion: Injury to the airway epithelium, overexpression of CysLTs, relative underproduction of prostaglandin E2, and greater airway eosinophilia are distinctive immunopathologic features of asthma with EIB. (J Allergy Clin Immunol 2005;116:586-93.)

Hallstrand, Teal S.; Moody, Mark W.; Aitken, Moira L.; Henderson, William R.

2007-01-01

269

Exercise-inducible factors to activate lipolysis in adipocytes.  

PubMed

We examined the effects of exercise training on the levels of lipid droplet (LD)-associated and mitochondria-related proteins in diet-induced obese (DIO) rats. Furthermore, we assessed putative factors induced by exercise to activate lipolysis in differentiated 3T3-L1 adipocytes. DIO Wistar male rats (age 20 wk) were divided into sedentary control (SED, n = 7) and exercise training (EX, n = 7) groups. EX animals were subjected to treadmill running (25 m/min, 1 h/day, 5 days/wk) for 6 wk. Epididymal fat was dissected and used for protein analyses. 3T3-L1 adipocytes were incubated with media containing hydrogen peroxide (H2O2), sodium-lactate, caffeine, AICAR, or SNAP (NO donor) for 6 h, or 1 mM H2O2 for 15 min, followed by incubation with normal media for up to 24 h total. Protein expression levels and lipolytic activities were biochemically assayed. Epididymal fat significantly decreased in EX animals compared with SED animals. Levels of cytochrome c oxidase (COx), perilipin, hormone sensitive lipase (HSL), and adipose triglyceride lipase (ATGL) proteins in epididymal fat pads of EX animals were significantly increased compared with those in SED animals. In 3T3-L1 cells, glycerol or fatty acid release was significantly increased by all treatments. Lactate or SNAP significantly increased PGC-1? expression, and H2O2 significantly increased COx protein levels compared with controls. Expression of perilipin, HSL, ATGL, or comparative gene identification (CGI)-58 was significantly increased by all treatments. By increasing lipolytic activity in adipocytes, the exercise-inducible factors are attractive therapeutic effectors against LD-associated metabolic diseases. PMID:23681914

Hashimoto, Takeshi; Sato, Koji; Iemitsu, Motoyuki

2013-07-15

270

Screening for Exercise-Induced Bronchoconstriction in College Athletes  

PubMed Central

Objective Previous studies have reported that the prevalence of exercise-induced bronchoconstriction (EIB) in athletes is higher than that of the general population. There is increasing evidence that athletes fail to recognize and report symptoms of EIB. As a result, there has been debate whether athletes should be screened for EIB, particularly in high-risk sports. Methods We prospectively studied 144 athletes from six different varsity sports at a large National Collegiate Athletic Association Division I collegiate athletic program. Baseline demographics and medical history were obtained and the presence of asthma symptoms during exercise was documented. Each athlete subsequently underwent a eucapnic voluntary hyperventilation (EVH) test to document the presence of EIB. Exhaled nitric oxide (eNO) quantification was performed immediately before EVH testing. EIB was defined as a ?10% decline in forced expiratory volume in 1 second compared with baseline. Results Only 4 of 144 (2.7%) athletes were EIB-positive after EVH testing. The presence of symptoms was not predictive of EIB as only 2 of the 64 symptomatic athletes (3%) were EIB-positive based on EVH testing. Two of the four athletes who were found to be EIB-positive denied such symptoms. The mean baseline eNO in the four EIB-positive athletes was 13.25 parts per billion (ppb) and 24.5 ppb in the EIB-negative athletes. Conclusions Our data argue that screening for EIB is not recommended given the surprisingly low prevalence of EIB in the population we studied. In addition, the presence or absence of symptoms was not predictive of EIB and eNO testing was not effective in predicting EIB.

Parsons, Jonathan P.; Cosmar, David; Phillips, Gary; Kaeding, Christopher; Best, Thomas M.; Mastronarde, John G.

2013-01-01

271

Exercise-induced hypoalgesia - interval versus continuous mode.  

PubMed

Aerobic exercise at approximately 70% of maximal aerobic capacity moderately reduces pain sensitivity and attenuates pain, even after a single session. If the analgesic effects depend on exercise intensity, then high-intensity interval exercise at 85% of maximal aerobic capacity should further reduce pain. The aim of this study was to explore the exercise-induced analgesic effects of high-intensity interval aerobic exercise and to compare them with the analgesic effects of moderate continuous aerobic exercise. Twenty-nine young untrained healthy males were randomly assigned to aerobic-continuous (70% heart rate reserve (HRR)) and interval (4 × 4 min at 85% HRR and 2 min at 60% HRR between cycles) exercise modes, each lasting 30 min. Psychophysical pain tests, pressure and heat pain thresholds (HPT), and tonic heat pain (THP) were conducted before and after exercise sessions. Repeated measures ANOVA was used for data analysis. HPT increased (p = 0.056) and THP decreased (p = 0.013) following exercise unrelated to exercise type. However, the main time effect (pre-/postexercise) was a trend of increased HPT (45.6 ± 1.9 °C to 46.2 ± 1.8 °C; p = 0.082) and a significant reduction in THP (from 50.7 ± 25 to 45.9 ± 25.4 numeric pain scale; p = 0.043) following interval exercise. No significant change was found for the pressure pain threshold following either exercise type. In conclusion, interval exercise (85% HRR) has analgesic effects on experimental pain perception. This, in addition to its cardiovascular, muscular, and metabolic advantages may promote its inclusion in pain management programs. PMID:24773287

Kodesh, Einat; Weissman-Fogel, Irit

2014-07-01

272

Intensity Thresholds for Aerobic Exercise-Induced Hypoalgesia  

PubMed Central

Despite many studies investigating exercise-induced hypoalgesia, there is limited understanding of the optimal intensity of aerobic exercise in producing hypoalgesic effects across different types of pain stimuli. Given that not all individuals are willing or capable of engaging in high intensity aerobic exercise, whether moderate intensity aerobic exercise is associated with a hypoalgesic response and whether this response generalizes to multiple pain induction techniques needs to be substantiated. Purpose This study’s purpose is to test for differences in the magnitude of pressure and heat pain modulation induced by moderate (MAE) and vigorous (VAE) intensity aerobic exercise. Methods Twelve healthy young males and 15 females completed one training session and three testing sessions consisting of 25 minutes of either 1) stationary cycling at 70% heart rate reserve (HRR), 2) stationary cycling at 50% HRR, or 3) quiet rest (control). Pain testing was conducted on both forearms prior to and immediately following each condition and included the following tests: pressure pain thresholds (PPT), suprathreshold pressure pain test, static continuous heat test, and repetitive pulse heat pain test. Repeated measures ANOVAs were conducted on each pain measure. Results VAE and MAE reduced pain ratings during static continuous heat stimuli and repetitive heat pulse stimuli, with VAE producing larger effects. VAE also increased PPTs, while neither exercise influenced suprathreshold pressure pain ratings. Conclusion These results suggest that MAE is capable of producing a hypoalgesic effect using continuous and repetitive pulse heat stimuli. However, a dose-response effect was evident as VAE produced larger effects than MAE.

Naugle, Kelly M.; Naugle, Keith E.; Fillingim, Roger B.; Samuels, Brian; Riley, Joseph L.

2014-01-01

273

Exercise-induced Arteriovenous Intrapulmonary Shunting in Dogs  

PubMed Central

Rationale: We have previously shown, using contrast echocardiography, that intrapulmonary arteriovenous pathways are inducible in healthy humans during exercise; however, this technique does not allow for determination of arteriovenous vessel size or shunt magnitude. Objectives: The purpose of this study was to determine whether large-diameter (more than 25 ?m) intrapulmonary arteriovenous pathways are present in the dog, and whether exercise recruits these conduits. Methods: Through the right forelimb, 10.8 million 25-?m stable isotope-labeled microspheres (BioPAL, Inc., Worcester, MA) were injected either at rest (n = 8) or during high-intensity exercise (6– 8 mph, 10–15% grade, n = 6). Systemic arterial blood was continuously sampled during and for 3 minutes after injection. After euthanasia, tissue samples were obtained from the heart, liver, kidney, and skeletal muscle. In addition, 25- and 50-?m microspheres were infused into four isolated dog lungs that were ventilated and perfused at constant pressures similar to exercise. Measurements and Main Results: Blood and tissue samples were commercially analyzed for the presence of microspheres. No microspheres were detected in the arterial blood or tissue samples from resting dogs. In contrast, five of six exercising dogs showed evidence of exercise-induced intrapulmonary arteriovenous shunting, as microspheres were detected in arterial blood and/or tissue. Furthermore, shunt magnitude was calculated to be 1.4 ± 0.8% of cardiac output (n = 3). Evidence of intrapulmonary arteriovenous anastomoses was also found in three of four isolated lungs. Conclusions: Consistent with previous human findings, these data demonstrate that intrapulmonary arteriovenous pathways are functional in the dog and are recruited with exercise.

Stickland, Michael K.; Lovering, Andrew T.; Eldridge, Marlowe W.

2007-01-01

274

Short and longer-term effects of creatine supplementation on exercise induced muscle damage  

PubMed Central

The purpose of this investigation was to determine if creatine supplementation assisted with reducing the amount of exercise induced muscle damage and if creatine supplementation aided in recovery from exercise induced muscle damage. Two groups of subjects (group 1 = creatine; group 2 = placebo) participated in an eccentric exercise protocol following 7 and 30 days of creatine or placebo supplementation (20 g.d-1 for 7 d followed by 6g.d-1 for 23 d = 30 d). Prior to the supplementation period, measurements were obtained for maximal dynamic strength, maximal isometric force, knee range of motion, muscle soreness, and serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH). Following 7 days of creatine supplementation, on day 8, subjects began consuming 6 g.d-1 of creatine for 23 days. Additionally on days 8 and 31, subjects performed an eccentric exercise protocol using the knee extensors to induce muscle damage. Indirect markers of muscle damage, including maximal isometric force, knee range of motion, muscle soreness, and serum levels of CK and LDH, were collected at 12, 24, and 48 hours following each exercise bout. The results indicated that acute bouts of creatine have no effect on indirect markers of muscle damage for the acute (7 days) bout. However, maximal isometric force was greater for the creatine group versus placebo for the chronic (30 days) bout. This suggests that the ergogenic effect of creatine following 30 days of supplementation may have a positive impact on exercise induced muscle damage. Key points Eccentric muscle actions highly associated with exercise induced muscle damage. Creatine supplementation has ergogenic effect to increase protein synthesis. Creatine supplementation does not attenuate exercise induced muscle damage with short term supplementation (7 days). Increased maximal isometric force seen with creatine supplementation after 30 days following exercise induced muscle damage. Ergogenic effect of creatine supplementation may contribute to reduced exercise induced muscle damage.

Rosene, John; Matthews, Tracey; Ryan, Christine; Belmore, Keith; Bergsten, Alisa; Blaisdell, Jill; Gaylord, James; Love, Rebecca; Marrone, Michael; Ward, Kristine; Wilson, Eric

2009-01-01

275

Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease  

PubMed Central

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors composed of iron and inorganic sulfur. They are required for the function of proteins involved in a wide range of activities, including electron transport in respiratory chain complexes, regulatory sensing, photosynthesis and DNA repair. The proteins involved in the biogenesis of Fe-S clusters are evolutionarily conserved from bacteria to humans, and many insights into the process of Fe-S cluster biogenesis have come from studies of model organisms, including bacteria, fungi and plants. It is now clear that several rare and seemingly dissimilar human diseases are attributable to defects in the basic process of Fe-S cluster biogenesis. Although these diseases –which include Friedreich’s ataxia (FRDA), ISCU myopathy, a rare form of sideroblastic anemia, an encephalomyopathy caused by dysfunction of respiratory chain complex I and multiple mitochondrial dysfunctions syndrome – affect different tissues, a feature common to many of them is that mitochondrial iron overload develops as a secondary consequence of a defect in Fe-S cluster biogenesis. This Commentary outlines the basic steps of Fe-S cluster biogenesis as they have been defined in model organisms. In addition, it draws attention to refinements of the process that might be specific to the subcellular compartmentalization of Fe-S cluster biogenesis proteins in some eukaryotes, including mammals. Finally, it outlines several important unresolved questions in the field that, once addressed, should offer important clues into how mitochondrial iron homeostasis is regulated, and how dysfunction in Fe-S cluster biogenesis can contribute to disease.

Rouault, Tracey A.

2012-01-01

276

Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease.  

PubMed

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors composed of iron and inorganic sulfur. They are required for the function of proteins involved in a wide range of activities, including electron transport in respiratory chain complexes, regulatory sensing, photosynthesis and DNA repair. The proteins involved in the biogenesis of Fe-S clusters are evolutionarily conserved from bacteria to humans, and many insights into the process of Fe-S cluster biogenesis have come from studies of model organisms, including bacteria, fungi and plants. It is now clear that several rare and seemingly dissimilar human diseases are attributable to defects in the basic process of Fe-S cluster biogenesis. Although these diseases -which include Friedreich's ataxia (FRDA), ISCU myopathy, a rare form of sideroblastic anemia, an encephalomyopathy caused by dysfunction of respiratory chain complex I and multiple mitochondrial dysfunctions syndrome - affect different tissues, a feature common to many of them is that mitochondrial iron overload develops as a secondary consequence of a defect in Fe-S cluster biogenesis. This Commentary outlines the basic steps of Fe-S cluster biogenesis as they have been defined in model organisms. In addition, it draws attention to refinements of the process that might be specific to the subcellular compartmentalization of Fe-S cluster biogenesis proteins in some eukaryotes, including mammals. Finally, it outlines several important unresolved questions in the field that, once addressed, should offer important clues into how mitochondrial iron homeostasis is regulated, and how dysfunction in Fe-S cluster biogenesis can contribute to disease. PMID:22382365

Rouault, Tracey A

2012-03-01

277

Mitochondrial Signaling: Forwards, Backwards, and In Between  

PubMed Central

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.

Whelan, Sean P.; Zuckerbraun, Brian S.

2013-01-01

278

Biogenesis of cytosolic ribosomes requires the essential iron–sulphur protein Rli1p and mitochondria  

Microsoft Academic Search

Mitochondria perform a central function in the biogenesis of cellular iron-sulphur (Fe\\/S) proteins. It is unknown to date why this biosynthetic pathway is indispensable for life, the more so as no essential mitochondrial Fe\\/S pro- teins are known. Here, we show that the soluble ATP- binding cassette (ABC) protein Rli1p carries N-terminal Fe\\/S clusters that require the mitochondrial and cytosolic

Gyula Kispal; Katalin Sipos; Heike Lange; Zsuzsanna Fekete; Tibor Bedekovics; Tamás Janáky; Jochen Bassler; Daili J Aguilar Netz; Janneke Balk; Carmen Rotte; Roland Lill

2005-01-01

279

Oxidants, Antioxidants, and the Beneficial Roles of Exercise-Induced Production of Reactive Species  

PubMed Central

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.

Gomes, Elisa Couto; Silva, Albena Nunes; de Oliveira, Marta Rubino

2012-01-01

280

Mitochondrial dysfunction during sepsis.  

PubMed

Sepsis and multiple organ failure remain leading causes of death in intensive care patients. Recent advances in our understanding of the pathophysiology of these syndromes include a likely prominent role for mitochondria. Patient studies have shown that the degree of mitochondrial dysfunction is related to the eventual outcome. Associated mechanisms include damage to mitochondria or inhibition of the electron transport chain enzymes by nitric oxide and other reactive oxygen species (the effects of which are amplified by co-existing tissue hypoxia), hormonal influences that decrease mitochondrial activity, and downregulation of mitochondrial protein expression. Notably, despite these findings, there is minimal cell death seen in most affected organs, and these organs generally regain reasonably normal function should the patient survive. It is thus plausible that multiple organ failure following sepsis may actually represent an adaptive state whereby the organs temporarily 'shut down' their normal metabolic functions in order to protect themselves from an overwhelming and prolonged insult. A decrease in energy supply due to mitochondrial inhibition or injury may trigger this hibernation/estivation-like state. Likewise, organ recovery may depend on restoration of normal mitochondrial respiration. Data from animal studies show histological recovery of mitochondria after a septic insult that precedes clinical improvement. Stimulation of mitochondrial biogenesis could offer a new therapeutic approach for patients in multi-organ failure. This review will cover basic aspects of mitochondrial function, mechanisms of mitochondrial dysfunction in sepsis, and approaches to prevent, mitigate or speed recovery from mitochondrial injury. PMID:20509844

Azevedo, Luciano Cesar Pontes

2010-09-01

281

Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice  

Microsoft Academic Search

Nitric oxide synthase-2 (NOS2) plays a critical role in reactive nitrogen species generation and cysteine modifications that influence mitochondrial function and signaling during inflammation. Here, we investigated the role of NOS2 in hepatic mitochondrial biogenesis during Escherichia coli peritonitis in mice. NOS2?\\/? mice displayed smaller mitochondrial biogenesis responses than Wt mice during E. coli infection according to differences in mRNA

Hagir B. Suliman; Abdelwahid Babiker; Crystal M. Withers; Timothy E. Sweeney; Martha S. Carraway; Lynn G. Tatro; Raquel R. Bartz; Karen E. Welty-Wolf; Claude A. Piantadosi

2010-01-01

282

Ischemia reperfusion injury, KATP channels, and exercise-induced cardioprotection against apoptosis.  

PubMed

Exercise is a potent stimulus against cardiac ischemia reperfusion (IR) injury, although the protective mechanisms are not completely understood. The study purpose was to examine whether the mitochondrial or sarcolemmal ATP-sensitive potassium channel (mito K(ATP) or sarc K(ATP), respectively) mediates exercise-induced cardioprotection against post-IR cell death and apoptosis. Eighty-six, 4-mo-old male Sprague Dawley rats were randomly assigned to treadmill exercise (Ex; 30 m/min, 3 days, 60 min, ?70 maximal oxygen uptake) and sedentary (Sed) treatments. Rats were exposed to regional cardiac ischemia (50 min) and reperfusion (120 min) or Sham (170 min; no ligation) surgeries. Exercise subgroups received placebo (saline), 5-hydroxydecanoate (5HD; 10 mg/kg ip), or HMR1098 (10 mg/kg ip) to inhibit mito K(ATP) or sarc K(ATP) channel. Comprehensive outcome assessments included post-IR ECG arrhythmias, cardiac tissue necrosis, redox perturbations, and autophagy biomarkers. No arrhythmia differences existed between exercised and sedentary hearts following extended-duration IR (P < 0.05). The sarc K(ATP) channel was confirmed essential (P = 0.002) for prevention of antinecrotic tissue death with exercise (percent infarct, Sed = 42%; Ex = 20%; Ex5HD = 16%; ExHMR = 42%), although neither the mito K(ATP) (P = 0.177) nor sarc K(ATP) (P = 0.274) channel provided post-IR protection against apoptosis (terminal deoxynucleotidyl transferase deoxy UTP-mediated nick-end labeling-positive nuclei/mm(2), Sham = 1.8 ± 0.5; Sed = 19.4 ± 6.7; Ex = 7.5 ± 4.6; Ex5HD = 14.0 ± 3.9; ExHMR = 11.1 ± 1.8). Exercise preconditioning also appears to preserve basal autophagy levels, as assessed by Beclin 1 (P ? 0.001), microtubule-associated protein-1 light-chain 3B ratios (P = 0.020), and P62 (P ? 0.001), in the hours immediately following IR. Further research is needed to better understand these findings and corresponding redox changes in exercised hearts. PMID:22653992

Quindry, John C; Miller, Lindsey; McGinnis, Graham; Kliszczewicz, Brian; Irwin, J Megan; Landram, Michael; Urbiztondo, Zea; Nanayakkara, Gayani; Amin, Rajesh

2012-08-01

283

Exercise-Induced Intrapulmonary Arteriovenous Shunt in a Patient Complaining of Dyspnea during Strenuous Exercise  

PubMed Central

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.

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

284

Exercise-induced acute renal failure associated with renal hypouricaemia: results of a questionnaire-based survey in Japan  

Microsoft Academic Search

Background. A retrospective investigation was con- ducted to define the clinical features of exercise- induced acute renal failure (ARF) associated with renal hypouricaemia with the aim of clarifying further the clinical features of the disease entity. Methods. A questionnaire was mailed to 43 institu- tions in Japan that had experienced case(s) of exercise- induced ARF associated with renal hypouricaemia. Fifty-four

Toshiyuki Ohta; Takashi Sakano; Takashi Igarashi; Noritomo Itami; Takahiko Ogawa

2004-01-01

285

Chronic exercise-induced compartment pressure elevation measured with a miniaturized fluid pressure monitorA laboratory and clinical study  

Microsoft Academic Search

Increased pressure within an osteofascial compartment may produce a compartment syndrome, one of the principal causes of circulatory compromise in acute traumatic and chronic exercise-induced elevated com partment pressure. Acute and chronic diagnostic quan titation of compartment pressures are a valuable ad junct to clinical diagnosis, particularly when used to evaluate the athlete with exercise-induced pain. This study evaluated a

Brian J. Awbrey; Paul S. Sienkiewicz; Henry J. Mankin

1988-01-01

286

Exercise Challenge for Exercise-Induced Bronchospasm. Confirming Presence, Evaluating Control.  

ERIC Educational Resources Information Center

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…

Kaplan, Ted A.

1995-01-01

287

Influence of artistic gymnastics on iron nutritional status and exercise-induced hemolysis in female athletes.  

PubMed

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

Sureira, Thaiz Mattos; Amancio, Olga Silverio; Pellegrini Braga, Josefina Aparecida

2012-08-01

288

Lack of effect of inhaled morphine on exercise-induced breathlessness in chronic obstructive pulmonary disease  

Microsoft Academic Search

BACKGROUND--Inhaled nebulised morphine may reduce breathlessness in patients with lung disease, although the results of controlled trials are conflicting. A direct action of morphine on the lung has been postulated. This study aimed to investigate whether nebulised morphine reduced exercise-induced breathlessness in patients with chronic obstructive pulmonary disease (COPD) and to determine if this was a local pulmonary effect or

A R Masood; J W Reed; S H Thomas

1995-01-01

289

Oral contraceptive use and exercise-induced muscle damage and recovery  

Microsoft Academic Search

Endogenous estrogen appears to attenuate muscle damage in animals; however, similar evidence in humans is not as strong. This investigation tested the hypothesis that women taking oral contraceptives, thereby having higher exogenous estrogen levels, would be more susceptible to damage or have an attenuated recovery from exercise-induced muscle damage. Muscle damage in women taking combined estrogen and progesterone oral contraceptives

Kathleen J Savage; Priscilla M Clarkson

2002-01-01

290

AMP-activated protein kinase is required for exercise-induced peroxisome proliferator-activated receptor ? co-activator 1? translocation to subsarcolemmal mitochondria in skeletal muscle  

PubMed Central

In skeletal muscle, mitochondria exist as two subcellular populations known as subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. SS mitochondria preferentially respond to exercise training, suggesting divergent transcriptional control of the mitochondrial genomes. The transcriptional co-activator peroxisome proliferator-activated receptor ? co-activator 1? (PGC-1?) and mitochondrial transcription factor A (Tfam) have been implicated in the direct regulation of the mitochondrial genome in mice, although SS and IMF differences may exist, and the potential signalling events regulating the mitochondrial content of these proteins have not been elucidated. Therefore, we examined the potential for PGC-1? and Tfam to translocate to SS and IMF mitochondria in human subjects, and performed experiments in rodents to identify signalling mechanisms regulating these translocation events. Acute exercise in humans and rats increased PGC-1? content in SS but not IMF mitochondria. Acute exposure to 5-aminoimidazole-4-carboxamide-1-?-ribofuranoside in rats recapitulated the exercise effect of increased PGC-1? protein within SS mitochondria only, suggesting that AMP-activated protein kinase (AMPK) signalling is involved. In addition, rendering AMPK inactive (AMPK kinase dead mice) prevented exercise-induced PGC-1? translocation to SS mitochondria, further suggesting that AMPK plays an integral role in these translocation events. In contrast to the conserved PGC-1? translocation to SS mitochondria across species (humans, rats and mice), acute exercise only increased mitochondrial Tfam in rats. Nevertheless, in rat resting muscle PGC-1? and Tfam co-immunoprecipate with ?-tubulin, suggesting a common cytosolic localization. These data suggest that exercise causes translocation of PGC-1? preferentially to SS mitochondria in an AMPK-dependent manner.

Smith, Brennan K; Mukai, Kazutaka; Lally, James S; Maher, Amy C; Gurd, Brendon J; Heigenhauser, George J F; Spriet, Lawrence L; Holloway, Graham P

2013-01-01

291

Novel mitochondrial targets for neuroprotection  

PubMed Central

Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca2+ overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O2 and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca2+-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.

Perez-Pinzon, Miguel A; Stetler, R Anne; Fiskum, Gary

2012-01-01

292

Polyphenols in Exercise Performance and Prevention of Exercise-Induced Muscle Damage  

PubMed Central

Although moderate physical exercise is considered an essential component of a healthy lifestyle that leads the organism to adapt itself to different stresses, exercise, especially when exhaustive, is also known to induce oxidative stress, inflammation, and muscle damage. Many efforts have been carried out to identify dietary strategies or micronutrients able to prevent or at least attenuate the exercise-induced muscle damage and stress. Unfortunately most studies have failed to show protection, and at the present time data supporting the protective effect of micronutrients, as antioxidant vitamins, are weak and trivial. This review focuses on those polyphenols, present in the plant kingdom, that have been recently suggested to exert some positive effects on exercise-induced muscle damage and oxidative stress. In the last decade flavonoids as quercetin, catechins, and other polyphenols as resveratrol have caught the scientists attention. However, at the present time drawing a clear and definitive conclusion seems to be untimely.

Hrelia, Silvana

2013-01-01

293

Exercise-induced central fatigue: a review of the literature with implications for dance science research.  

PubMed

The complex interplay between cortical and subcortical networks essential to motor performance is altered when muscles fatigue. The construct of exercise-induced human muscle fatigue has been attributed largely to the loss of a peripheral muscle's ability to produce force. Far less understood is "central fatigue," the result of alterations in central nervous system function. Central fatigue manifests as inadequate motor drive to the muscles and can occur even at sub-maximal levels of voluntary force. This study reviews the literature on exercise-induced central fatigue and its impact on motor performance. In reviewing conditions that may contributed to central fatigue, it addresses perceived exertion and repetitive strain and their relationship to central fatigue. Evidence supporting possible training protocols designed to offset central fatigue, while speculative, will be cited as potential areas of investigation for dance scientists. PMID:23759479

Batson, Glenna

2013-01-01

294

Ganoderma lucidum polysaccharides supplementation attenuates exercise-induced oxidative stress in skeletal muscle of mice  

PubMed Central

The present study was designed to determine the effects of Ganoderma lucidum polysaccharides (GL-PS) on exhaustive exercise-induced oxidative stress in skeletal muscle tissues of mice. The mice were divided into four groups (three GL-PS administered groups and the control group). The control group was administered with distilled water and GL-PS administered groups were administered with GL-PS (50, 100 and 200 mg/kg body weight per day). After 28 days, the mice performed an exhaustive swimming exercise, along with the determination of superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) activities and malondialdehyde (MDA) levels in the skeletal muscle of mice. The results showed that GL-PS could increase antioxidant enzymes activities and decrease the MDA levels in the skeletal muscle of mice. This study provides strong evidence that GL-PS supplementation possessed protective effects against exhaustive exercise-induced oxidative stress.

Zhonghui, Zhao; Xiaowei, Zheng; Fang, Fang

2013-01-01

295

Mammalian Fe-S cluster biogenesis and its implication in disease.  

PubMed

Iron-sulfur (Fe-S) clusters are inorganic cofactors that are ubiquitous and essential. Due to their chemical versatility, Fe-S clusters are implicated in a wide range of protein functions including mitochondrial respiration and DNA repair. Composed of iron and sulfur, they are sensible to oxygen and their biogenesis requires a highly conserved protein machinery that facilitates assembly of the cluster as well as its insertion into apoproteins. Mitochondria are the central cellular compartment for Fe-S cluster biogenesis in eukaryotic cells and the importance of proper function of this biogenesis for life is highlighted by a constantly increasing number of human genetic diseases that are associated with dysfunction of this Fe-S cluster biogenesis pathway. Although these disorders are rare and appear dissimilar, common aspects are found among them. This review will give an overview on what is known on mammalian Fe-S cluster biogenesis today, by putting it into the context of what is known from studies from lower model organisms, and focuses on the associated diseases, by drawing attention to the respective mutations. Finally, it outlines the importance of adequate cellular and murine models to uncover not only each protein function, but to resolve their role and requirement throughout the mammalian organism. PMID:24440636

Beilschmidt, Lena K; Puccio, Hélène M

2014-05-01

296

Etiology of exercise-induced asthma: Physical stress-induced transcription  

Microsoft Academic Search

Exercise-induced asthma (EIA) occurs with a high prevalence in both asthmatic and nonasthmatic individuals. Although understanding\\u000a of the functional genomics (proteomics) in sports medicine remains limited, this review focuses on immunologic changes as\\u000a reflected in transcriptional regulation in respect to EIA. Studies demonstrated that leukotrienes play a significant role\\u000a in EIA. Exercise increases the distribution of leukotrienes and influences the

Thomas Hilberg

2007-01-01

297

Detection of exercise-induced ischemia by changes in B-type natriuretic peptides  

Microsoft Academic Search

OBJECTIVES The purpose of this study was to examine the effect of exercise-induced ischemia on levels of B-type natriuretic peptide (BNP) and its inactive N-terminal fragment (NT-pro-BNP) and to determine whether measurement of these peptides can improve the diagnostic accuracy of exercise testing. BACKGROUND The ability of exercise testing to detect coronary artery disease (CAD) is limited by modest sensitivity

Robert S. Foote; Justin D. Pearlman; Alan H. Siegel; Kiang-Teck J. Yeo

2005-01-01

298

Food-Dependent Exercise-Induced Anaphylaxis: Clinical and Laboratory Findings in 54 Subjects  

Microsoft Academic Search

Background: In some subjects, specific foods trigger anaphylaxis when exercise follows ingestion (specific food-dependent exercise-induced anaphylaxis, FDEIAn). Skin test and\\/or RAST positivity to foods suggest an IgE-mediated pathogenic mechanism. Others suffer from anaphylaxis after all meals followed by exercise, regardless of the food eaten (nonspecific FDEIAn). We sought to identify the culprit foods with a diagnostic protocol. Methods: We collected

Antonino Romano; Marina Di Fonso; Francesca Giuffreda; Giuseppe Papa; Maria Cristina Artesani; Marinella Viola; Alberto Venuti; Vincenzo Palmieri; Paolo Zeppilli

2001-01-01

299

Leg Immersion in Warm Water, Stretch-Shortening Exercise, and Exercise-Induced Muscle Damage  

PubMed Central

Context: Whether muscle warming protects against exercise-induced muscle damage is unknown. Objective: To determine the effect of leg immersion in warm water before stretch-shortening exercise on the time course of indirect markers of exercise-induced muscle damage. Design: Crossover trial. Setting: Human kinetics laboratory. Patients or Other Participants: Eleven healthy, untrained men (age ?=? 21.5 ± 1.7 years). Intervention(s): Participants' legs were immersed in a water bath at 44 ± 1°C for 45 minutes. Main Outcome Measure(s): Creatine kinase changes in the blood, muscle soreness, prolonged (within 72 hours) impairment in maximal voluntary contraction force and height of drop jump, and electrically evoked muscle force at low and high stimulation frequencies at short and long muscle lengths. Results: Leg immersion in warm water before stretch-shortening exercise reduced most of the indirect markers of exercise-induced muscle damage, including creatine kinase activity in the blood, muscle soreness, maximal voluntary contraction force, and jump height. The values for maximal voluntary contraction force and jump height, however, were higher during prewarming than for the control condition at 48 hours after stretch-shortening exercise, but this difference was only minor at other time points. Muscle prewarming did not bring about any changes in the dynamics of low-frequency fatigue, registered at either short or long muscle length, within 72 hours of stretch-shortening exercise. Conclusions: Leg immersion in warm water before stretch-shortening exercise reduced most of the indirect markers of exercise-induced muscle damage. However, the clinical application of muscle prewarming may be limited, because decreasing muscle damage did not necessarily lead to improved voluntary performance.

Skurvydas, Albertas; Kamandulis, Sigitas; Stanislovaitis, Aleksas; Streckis, Vytautas; Mamkus, Gediminas; Drazdauskas, Adomas

2008-01-01

300

Intermittent pneumatic compression effect on eccentric exercise-induced swelling, stiffness, and strength loss  

Microsoft Academic Search

Objective: The purpose was to determine if intermittent pneumatic compression (IPC) affects muscle swelling, stiffness, and strength loss resulting from eccentric exercise-induced injury of the elbow flexors. We hypothesized that the compression would decrease swelling and stiffness. Design: Repeated measures design with a before-after trial comparison within each day. Setting: Conducted at a university Somatic Dysfunction Laboratory. Subjects: Twenty-two college

Gary S. Chleboun; John N. Howell; Heather L. Baker; Tina N. Ballard; Jennifer L. Graham; Holly L. Hallman; Lori E. Perkins; Jonathan H. Schauss; Robert R. Conatser

1995-01-01

301

The Effects of Creatine Supplementation on Exercise-Induced Muscle Damage  

Microsoft Academic Search

This investigation evaluated the effects of oral creatine (Cr) supplementation on markers of exercise-induced muscle damage following high-force eccentric exercise in subjects randomly administered Cr or placebo (P) in a double-blind fashion. When injected, exogenous phosphocreatine has been shown to stabilize the muscle membrane in cardiac tissue and enhance recovery of strength and power following in- jury. Twenty-three men aged

ERIC S. RAWSON; BRIDGET GUNN; PRISCILLA M. CLARKSON

2001-01-01

302

Influence of previous concentric exercise on eccentric exercise-induced muscle damage  

Microsoft Academic Search

This study investigated whether a fatiguing concentric exercise performed immediately before eccentric exercise would exacerbate eccentric exercise-induced muscle damage. One arm of nine female subjects (mean - s: 23.3- 6.7 years) performed 12 maximal eccentric actions of the elbow flexors (ECC), and the other arm performed 100 repetitions of isokinetic concentric actions of the elbow flexors followed by the same

Kazunori Nosaka; Priscilla M. Clarkson

1997-01-01

303

Patient pain drawing in diagnosing the cause of exercise-induced leg pain  

Microsoft Academic Search

IntroductionClassifying symptoms by patient pain drawing (PPD) may be helpful in diagnosing chronic anterior compartment syndrome (CACS). We have investigated the sensitivity and interobserver reliability of the PPD to diagnose CACS among patients with exercise-induced leg pain (EILP).MethodsThis study included 88 consecutive patients (48 men, 40 women; mean age 33, range 13–66, years). Two observers independently diagnosed the causes of

K Rennerfelt; Q Zhang; J Styf

2011-01-01

304

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children  

Microsoft Academic Search

The effect over time of regular treatment with montelukast (MNT) in inhibiting exercise-induced bronchoconstriction (EIB) has never been evaluated in children. The aim of the present study was to examine the preventive effect of MNT against EIB in children at different time-points over a 4-week treatment period. Thirty-two asthmatic children (aged 6-12 yrs) were enrolled in a double-blinded, randomised, parallel

F. M. de Benedictis; M. M. del Giudice; N. Forenza; F. Decimo; D. de Benedictis; A. Capristo

2006-01-01

305

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability  

PubMed Central

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.

de Beer, Vincent J.; Merkus, Daphne; Bender, Shawn B.; Tharp, Darla L.; Bowles, Douglas K.; Duncker, Dirk J.

2013-01-01

306

Exercise-induced asthma: critical analysis of the protective role of montelukast  

PubMed Central

Exercise-induced asthma/exercise-induced bronchospasm (EIA/EIB) is a prevalent and clinically important disease affecting young children through older adulthood. These terms are often used interchangeably and the differences are not clearly defined in the literature. The pathogenesis of EIA/EIB may be different in those with persistent asthma compared to those with exercise-induced symptoms only. The natural history of EIA is unclear and may be different for elite athletes. Leukotriene biology has helped the understanding of EIB. The type and intensity of exercise are important factors for EIB. Exercise participation is necessary for proper development and control of EIA is recommended. Symptoms of EIB should be confirmed by proper testing. Biologic markers may also be helpful in diagnosis. Not all exercise symptoms are from EIB. Many medication and nonpharmacologic treatments are available. Asthma education is an important component of managing EIA. Many medications have been tested and the comparisons are complicated. Montelukast is a US Food and Drug Administration-approved asthma and EIB controller and has a number of potential advantages to other asthma medications including short onset of action, ease of use, and lack of tolerance. Not all patients improve with montelukast and rescue medication should be available.

Carver, Terrence W

2009-01-01

307

Acute exercise induces biphasic increase in respiratory mRNA in skeletal muscle  

SciTech Connect

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.

Ikeda, Shin-ichi [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8574 (Japan); Kizaki, Takako [Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Haga, Shukoh [Department of Exercise Physiology, Graduate School of Science, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo 192-0397 (Japan); Ohno, Hideki [Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Takemasa, Tohru [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8574 (Japan)], E-mail: takemasa@taiiku.tsukuba.ac.jp

2008-04-04

308

Exercise-induced left bundle branch block: a case report of false positive MIBI imaging and review of the literature.  

PubMed

Exercise-induced left bundle branch block is a relatively rare finding during exercise tolerance testing. A 36-year-old female with intermittent exercise-induced left bundle branch block, a MIBI study suggesting anterior ischemia and normal coronary arteries is reported. A review of the English and French language literature published from January 1985 to January 1996 is presented. Exercise-induced left bundle branch block has been reported in association with and without structural heart disease. Pooled mortality in the group with structural heart disease was 2.7% per year, and mortality was 0.17% per year when no structural heart disease was identified. Exercise-induced left bundle branch block has been reported to resolve with therapy. Noninvasive testing appears to have limited ability to detect or exclude coronary artery disease in this group. If a definitive cardiac diagnosis is required, strong consideration should be given to coronary angiography. PMID:9179091

Munt, B; Huckell, V F; Boone, J

1997-05-01

309

NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.  

PubMed

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

Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza; Marchet, Silvia; Sauve, Anthony A; Li, Wei; Leoni, Valerio; Schon, Eric A; Dantzer, Françoise; Auwerx, Johan; Viscomi, Carlo; Zeviani, Massimo

2014-06-01

310

NAD+-Dependent Activation of Sirt1 Corrects the Phenotype in a Mouse Model of Mitochondrial Disease  

PubMed Central

Summary 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.

Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza; Marchet, Silvia; Sauve, Anthony A.; Li, Wei; Leoni, Valerio; Schon, Eric A.; Dantzer, Francoise; Auwerx, Johan; Viscomi, Carlo; Zeviani, Massimo

2014-01-01

311

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...

312

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...

313

Mitochondrial Dysfunction in Cancer  

PubMed Central

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.

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

2013-01-01

314

Increased Insulin Sensitivity and Distorted Mitochondrial Adaptations during Muscle Unloading  

PubMed Central

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.

Qi, Zhengtang; Zhang, Yuan; Guo, Wei; Ji, Liu; Ding, Shuzhe

2012-01-01

315

The ubiquitin-proteasome system regulates mitochondrial intermembrane space proteins.  

PubMed

Mitochondrial precursor proteins are synthesized in the cytosol and subsequently imported into mitochondria. The import of mitochondrial intermembrane space proteins is coupled with their oxidative folding and governed by the mitochondrial intermembrane space import and assembly (MIA) pathway. The cytosolic steps that precede mitochondrial import are not well understood. We identified a role for the ubiquitin-proteasome system in the biogenesis of intermembrane space proteins. Interestingly, the function of the ubiquitin-proteasome system is not restricted to conditions of mitochondrial protein import failure. The ubiquitin-proteasome system persistently removes a fraction of intermembrane space proteins under physiological conditions, acting as a negative regulator in the biogenesis of this class of proteins. Thus, the ubiquitin-proteasome system plays an important role in determining the levels of proteins targeted to the intermembrane space of mitochondria. PMID:23508107

Bragoszewski, Piotr; Gornicka, Agnieszka; Sztolsztener, Malgorzata E; Chacinska, Agnieszka

2013-06-01

316

The Ubiquitin-Proteasome System Regulates Mitochondrial Intermembrane Space Proteins  

PubMed Central

Mitochondrial precursor proteins are synthesized in the cytosol and subsequently imported into mitochondria. The import of mitochondrial intermembrane space proteins is coupled with their oxidative folding and governed by the mitochondrial intermembrane space import and assembly (MIA) pathway. The cytosolic steps that precede mitochondrial import are not well understood. We identified a role for the ubiquitin-proteasome system in the biogenesis of intermembrane space proteins. Interestingly, the function of the ubiquitin-proteasome system is not restricted to conditions of mitochondrial protein import failure. The ubiquitin-proteasome system persistently removes a fraction of intermembrane space proteins under physiological conditions, acting as a negative regulator in the biogenesis of this class of proteins. Thus, the ubiquitin-proteasome system plays an important role in determining the levels of proteins targeted to the intermembrane space of mitochondria.

Bragoszewski, Piotr; Gornicka, Agnieszka; Sztolsztener, Malgorzata E.

2013-01-01

317

Mitochondrial alteration in type 2 diabetes and obesity  

PubMed Central

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 PGC1? 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.

Cheng, Zhiyong; Almeida, Fabio A

2014-01-01

318

The influence of ice slushy on voluntary contraction force following exercise-induced hyperthermia.  

PubMed

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

Burdon, Catriona A; Easthope, Christopher S; Johnson, Nathan A; Chapman, Phillip G; O'Connor, Helen

2014-07-01

319

[Effect of atorvastatin on exercise tolerance in patients with diastolic dysfunction and exercise-induced hypertension].  

PubMed

OBJECTIVE? To investigate the effect of atorvastatin on exercise tolerance in patients with diastolic dysfunction and exercise-induced hypertension. METHODS? A randomized? double-blind? placebo-controlled prospective study was performed. Sixty patients with diastolic dysfunction ?mitral flow velocity E/A <1? and exercise-induced hypertension ?SBP>200 mm Hg? treated with atorvastatin ?20 mg q.d? or placebo for 1 year. Cardiopulmonary exercise test and exercise blood pressure measurement were performed. Plasma B-natriuretic peptide ?BNP? concentration at rest and at peak exercise? plasma high sensitive-C reaction protein ?hs-CRP? and endothelin ?ET? concentration were determined at baseline and after treatment. RESULTS? After treatment by atorvastatin? the resting SBP? pulse pressure? the peak exercise SBP and BNP were significantly decreased; and the exercise time? metabolic equivalent? maximal oxygen uptake and anaerobic threshold were increased. All of these parameters had significant differences with baseline levels ?P<0.05?? and the rest pulse pressure? the peak exercise SBP and BNP? and the exercise time had significant differences compared with placebo treatment ?P<0.05?. Plasma concentrations of hs-CRP and ET were markedly reduced by atorvastatin treatment compared with baseline and placebo ?P<0.05?. No difference in above parameters was found before and after placebo treatment ?P>0.05?. CONCLUSION? In patients with diastolic dysfunction at rest and exercise-induced hypertension? atorvastatin can effectively reduce plasma hs-CRP and ET level? lower blood pressure and peak exercise SBP? decrease peak exercise plasma BNP concentration? and ultimately improve exercise tolerance? PMID:24998653

Ye, Ping-Xian; Ye, Ping-Zhen; Zhu, Jian-Hua; Chen, Wei; Gao, Dan Chen

2014-05-25

320

Exercise-induced changes in interleukin-10 in patients with knee osteoarthritis: new perspectives?  

PubMed Central

Osteoarthritis (OA) of the knee is a common chronic disease leading to increased morbidity and reduced quality of life. Although exercise therapy has been shown to be beneficial for both pain and physical functioning, its underlying mechanism is not fully understood. However, a recent study found an exercise-induced increase in interleukin-10 levels, to which anti-inflammatory and chondroprotective properties are ascribed, in the (peri-)synovial fluid of patients with knee OA. These interesting results provide more insight into the effects of exercise in OA and need to be validated and confirmed. Hopefully, the study offers a promising basis for further research

2010-01-01

321

Assessment of exercise-induced bronchoconstriction in adolescents and young children.  

PubMed

Recent research shows important differences in exercise-induced bronchoconstriction (EIB) between children and adults, suggesting a different pathophysiology of EIB in children. Although exercise can trigger classic symptoms of asthma, in children symptoms can be subtle and nonspecific; parents, children, and clinicians often do not recognize EIB. With an age-adjusted protocol, an exercise challenge test can be performed in children as young as 3 years of age. However, an alternative challenge test is sometimes necessary to assess potential for EIB in children. This review summarizes age-related features of EIB and recommendations for assessing EIB in young children and adolescents. PMID:23830131

van Leeuwen, Janneke C; Driessen, Jean M M; Kersten, Elin T G; Thio, Bernard J

2013-08-01

322

Exercise-induced muscle damage and the repeated bout effect: evidence for cross transfer  

Microsoft Academic Search

We examined whether a prior bout of eccentric exercise in the elbow flexors provided protection against exercise-induced muscle\\u000a damage in the contralateral arm. Fifteen males (age 22.7 ± 2.1 years; height 178.6 ± 6.8 cm, mass 75.8 ± 9.3 kg) were randomly\\u000a assigned to two groups who performed two bouts of 60 eccentric contractions (30°\\/s) separated by 2 weeks: ipsilateral (n = 7, both bouts performed in the same arm), contralateral (n = 8,

Chelsea Starbuck; Roger G. Eston

323

Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension.  

PubMed

Renovascular hypertension alters cardiac structure and function. Autophagy is activated during left ventricular hypertrophy and linked to adverse cardiac function. The angiotensin II receptor blocker, valsartan, lowers blood pressure and is cardioprotective, but whether it modulates autophagy in the myocardium is unclear. We hypothesized that valsartan would alleviate autophagy and improve left ventricular myocardial mitochondrial turnover in swine renovascular hypertension. Domestic pigs were randomized to control, unilateral renovascular hypertension, and renovascular hypertension treated with valsartan (320 mg/d) or conventional triple therapy (reserpine+hydralazine+hydrochlorothiazide) for 4 weeks after 6 weeks of renovascular hypertension (n=7 each group). Left ventricular remodeling, function, and myocardial oxygenation and microcirculation were assessed by multidetector computer tomography, blood oxygen level-dependent MRI, and microcomputer tomography. Myocardial autophagy, markers for mitochondrial degradation and biogenesis, and mitochondrial respiratory-chain proteins were examined ex vivo. Renovascular hypertension induced left ventricular hypertrophy and myocardial hypoxia, enhanced cellular autophagy and mitochondrial degradation, and suppressed mitochondrial biogenesis. Valsartan and triple therapy similarly decreased blood pressure, but valsartan solely alleviated left ventricular hypertrophy, ameliorated myocardial autophagy and mitophagy, and increased mitochondrial biogenesis. In contrast, triple therapy only slightly attenuated autophagy and preserved mitochondrial proteins, but elicited no improvement in mitophagy. These data suggest a novel potential role of valsartan in modulating myocardial autophagy and mitochondrial turnover in renovascular hypertension-induced hypertensive heart disease, which may possibly bolster cardiac repair via a blood pressure-independent manner. PMID:24752430

Zhang, Xin; Li, Zi-Lun; Crane, John A; Jordan, Kyra L; Pawar, Aditya S; Textor, Stephen C; Lerman, Amir; Lerman, Lilach O

2014-07-01

324

Biogenesis of Bacterial Membrane Vesicles  

PubMed Central

Membrane vesicle (MV) release remains undefined, despite its conservation among replicating Gram-negative bacteria both in vitro and in vivo. Proteins identified in Salmonella MVs, derived from the envelope, control MV production via specific defined domains that promote outer membrane protein-peptidoglycan (OM-PG) and OM protein-inner membrane protein (OM-PG-IM) interactions within the envelope structure. Modulation of OM-PG and OM-PG-IM interactions along the cell body and at division septa, respectively, maintains membrane integrity while coordinating localized release of MVs with distinct size distribution and protein content. These data support a model of MV biogenesis, wherein bacterial growth and division invoke temporary, localized reductions in the density of OM-PG and OM-PG-IM associations within the envelope structure, thus releasing outer membrane as MVs.

Deatherage, Brooke L.; Lara, J. Cano; Bergsbaken, Tessa; Barrett, Sara L. Rassoulian; Lara, Stephanie; Cookson, Brad T.

2009-01-01

325

Plant Peroxisomes: Biogenesis and Function  

PubMed Central

Peroxisomes are eukaryotic organelles that are highly dynamic both in morphology and metabolism. Plant peroxisomes are involved in numerous processes, including primary and secondary metabolism, development, and responses to abiotic and biotic stresses. Considerable progress has been made in the identification of factors involved in peroxisomal biogenesis, revealing mechanisms that are both shared with and diverged from non-plant systems. Furthermore, recent advances have begun to reveal an unexpectedly large plant peroxisomal proteome and have increased our understanding of metabolic pathways in peroxisomes. Coordination of the biosynthesis, import, biochemical activity, and degradation of peroxisomal proteins allows for highly dynamic responses of peroxisomal metabolism to meet the needs of a plant. Knowledge gained from plant peroxisomal research will be instrumental to fully understanding the organelle’s dynamic behavior and defining peroxisomal metabolic networks, thus allowing the development of molecular strategies for rational engineering of plant metabolism, biomass production, stress tolerance, and pathogen defense.

Hu, Jianping; Baker, Alison; Bartel, Bonnie; Linka, Nicole; Mullen, Robert T.; Reumann, Sigrun; Zolman, Bethany K.

2012-01-01

326

Tdrkh is essential for spermatogenesis and participates in primary piRNA biogenesis in the germline  

PubMed Central

Piwi proteins and Piwi-interacting RNAs (piRNAs) repress transposition, regulate translation, and guide epigenetic programming in the germline. Here, we show that an evolutionarily conserved Tudor and KH domain-containing protein, Tdrkh (a.k.a. Tdrd2), is required for spermatogenesis and involved in piRNA biogenesis. Tdrkh partners with Miwi and Miwi2 via symmetrically dimethylated arginine residues in Miwi and Miwi2. Tdrkh is a mitochondrial protein often juxtaposed to pi-bodies and piP-bodies and is required for Tdrd1 cytoplasmic localization and Miwi2 nuclear localization. Tdrkh mutants display meiotic arrest at the zygotene stage, attenuate methylation of Line1 DNA, and upregulate Line1 RNA and protein, without inducing apoptosis. Furthermore, Tdrkh mutants have severely reduced levels of mature piRNAs but accumulate a distinct population of 1?U-containing, 2?O-methylated 31–37?nt RNAs that largely complement the missing mature piRNAs. Our results demonstrate that the primary piRNA biogenesis pathway involves 3??5? processing of 31–37?nt intermediates and that Tdrkh promotes this final step of piRNA biogenesis but not the ping-pong cycle. These results shed light on mechanisms underlying primary piRNA biogenesis, an area in which information is conspicuously absent.

Saxe, Jonathan P; Chen, Mengjie; Zhao, Hongyu; Lin, Haifan

2013-01-01

327

Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis  

PubMed Central

Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes1. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control2. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism3. Moreover, in animal models, autophagy protects against diseases such as cancer, neuro-degenerative disorders, infections, inflammatory diseases, ageing and insulin resistance4-6. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)- induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.

He, Congcong; Bassik, Michael C.; Moresi, Viviana; Sun, Kai; Wei, Yongjie; Zou, Zhongju; An, Zhenyi; Loh, Joy; Fisher, Jill; Sun, Qihua; Korsmeyer, Stanley; Packer, Milton; May, Herman I.; Hill, Joseph A.; Virgin, Herbert W.; Gilpin, Christopher; Xiao, Guanghua; Bassel-Duby, Rhonda; Scherer, Philipp E.; Levine, Beth

2012-01-01

328

Effects of curcumin supplementation on exercise-induced oxidative stress in humans.  

PubMed

The purpose of this study was to investigate the effects of curcumin supplementation on exercise-induced oxidative stress in humans. 10 male participants, ages 26.8±2.0 years (mean±SE), completed 3 trials in a random order: (1) placebo (control), (2) single (only before exercise) and (3) double (before and immediately after exercise) curcumin supplementation trials. Each participant received oral administration of 90?mg of curcumin or the placebo 2h before exercise and immediately after exercise. Each participant walked or ran at 65% of V?2max on a treadmill for 60min. Blood samples were collected pre-exercise, immediately after exercise and 2h after exercise. The concentrations of serum derivatives of reactive oxygen metabolites measured immediately after exercise were significantly higher than pre-exercise values in the placebo trial (308.8±12.9 U. CARR, P<0.05), but not in the single (259.9±17.1 U. CARR) or double (273.6±19.7 U. CARR) curcumin supplementation trials. Serum biological antioxidant potential concentrations measured immediately after exercise were significantly elevated in the single and double curcumin supplementation trials compared with pre-exercise values (P<0.05). These findings indicate that curcumin supplementation can attenuate exercise-induced oxidative stress by increasing blood antioxidant capacity. PMID:24165958

Takahashi, M; Suzuki, K; Kim, H K; Otsuka, Y; Imaizumi, A; Miyashita, M; Sakamoto, S

2014-06-01

329

The endocannabinoid system mediates aerobic exercise-induced antinociception in rats.  

PubMed

Exercise-induced antinociception is widely described in the literature, but the mechanisms involved in this phenomenon are poorly understood. Systemic (s.c.) and central (i.t., i.c.v.) pretreatment with CB? and CB? cannabinoid receptor antagonists (AM251 and AM630) blocked the antinociception induced by an aerobic exercise (AE) protocol in both mechanical and thermal nociceptive tests. Western blot analysis revealed an increase and activation of CB? receptors in the rat brain, and immunofluorescence analysis demonstrated an increase of activation and expression of CB? receptors in neurons of the periaqueductal gray matter (PAG) after exercise. Additionally, pretreatment (s.c., i.t. and i.c.v.) with endocannabinoid metabolizing enzyme inhibitors (MAFP and JZL184) and an anandamide reuptake inhibitor (VDM11) prolonged and intensified this antinociceptive effect. These results indicate that exercise could activate the endocannabinoid system, producing antinociception. Supporting this hypothesis, liquid-chromatography/mass-spectrometry measurements demonstrated that plasma levels of endocannabinoids (anandamide and 2-arachidonoylglycerol) and of anandamide-related mediators (palmitoylethanolamide and oleoylethanolamide) were increased after AE. Therefore, these results suggest that the endocannabinoid system mediates aerobic exercise-induced antinociception at peripheral and central levels. PMID:24148812

Galdino, Giovane; Romero, Thiago R L; Silva, José Felipe P; Aguiar, Daniele C; de Paula, Ana Maria; Cruz, Jader S; Parrella, Cosimo; Piscitelli, Fabiana; Duarte, Igor D; Di Marzo, Vincenzo; Perez, Andrea C

2014-02-01

330

Effects of supplementation with alpha-lipoic acid on exercise-induced activation of coagulation.  

PubMed

Physical exercise leads to minor activation of blood coagulation, which appears to be balanced by a concomitant activation of the fibrinolytic system. The mechanisms underlying this physiological phenomenon are still unknown. To evaluate the role of oxidative stress for exercise-induced activation of coagulation, we investigated if supplementation with alpha -lipoic acid (LA) as an antioxidant reduces the hemostatic response to exercise. Ten young men (age, 25 +/- 4 years; maximal oxygen consumption [V o 2 max], 61 +/- 6 mL/(kg min) [mean +/- SD]) were subjected to a 1-hour run on a treadmill at a velocity corresponding to an oxygen demand of 75% to 80% of maximum (anaerobic threshold). Exercise testing was repeated in the same subjects after supplementation with LA (1200 mg/d PO) for 10 days. Molecular markers of thrombin (prothrombin fragment 1 + 2, thrombin-antithrombin complexes) and fibrin formation (fibrinopeptide A) as well as markers of the fibrinolytic activity (tissue-plasminogen activator, plasmin-antiplasmin complexes, d -dimers) and of lipid peroxidation (malondialdehyde) were determined before and immediately after exercise. Supplementation therapy with LA had no effect on hemostatic and fibrinolytic variables either at rest or in response to exercise. Likewise, concentrations of malondialdehyde at rest and after exercise were not influenced by LA. In summary, the hemostatic response to exercise is not affected by supplementation with LA in young healthy male individuals. The role of oxidative stress for exercise-induced activation of coagulation has to be defined in further studies. PMID:15931620

Weiss, Claus; Bierhaus, Angelika; Nawroth, Peter P; Bärtsch, Peter

2005-06-01

331

Exercise-induced muscle glucose uptake in mice with graded, muscle-specific GLUT-4 deletion  

PubMed Central

To investigate the importance of the glucose transporter GLUT-4 for muscle glucose uptake during exercise, transgenic mice with skeletal muscle GLUT-4 expression approximately 30–60% of normal (CON) and approximately 5–10% of normal (KO) were generated using the Cre/Lox system and compared with wild-type (WT) mice during approximately 40 min of treadmill running (KO: 37.7 ± 1.3 min; WT: 40 min; CON: 40 min, P = 0.18). In WT and CON animals, exercise resulted in an overall increase in muscle glucose uptake. More specifically, glucose uptake was increased in red gastrocnemius of WT mice and in the soleus and red gastrocnemius of CON mice. In contrast, the exercise-induced increase in muscle glucose uptake in all muscles was completely abolished in KO mice. Muscle glucose uptake increased during exercise in both red and white quadriceps of WT mice, while the small increases in CON mice were not statistically significant. In KO mice, there was no change at all in quadriceps muscle glucose uptake. No differences in muscle glycogen use during exercise were observed between any of the groups. However, there was a significant increase in plasma glucose levels after exercise in KO mice. The results of this study demonstrated that a reduction in skeletal muscle GLUT-4 expression to approximately 10% of normal levels completely abolished the exercise-induced increase in muscle glucose uptake.

Howlett, Kirsten F; Andrikopoulos, Sofianos; Proietto, Joseph; Hargreaves, Mark

2013-01-01

332

Exercise-induced silent myocardial ischemia: Evaluation by thallium-201 emission computed tomography  

SciTech Connect

Factors associated with silent myocardial ischemia (SMI) during exercise testing were studied by means of thallium-201 emission computed tomography (ECT) in 471 patients. Coronary angiography was done in 290, of whom 167 were found to have significant coronary artery disease (CAD). Exercise-induced ischemia and its severity were defined with ECT. During exercise 108 (62%) of 173 patients with ischemia and 57 (50%) of 115 with ischemia and angiographically documented CAD had no chest pain. One third of the patients showed an inconsistency between scintigraphic ischemia and ischemia ST depression. Age, sex, prior myocardial infarction, and diabetes mellitus were not related to SMI. Patients with SMI had less severe ischemia despite a higher peak double product compared to those with painful ischemia. Among 91 with prior myocardial infarction and exercise-induced ischemia, 51 with periinfarction ischemia had a higher frequency of SMI than did 14 with ischemia remote from the prior infarct zone despite similarities in the severity of ischemia. In conclusion, factors localized within ischemic myocardium such as less severe ischemia or adjacency to a prior infarct made SMI more prevalent.

Kurata, C.; Sakata, K.; Taguchi, T.; Kobayashi, A.; Yamazaki, N. (Hamamatsu Univ. School of Medicine (Japan))

1990-03-01

333

Sex Differences in Exercise-Induced Muscle Pain and Muscle Damage  

PubMed Central

There is uncertainty about sex differences in exercise-induced muscle pain and muscle damage due to several methodological weaknesses in the literature. This investigation tested the hypothesis that higher levels of exercise-induced muscle pain and muscle damage indicators would be found in women than men when several methodological improvements were executed in the same study. Participants (N = 33; 42% women) with an average age of 23 years (SD = 2.82) consented to participate. After a familiarization session, participants visited the laboratory before and across four days after eccentric exercise was completed to induce arm muscle pain and muscle damage. Our primary outcomes were arm pain ratings and pressure pain thresholds. However, we also measured the following indicators of muscle damage: arm girth; resting elbow extension; isometric elbow flexor strength; myoglobin (Mb); tumor necrosis factor (TNFa); interleukin 1beta (IL1b); and total nitric oxide (NO). Temporary induction of muscle damage was indicated by changes in all outcome measures except TNFa, and IL1b. In contrast to our hypotheses, women reported moderately lower and less frequent muscle pain than men. Also, women’s arm girth and Mb levels increased moderately less than men’s, but the differences were not significant. Few large sex differences were detected.

Dannecker, Erin A.; Liu, Ying; Rector, R. Scott; Thomas, Tom R.; Fillingim, Roger B.; Robinson, Michael E.

2012-01-01

334

Statins alter oxidant-antioxidant status and lower exercise-induced oxidative stress.  

PubMed

Data on effects of statins on resting oxidant-antioxidant status are contradictory and no study has been published on the effects of statins on exercise-induced oxidative stress. We carried out a 6-month longitudinal study in 10 dyslipidemic patients receiving 10 mg/day atorvastatin and 13 healthy sedentary subjects. Thiobarbituric acid reactive substances (TBARS) and reduced ascorbic acid (RAA) were measured in plasma at rest and every 5 minutes after submaximal isometric thumb adduction and handgrip sustained until exhaustion. At inclusion, resting TBARS and RAA levels in controls and patients did not differ and exercise increased TBARS and decreased RAA. Atorvastatin reduced resting TBARS and RAA levels in a time-dependent but lipid-independent manner. The main effect was a post-exercise increase in TBARS, without affecting the post-exercise RAA levels. The reduction in oxidative stress occurred earlier in oxidative muscles involved in thumb adduction. In conclusion, atorvastatin lowers resting oxidant-antioxidant activity: exercise-induced oxidative stress occurs mainly in muscles having a high oxidative capacity. PMID:17474543

Delliaux, S; Steinberg, J G; Bechis, G; Paganelli, F; Oliver, C; Lesavre, N; Jammes, Y

2007-04-01

335

Eccentric exercise induces chronic alterations in musculoskeletal nociception in the rat  

PubMed Central

Eccentric muscle exercise is a common cause of acute and chronic (lasting days to weeks) musculoskeletal pain. To evaluate mechanisms involved, we have employed a model in the rat, in which eccentric hind limb exercise produces both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to subsequent exposure to an inflammatory mediator. Eccentric exercise of the hind limb produced mechanical hyperalgesia, measured in the gastrocnemius muscle, that returned to baseline 120 h post-exercise. When nociceptive thresholds had returned to baseline, intramuscular injection of prostaglandin E2 (PGE2) induced hyperalgesia that was unattenuated 240 h later, much longer than PGE2–induced hyperalgesia in unexercised rats (4 h). This marked prolongation of PGE2 hyperalgesia induced by eccentric exercise was prevented by spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase C?, a second messenger in nociceptors implicated in the induction of chronic pain. Exercise-induced hyperalgesia and prolongation of PGE2 hyperalgesia was inhibited by spinal intrathecal administration of antisense for the interleukin-6, but not the tumor necrosis factor-? type-1 receptor. These findings provide further insight into the mechanism underlying exercise-induced chronic muscle pain, which suggest novel approaches for the prevention and treatment of exercise or work-related chronic musculoskeletal pain syndromes.

Alvarez, Pedro; Levine, Jon D.; Green, Paul G.

2010-01-01

336

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children.  

PubMed

The effect over time of regular treatment with montelukast (MNT) in inhibiting exercise-induced bronchoconstriction (EIB) has never been evaluated in children. The aim of the present study was to examine the preventive effect of MNT against EIB in children at different time-points over a 4-week treatment period. Thirty-two asthmatic children (aged 6-12 yrs) were enrolled in a double-blinded, randomised, parallel group design to receive a 4-week treatment with MNT (5 mg chewable tablets administered once daily in the evening) or placebo. Exercise challenge was performed at baseline and after 3, 7 and 28 days of treatment, 20-24 h after dosing. MNT was significantly more protective than placebo against EIB at each time. The mean percentage drop of forced expiratory volume in one second (FEV1) was 24.6, 13.6, 12.0 and 11.6 for MNT, and 24.4, 22.4, 21.8 and 21.0 for placebo, at baseline and after 3, 7 and 28 days, respectively. For each drug, no significant difference in the percentage drop of FEV1 was found between different days. Regular treatment with montelukast provided significant protection against exercise-induced bronchoconstriction in asthmatic children over a 4-week period with no tolerance to the bronchoprotective effect. PMID:16641126

de Benedictis, F M; del Giudice, M M; Forenza, N; Decimo, F; de Benedictis, D; Capristo, A

2006-08-01

337

Unravelling mitochondrial pathways to Parkinson's disease.  

PubMed

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson's disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson's disease models. However, identification of the recessive genes implicated in Parkinson's disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson's disease. PMID:24117181

Celardo, I; Martins, L M; Gandhi, S

2014-04-01

338

Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction?  

PubMed

Mitochondrial dysfunction is central to numerous diseases of oxidative stress. Changes in mitochondrial DNA (MtDNA) content, often measured as mitochondrial genome to nuclear genome ratio (Mt/N) using real time quantitative PCR, have been reported in a broad range of human diseases, such as diabetes and its complications, obesity, cancer, HIV complications, and ageing. We propose the hypothesis that MtDNA content in body fluids and tissues could be a biomarker of mitochondrial dysfunction and review the evidence supporting this theory. Increased reactive oxygen species resulting from an external trigger such as hyperglycaemia or increased fat in conditions of oxidative stress could lead to enhanced mitochondrial biogenesis, and increased Mt/N. Altered MtDNA levels may contribute to enhanced oxidative stress and inflammation and could play a pathogenic role in mitochondrial dysfunction and disease. Changes in Mt/N are detectable in circulating cells such as peripheral blood mononuclear cells and these could be used as surrogate to predict global changes in tissues and organs. We review a large number of studies reporting changes in MtDNA levels in body fluids such as circulating blood cells, cell free serum, saliva, sperm, and cerebrospinal fluid as well as in tumour and normal tissue samples. However, the data are often conflicting as the current methodology used to measure Mt/N can give false results because of one or more of the following reasons (1) use of mitochondrial primers which co-amplify nuclear pseudogenes (2) use of nuclear genes which are variable and/or duplicated in numerous locations (3) a dilution bias caused by the differing genome sizes of the mitochondrial and nuclear genome and (4) template preparation protocols which affect the yields of nuclear and mitochondrial genomes. Development of robust and reproducible methodology is needed to test the hypothesis that MtDNA content in body fluids is biomarker of mitochondrial dysfunction. PMID:23085537

Malik, Afshan N; Czajka, Anna

2013-09-01

339

Therapeutic prospects for mitochondrial disease  

PubMed Central

Until even only a few years ago, the idea that effective therapies for human mitochondrial disorders resulting from dysfunction of the respiratory chain/oxidative phosphorylation system (OxPhos) could be developed was unimaginable. The obstacles to treating diseases caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), and which had the potential to affect nearly every organ system, seemed overwhelming. However, while clinically applicable therapies still remain largely in the future, the landscape has changed dramatically; we can now envision the possibility of treating some of these disorders. Among these are techniques to upregulate mitochondrial biogenesis, to enhance organellar fusion and fission, to “shift heteroplasmy,” and to eliminate the burden of mutant mtDNAs via cytoplasmic transfer.

Schon, Eric A.; DiMauro, Salvatore; Hirano, Michio; Gilkerson, Robert W.

2010-01-01

340

Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: a randomised controlled trial  

Microsoft Academic Search

Aims\\/hypothesis  Patients with type 1 diabetes mellitus are more susceptible than healthy individuals to exercise-induced oxidative stress\\u000a and vascular endothelial dysfunction, which has important implications for the progression of disease. Thus, in the present\\u000a study, we designed a randomised double-blind, placebo-controlled trial to test the original hypothesis that oral prophylaxis\\u000a with vitamin C attenuates rest and exercise-induced free radical-mediated lipid peroxidation

G. W. Davison; T. Ashton; L. George; I. S. Young; J. McEneny; B. Davies; S. K. Jackson; J. R. Peters; D. M. Bailey

2008-01-01

341

Molecular Mechanisms for Age-Associated Mitochondrial Deficiency in Skeletal Muscle  

PubMed Central

The abundance, morphology, and functional properties of mitochondria decay in skeletal muscle during the process of ageing. Although the precise mechanisms remain to be elucidated, these mechanisms include decreased mitochondrial DNA (mtDNA) repair and mitochondrial biogenesis. Mitochondria possess their own protection system to repair mtDNA damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes. However, mtDNA mutations have shown to be accumulated with age in skeletal muscle. When damaged mitochondria are eliminated by autophagy, mitochondrial biogenesis plays an important role in sustaining energy production and physiological homeostasis. The capacity for mitochondrial biogenesis has shown to decrease with age in skeletal muscle, contributing to progressive mitochondrial deficiency. Understanding how these endogenous systems adapt to altered physiological conditions during the process of ageing will provide a valuable insight into the underlying mechanisms that regulate cellular homeostasis. Here we will summarize the current knowledge about the molecular mechanisms responsible for age-associated mitochondrial deficiency in skeletal muscle. In particular, recent findings on the role of mtDNA repair and mitochondrial biogenesis in maintaining mitochondrial functionality in aged skeletal muscle will be highlighted.

Wagatsuma, Akira; Sakuma, Kunihiro

2012-01-01

342

Mitochondrial Respiration Regulates Adipogenic Differentiation of Human Mesenchymal Stem Cells  

PubMed Central

Human mesenchymal stem cells (MSCs) are adult multipotent stem cells which can be isolated from bone marrow, adipose tissue as well as other tissues and have the capacity to differentiate into a variety of mesenchymal cell types such as adipocytes, osteoblasts and chondrocytes. Differentiation of stem cells into mature cell types is guided by growth factors and hormones, but recent studies suggest that metabolic shifts occur during differentiation and can modulate the differentiation process. We therefore investigated mitochondrial biogenesis, mitochondrial respiration and the mitochondrial membrane potential during adipogenic differentiation of human MSCs. In addition, we inhibited mitochondrial function to assess its effects on adipogenic differentiation. Our data show that mitochondrial biogenesis and oxygen consumption increase markedly during adipogenic differentiation, and that reducing mitochondrial respiration by hypoxia or by inhibition of the mitochondrial electron transport chain significantly suppresses adipogenic differentiation. Furthermore, we used a novel approach to suppress mitochondrial activity using a specific siRNA-based knockdown of the mitochondrial transcription factor A (TFAM), which also resulted in an inhibition of adipogenic differentiation. Taken together, our data demonstrates that increased mitochondrial activity is a prerequisite for MSC differentiation into adipocytes. These findings suggest that metabolic modulation of adult stem cells can maintain stem cell pluripotency or direct adult stem cell differentiation.

Toth, Peter T.; Rehman, Jalees

2013-01-01

343

The effect of exercise-induced hypoxemia on blood redox status in well-trained rowers.  

PubMed

Exercise-induced arterial hypoxemia (EIAH), characterized by decline in arterial oxyhemoglobin saturation (SaO(2)), is a common phenomenon in endurance athletes. Acute intensive exercise is associated with the generation of reactive species that may result in redox status disturbances and oxidation of cell macromolecules. The purpose of the present study was to investigate whether EIAH augments oxidative stress as determined in blood plasma and erythrocytes in well-trained male rowers after a 2,000-m rowing ergometer race. Initially, athletes were assigned into either the normoxemic (n = 9, SaO(2) >92%, [Formula: see text]: 62.0 ± 1.9 ml kg(-1) min(-1)) or hypoxemic (n = 12, SaO(2) <92%, [Formula: see text]: 60.5 ± 2.2 ml kg(-1 )min(-1), mean ± SEM) group, following an incremental [Formula: see text] test on a wind resistance braked rowing ergometer. On a separate day the rowers performed a 2,000-m all-out effort on the same rowing ergometer. Following an overnight fast, blood samples were drawn from an antecubital vein before and immediately after the termination of the 2,000-m all-out effort and analyzed for selective oxidative stress markers. In both the normoxemic (SaO(2): 94.1 ± 0.9%) and hypoxemic (SaO(2): 88.6 ± 2.4%) rowers similar and significant exercise increase in serum thiobarbituric acid-reactive substances, protein carbonyls, catalase and total antioxidant capacity concentration were observed post-2,000 m all-out effort. Exercise significantly increased the oxidized glutathione concentration and decreased the ratio of reduced (GSH)-to-oxidized (GSSG) glutathione in the normoxemic group only, whereas the reduced form of glutathione remained unaffected in either groups. The increased oxidation of GSH to GSSG in erythrocytes of normoxemic individuals suggest that erythrocyte redox status may be affected by the oxygen saturation degree of hemoglobin. Our findings indicate that exercise-induced hypoxemia did not further affect the increased blood oxidative damage of lipids and proteins observed after a 2,000-m rowing ergometer race in highly-trained male rowers. The present data do not support any potential link between exercise-induced hypoxemia, oxidative stress increase and exercise performance. PMID:21947454

Kyparos, Antonios; Riganas, Christos; Nikolaidis, Michalis G; Sampanis, Michalis; Koskolou, Maria D; Grivas, Gerasimos V; Kouretas, Dimitrios; Vrabas, Ioannis S

2012-06-01

344

Renal hypouricemia: prevention of exercise-induced acute renal failure and a review of the literature.  

PubMed

Isolated renal hypouricemia from defective uric acid reabsorption and/or secretion is a well-described entity, with a prevalence of 0.12% to 0.20% in Japan. It is rarely associated with exercise-induced acute renal failure (ARF). The etiology of ARF is debated. Prevention of ARF in renal hypouricemia has not been previously addressed. A 29-year-old Pakistani man had recurrent exercise-induced ARF. He was found to have isolated renal hypouricemia; serum uric acid 0.5 mg/dL, 24-hour urine uric acid 472 +/- 25 mg (+/- SD), and fractional excretion of uric acid 55.2% to 69.4%. Both pyrazinamide and probenecid decreased fractional excretion of uric acid and uric acid excretion rate (UV(Urate)) in our patient, suggesting either a partial presecretory and postsecretory reabsorption defect or increased secretion. We investigated renal uric acid excretion during exercise in our patient and four control subjects. All five subjects underwent a physical fitness test (PFT). Our patient developed ARF. Uric acid excretion rate increased in our patient, from 0.48 mg/min at baseline to 1.49 mg/min 4 hours after the PFT, as did the urine uric acid to urine creatinine ratio (UUa)/UCr) (0.29 to 1.49). In the controls, UV(Urate) and UUA/UCr were unchanged after the PFT: UV(Urate) was 0.46 +/- 0.10 mg/min at baseline and 0.59 +/- 0.04 mg/min 4 hours after the PFT, while UUA/UCr was 0.30 +/- 0.04 at baseline and 0.36 +/- 0.04 at 4 hours. All five subjects took allopurinol 300 mg daily for 5 days and repeated the PFT. In our patient, allopurinol prevented the ARF as well as the exercise-induced increases in UV(Urate) (0.28 mg/min to 0.22 mg/min) and UUA/UCr (0.25 to 0.17). In the controls, the UV(Urate) and UUA/UCr responses to exercise were not altered. We conclude that increased renal excretion of uric acid during exercise was responsible for the ARF in our patient with renal hypouricemia and that successful prophylaxis with allopurinol is possible. PMID:7771493

Yeun, J Y; Hasbargen, J A

1995-06-01

345

Exercise-induced left bundle branch block: an infrequent phenomenon: Report of two cases  

PubMed Central

Exercise-induced left bundle branch block (EI-LBBB) is infrequent phenomenon. We present two patients with angina pectoris who developed EI-LBBB during exercise tolerance test. The first patient with typical angina pectoris had significant obstructive coronary artery disease (CAD) requiring percutaneous coronary intervention of multiple lesions including placement of drug eluting stents. The second patient had atypical chest pain without signs of CAD at all. EI-LBBB occurred at a heart rate of 80 bpm and 141 bpm in the first and second patient, respectively. EI-LBBB remained visible through the test till the recovery period in the first patient at a heart rate of 83 bpm and disappeared at 96 bpm in the second patient. Both patients with this infrequent phenomenon are discussed and the literature is reviewed.

Said, Salah AM; Bultje-Peters, Marisa; Nijhuis, Rogier LG

2013-01-01

346

Exercise-induced pulmonary hemorrhage in a nonathlete: case report and review of physiology.  

PubMed

The integrity of the pulmonary blood-gas barrier is vulnerable to intense exercise in elite athletes, similar to the phenomenon of exercise-induced pulmonary hemorrhage in thoroughbred racehorses. A 50-year-old previously healthy man presented with acute onset shortness of breath, dry cough, and hypoxemia after engaging in an extremely vigorous game of handball. CT scan of the chest showed diffuse patchy air-space disease. Bronchoalveolar lavage revealed diffuse alveolar hemorrhage. Infectious etiologies and bleeding diatheses were excluded by laboratory testing. Serological tests for ANCA-associated vasculitis, lupus, and Goodpasture's disease also were negative. A transthoracic echocardiogram was normal. The patient recovered completely on supportive therapy in less than 72 h. This case demonstrates strenuous exercise as a cause of diffuse alveolar hemorrhage in a previously healthy male with no apparent underlying cardiopulmonary disease. PMID:24532148

Diwakar, Amit; Schmidt, Gregory A

2014-04-01

347

Cognitive awareness of carbohydrate intake does not alter exercise-induced lymphocyte apoptosis  

PubMed Central

OBJECTIVE: The purpose of this investigation was to determine whether cognitive awareness of carbohydrate beverage consumption affects exercise?induced lymphocyte apoptosis, independent of actual carbohydrate intake. INTRODUCTION: Carbohydrate supplementation during aerobic exercise generally protects against the immunosuppressive effects of exercise. It is not currently known whether carbohydrate consumption or simply the knowledge of carbohydrate consumption also has that effect. METHODS: Endurance trained male and female (N ?=? 10) athletes were randomly assigned to one of two groups based on either a correct or incorrect cognitive awareness of carbohydrate intake. In the incorrect group, the subjects were informed that they were receiving the carbohydrate beverage but actually received the placebo beverage. Participants completed a 60?min ride on a cycle ergometer at 80% VO2peak under carbohydrate and placebo supplemented conditions. Venous blood samples were collected at rest and immediately after exercise and were used to determine the plasma glucose concentration, lymphocyte count, and extent of lymphocyte apoptosis. Cognitive awareness, either correct or incorrect, did not have an effect on any of the measured variables. RESULTS: Carbohydrate supplementation during exercise did not have an effect on lymphocyte count or apoptotic index. Independent of drink type, exercise resulted in significant lymphocytosis and lymphocyte apoptosis (apoptotic index at rest ?=? 6.3±3% and apoptotic index following exercise ?=? 11.6±3%, P<0.01). CONCLUSION: Neither carbohydrate nor placebo supplementation altered the typical lymphocyte apoptotic response following exercise. While carbohydrate supplementation generally has an immune?boosting effect during exercise, it appears that this influence does not extend to the mechanisms that govern exercise?induced lymphocyte cell death.

Navalta, James Wilfred; McFarlin, Brian Keith; Lyons, Scott; Arnett, Scott Wesley; Schafer, Mark Anthony

2011-01-01

348

Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans  

NASA Technical Reports Server (NTRS)

We tested the hypothesis that renal tubular Na(+) reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O(2) uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P < 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na(+) in the proximal tubules was higher in Ex than in C (P < 0.05). Saline loading decreased fractional tubular reabsorption of Na(+) from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P < 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P < 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na(+) reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na(+) reabsorption during saline infusion 24 h after exercise.

Nagashima, K.; Wu, J.; Kavouras, S. A.; Mack, G. W.

2001-01-01

349

Neuromuscular function after exercise-induced muscle damage: theoretical and applied implications.  

PubMed

Exercise-induced muscle damage is a well documented phenomenon particularly resulting from eccentric exercise. When eccentric exercise is unaccustomed or is performed with an increased intensity or duration, the symptoms associated with muscle damage are a common outcome and are particularly associated with participation in athletic activity. Muscle damage results in an immediate and prolonged reduction in muscle function, most notably a reduction in force-generating capacity, which has been quantified in human studies through isometric and dynamic isokinetic testing modalities. Investigations of the torque-angular velocity relationship have failed to reveal a consistent pattern of change, with inconsistent reports of functional change being dependent on the muscle action and/or angular velocity of movement. The consequences of damage on dynamic, multi-joint, sport-specific movements would appear more pertinent with regard to athletic performance, but this aspect of muscle function has been studied less often. Reductions in the ability to generate power output during single-joint movements as well as during cycling and vertical jump movements have been documented. In addition, muscle damage has been observed to increase the physiological demand of endurance exercise and to increase thermal strain during exercise in the heat. The aims of this review are to summarise the functional decrements associated with exercise-induced muscle damage, relate these decrements to theoretical views regarding underlying mechanisms (i.e. sarcomere disruption, impaired excitation-contraction coupling, preferential fibre type damage, and impaired muscle metabolism), and finally to discuss the potential impact of muscle damage on athletic performance. PMID:14715039

Byrne, Christopher; Twist, Craig; Eston, Roger

2004-01-01

350

Exercise-Induced Wheezing among Japanese Pre-School Children and Pupils.  

PubMed

Background: Exercise-induced wheezing (EIW) may be a symptom of asthma and is a predictor of exercise-induced bronchoconstriction, transient narrowing of the lower airway following exercise in the presence or absence of diagnosed asthma. Population-based studies with a large sample of EIW in relation to age, sex, current asthma severity and medication usage have been sparse. Methods: International Study of Asthma and Allergies in Childhood questionnaires were distributed at 885 nurseries, 535 primary schools, 321 junior high schools and 190 high schools, respectively, across Japan, and the corresponding data on 46,597, 41,216, 45,960 and 51,104 children were analyzed. Results: Prevalence of EIW was 4.8, 4.7, 17.9 and 15.4% for each of the four educational facility types, respectively. Among 24,103 current asthmatics, 20.9, 28.7, 76.1 and 73.6% of subjects for the 4 educational facility groups reported to have experienced EIW, respectively. Severity of current asthma was associated with the risk of EIW; odds ratio (95% confidence interval) of children with asthma attack every day for having EIW once a week or more, using intermittent asthmatics as reference group, were 24.48 (19.33 to 31.01) adjusted for other covariates. Among current asthmatic kindergartners, increase in risk for EIW due to ascending severity of current asthma was mitigated by daily use of leukotriene receptor antagonist (p for interaction = 0.071). Conclusions: EIW was not rare among current asthmatic children. An increased risk for EIW was in accordance with increasing severity of current asthma and this relation was mitigated with leukotriene receptor antagonist daily use among kindergartners. PMID:24759555

Murakami, Yoko; Honjo, Satoshi; Odajima, Hiroshi; Adachi, Yuichi; Yoshida, Koichi; Ohya, Yukihiro; Akasawa, Akira

2014-06-01

351

Low chemoresponsiveness and inadequate hyperventilation contribute to exercise-induced hypoxemia.  

PubMed

Is inadequate hyperventilation a cause of the exercise-induced hypoxemia observed in some athletes during intense exercise? If so, is this related to low chemoresponsiveness? To test the hypothesis that exercise-induced hypoxemia, inadequate hyperventilation, and chemoresponsiveness are related, 36 nonsmoking healthy men were divided into hypoxemic (Hyp; n = 13) or normoxemic (Nor; n = 15) groups based on arterial oxygen saturation (SaO2; Hyp < or = 90%, Nor > 92%) observed during maximum O2 uptake (VO2max). Men with intermediate SaO2 values (n = 8) were only included in correlation analysis. Ventilatory parameters were collected at rest, during a treadmill maximal oxygen consumption (VO2max) test, and during a 5-min run at 90% VO2max. Chemoresponsiveness at rest was assessed via hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR). VO2max was not significantly different between Nor and Hyp. SaO2 was 93.8 +/- 0.9% (Nor) and 87.7 +/- 2.0% (Hyp) at VO2max. End-tidal PO2 and the ratio of minute ventilation to oxygen consumption (VE/VO2) were lower while PETCO2 was higher for Hyp (P < or = 0.01). End-tidal PO2, end-tidal PCO2, and VE/VO2 correlated (P < or = 0.05) to SaO2 (r = 0.84, r = -0.70, r = 0.72, respectively), suggesting that differences in oxygenation were due to differences in ventilation. HVR and HCVR were significantly lower for Hyp. HVR was related to VE/VO2 (r = 0.43), and HCVR was related to the ratio of VE to CO2 production at VO2max (r = 0.61).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7592220

Harms, C A; Stager, J M

1995-08-01

352

Two male siblings with hereditary renal hypouricemia and exercise-induced ARF.  

PubMed

Familial renal hypouricemia with exercise-induced acute renal failure (ARF) is rare. A 45-year-old man presented with abdominal pain, vomiting, and oliguria after severe exercise. The diagnosis was ARF based on high serum creatinine (SCr) level (5.1 mg/dL [451 micromol/L]). Renal function recovered completely within 2 weeks of conservative treatment (creatinine clearance [Ccr], 100.4 mL/min [1.67 mL/s]). After remission, laboratory results showed serum urate (SUA) of 0.8 mg/dL (48 micromol/L), and fractional excretion of uric acid (FE(UA)) of 46%. The final diagnosis was ARF associated with idiopathic renal hypouricemia. Other diseases that could increase the excretion of urate were excluded. Because only mild responses were observed both in pyradinamide and benzbromarone loading tests, he was considered to be a presecretory reabsorption disorder type. The younger brother (42 years old) also had episodes of low and middle back pain after severe exercise and experienced similar attacks at least 5 times since the age of 29. SCr level was elevated in every attack. Hypouricemia (SUA, 1.0 mg/dL [59 micromol/L]) and high urinary urate excretion (FE(UA), 65.7%) also were detected. Renal function recovered almost completely without any specific treatment. Radiologic examination of the 2 cases showed bilateral urolithiasis probably caused by the high urinary urate excretion. Sequence analysis of a urate anion exchanger known to regulate blood urate level (URAT1 gene) in both brothers showed homozygous mutation in exon 4 (W258Stop), resulting in a premature truncated URAT1 protein. Both their parents and their children showed heterozygous mutation of the URAT1 gene. This is the first report of the 2 male siblings of familial renal hypouricemia complicated with exercise-induced ARF, with definite demonstration of genetic abnormality in the responsible gene (URAT1). PMID:14655203

Tanaka, Motoko; Itoh, Kazuko; Matsushita, Kazunori; Matsushita, Kazutaka; Wakita, Naoki; Adachi, Masataka; Nonoguchi, Hiroshi; Kitamura, Kenichiro; Hosoyamada, Makoto; Endou, Hitoshi; Tomita, Kimio

2003-12-01

353

Magnitude of Exercise-Induced ?-Endorphin Response Is Associated with Subsequent Development of Altered Hypoglycemia Counterregulation  

PubMed Central

Context: ?-Endorphin release in response to recurrent hypoglycemia is implicated in the pathogenesis of hypoglycemia-associated autonomic failure. Objective: We hypothesized that exercise-induced ?-endorphin release will also result in the deterioration of subsequent hypoglycemia counterregulation and that the counterregulatory response will negatively correlate with the degree of antecedent ?-endorphin elevation. Design, Setting, Participants, and Interventions: Sixteen healthy subjects (six females, aged 26 ± 4.3 yr, body mass index 26.1 ± 5.6 kg/m2) were studied with three experimental paradigms on 2 consecutive days. Day 1 consisted of one of the following: 1) two 90-min hyperinsulinemic hypoglycemic clamps (3.3 mmol/liter); 2) two 90-min hyperinsulinemic euglycemic clamps while subjects exercised at 60% maximal oxygen uptake; or 3) two 90-min hyperinsulinemic euglycemic clamps (control). Day 2 followed with hyperinsulinemic (396 ± 7 pmol/liter) stepped hypoglycemic clamps (5.0, 4.4, 3.9, and 3.3 mmol/liter plasma glucose steps). Main Outcome Measures: Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover ([3-3H]-glucose) as indicators of recovery from hypoglycemia. Results: There was a significant inverse correlation between plasma ?-endorphin levels during exercise and catecholamine release during subsequent hypoglycemia. Subjects with an exercise-induced rise in ?-endorphin levels to above 25 pg/ml (n = 7) exhibited markedly reduced levels of plasma epinephrine and norepinephrine compared with control (2495 ± 306 vs. 4810 ± 617 pmol/liter and 1.9 ± 0.3 vs. 2.9 ± 0.4 nmol/liter, respectively, P < 0.01 for both). The rate of endogenous glucose production recovery in this group was also much lower than in controls (42 vs. 89%, P < 0.01). Conclusions: The physiological increase in ?-endorphin levels during exercise is associated with the attenuation of counterregulation during subsequent hypoglycemia.

Milman, Sofiya; Leu, James; Shamoon, Harry; Vele, Septimiu

2012-01-01

354

MELAS syndrome, cardiomyopathy, rhabdomyolysis, and autism associated with the A3260G mitochondrial DNA mutation.  

PubMed

The A to G transition mutation at position 3260 of the mitochondrial genome is usually associated with cardiomyopathy and myopathy. One Japanese kindred reported the phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS syndrome) in association with the A3260G mtDNA mutation. We describe the first Caucasian cases of MELAS syndrome associated with the A3260G mutation. Furthermore, this mutation was associated with exercise-induced rhabdomyolysis, hearing loss, seizures, cardiomyopathy, and autism in the large kindred. We conclude that the A3260G mtDNA mutation is associated with wide phenotypic heterogeneity with MELAS and other "classical" mitochondrial phenotypes being manifestations. PMID:20965148

Connolly, Barbara S; Feigenbaum, Annette S J; Robinson, Brian H; Dipchand, Anne I; Simon, David K; Tarnopolsky, Mark A

2010-11-12

355

Mitochondrial Myopathies  

MedlinePLUS

... include: • Kearns-Sayre syndrome (KSS) • Leigh syndrome • mitochondrial DNA depletion syndrome (MDS) • mitochondrial encephalomyopathy, lactic acidosis and ... on swallowing, speech and eye movements. MDS: mitochondrial DNA depletion syndrome Inheritance pattern: Mendelian Onset: infancy Features: ...

356

Effect of Ambrotose AO® on resting and exercise-induced antioxidant capacity and oxidative stress in healthy adults  

Microsoft Academic Search

BACKGROUND: The purpose of this investigation was to determine the effects of a dietary supplement (Ambrotose AO®) on resting and exercise-induced blood antioxidant capacity and oxidative stress in exercise-trained and untrained men and women. METHODS: 25 individuals (7 trained and 5 untrained men; 7 trained and 6 untrained women) received Ambrotose AO® (4 capsules per day = 2 grams per

Richard J Bloomer; Robert E Canale; Megan M Blankenship; Kelsey H Fisher-Wellman

2010-01-01

357

Exercise-Induced Hematuria as the Main Manifestation of Migration of Intrauterine Contraceptive Device into the Bladder  

PubMed Central

Intrauterine device (IUD) is a common contraceptive method, due to its cost-effectiveness and low complication rates. Uterine perforation is a possible complication and IUD migration to the bladder is a rare and morbid condition. The present report describes an interesting case in which the urinary manifestations started 13 years after insertion, and the main clinical finding was exercise-induced hematuria.

Mascarenhas, Michel Platiny; Tiraboschi, Ricardo Brianezi; Paschoalin, Victor Pereira; Costa, Ellen Almeida Possidonio; Suzuki Bellucci, Carlos Henrique; Bessa Junior, Jose

2012-01-01

358

PPAR? activation rescues mitochondrial function from inhibition of complex I and loss of PINK1.  

PubMed

Parkinson's disease has long been associated with impaired mitochondrial complex I activity, while several gene defects associated with familial Parkinson's involve defects in mitochondrial function or 'quality control' pathways, causing an imbalance between mitochondrial biogenesis and removal of dysfunctional mitochondria by autophagy. Amongst these are mutations of the gene for PTEN-induced kinase 1 (PINK1) in which mitochondrial function is abnormal. Peroxisome proliferator-activated receptor gamma (PPAR?), a nuclear receptor and ligand-dependent transcription factor, regulates pathways of inflammation, lipid and carbohydrate metabolism, antioxidant defences and mitochondrial biogenesis. We have found that inhibition of complex I in human differentiated SHSY-5Y cells by the complex I inhibitor rotenone irreversibly decrease mitochondrial mass, membrane potential and oxygen consumption, while increasing free radical generation and autophagy. Similar changes are seen in PINK1 knockdown cells, in which potential, oxygen consumption and mitochondrial mass are all decreased. In both models, all these changes were reversed by pre-treatment of the cells with the PPAR? agonist, rosiglitazone, which increased mitochondrial biogenesis, increased oxygen consumption and suppressed free radical generation and autophagy. Thus, rosiglitazone is neuroprotective in two different models of mitochondrial dysfunction associated with Parkinson's disease through a direct impact on mitochondrial function. PMID:24374061

Corona, Juan Carlos; de Souza, Senio Campos; Duchen, Michael R

2014-03-01

359

Adrenaline but not noradrenaline is a determinant of exercise-induced lipid mobilization in human subcutaneous adipose tissue.  

PubMed

The relative contribution of noradrenaline (norepinephrine) and adrenaline (epinephrine) in the control of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise was evaluated in men treated with a somatostatin analogue, octreotide. Eight lean and eight obese young men matched for age and physical fitness performed 60 min exercise bouts at 50% of their maximal oxygen consumption on two occasions: (1) during i.v. infusion of octreotide, and (2) during placebo infusion. Lipolysis and local blood flow changes in SCAT were evaluated using in situ microdialysis. Infusion of octreotide suppressed plasma insulin and growth hormone levels at rest and during exercise. It blocked the exercise-induced increase in plasma adrenaline while that of noradrenaline was unchanged. Plasma natriuretic peptides (NPs) level was higher at rest and during exercise under octreotide infusion in lean men. Under placebo, no difference was found in the exercise-induced increase in glycerol between the probe perfused with Ringer solution alone and that with phentolamine (an alpha-adrenergic receptor antagonist) in lean subjects while a greater increase in glycerol was observed in the obese subjects. Under placebo, propranolol infusion in the probe containing phentolamine reduced by about 45% exercise-induced glycerol release; this effect was fully suppressed under octreotide infusion while noradrenaline was still elevated and exercise-induced lipid mobilization maintained in both lean and obese individuals. In conclusion, blockade of beta-adrenergic receptors during exercise performed during infusion of octreotide (blocking the exercise-induced rise in adrenaline but not that of noradrenaline) does not alter the exercise-induced lipolysis. This suggests that adrenaline is the main adrenergic agent contributing to exercise-induced lipolysis in SCAT. Moreover, it is the combined action of insulin suppression and NPs release which explains the lipolytic response which remains under octreotide after full local blockade of fat cell adrenergic receptors. For the moment, it is unknown if results apply specifically to SCAT and exercise only or if conclusions could be extended to all forms of lipolysis in humans. PMID:19417097

de Glisezinski, I; Larrouy, D; Bajzova, M; Koppo, K; Polak, J; Berlan, M; Bulow, J; Langin, D; Marques, M A; Crampes, F; Lafontan, M; Stich, V

2009-07-01

360

Mitochondrial Aging and Age-Related Dysfunction of Mitochondria  

PubMed Central

Age-related changes in mitochondria are associated with decline in mitochondrial function. With advanced age, mitochondrial DNA volume, integrity and functionality decrease due to accumulation of mutations and oxidative damage induced by reactive oxygen species (ROS). In aged subjects, mitochondria are characterized by impaired function such as lowered oxidative capacity, reduced oxidative phosphorylation, decreased ATP production, significant increase in ROS generation, and diminished antioxidant defense. Mitochondrial biogenesis declines with age due to alterations in mitochondrial dynamics and inhibition of mitophagy, an autophagy process that removes dysfunctional mitochondria. Age-dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function. In aged tissues, enhanced mitochondria-mediated apoptosis contributes to an increase in the percentage of apoptotic cells. However, implementation of strategies such as caloric restriction and regular physical training may delay mitochondrial aging and attenuate the age-related phenotype in humans.

Chistiakov, Dimitry A.; Sobenin, Igor A.; Revin, Victor V.; Orekhov, Alexander N.; Bobryshev, Yuri V.

2014-01-01

361

Evidence of a bigenomic regulation of mitochondrial gene expression by thyroid hormone during rat brain development  

SciTech Connect

Hypothyroidism during early mammalian brain development is associated with decreased expression of various mitochondrial encoded genes along with evidence for mitochondrial dysfunction. However, in-spite of the similarities between neurological disorders caused by perinatal hypothyroidism and those caused by various genetic mitochondrial defects we still do not know as to how thyroid hormone (TH) regulates mitochondrial transcription during development and whether this regulation by TH is nuclear mediated or through mitochondrial TH receptors? We here in rat cerebellum show that hypothyroidism causes reduction in expression of nuclear encoded genes controlling mitochondrial biogenesis like PGC-1{alpha}, NRF-1{alpha} and Tfam. Also, we for the first time demonstrate a mitochondrial localization of thyroid hormone receptor (mTR) isoform in developing brain capable of binding a TH response element (DR2) present in D-loop region of mitochondrial DNA. These results thus indicate an integrated nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by TH during brain development.

Sinha, Rohit Anthony; Pathak, Amrita; Mohan, Vishwa; Babu, Satish; Pal, Amit; Khare, Drirh [Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (India)] [Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (India); Godbole, Madan M., E-mail: madangodbole@yahoo.co.in [Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (India)

2010-07-02

362

Association of LETM1 and MRPL36 contributes to the regulation of mitochondrial ATP production and necrotic cell death.  

PubMed

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome, and was deleted in nearly all patients with the syndrome. LETM1 encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. Here, we describe LETM1-mediated regulation of mitochondrial ATP production and biogenesis. We show that LETM1 overexpression can induce necrotic cell death in HeLa cells, in which LETM1 reduces mitochondrial biogenesis and ATP production. LETM1 acts as an anchor protein and associates with mitochondrial ribosome protein L36. Adenovirus-mediated overexpression of LETM1 reduced mitochondrial mass and expression of many mitochondrial proteins. LETM1-mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling. The expression levels of LETM1 were significantly increased in multiple human cancer tissues compared with normals. These data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. The increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 is a key feature of tumorigenesis. PMID:19318571

Piao, Longzhen; Li, Yuwen; Kim, Soung Jung; Byun, Hee Sun; Huang, Song Mei; Hwang, Soon-Kyung; Yang, Keum-Jin; Park, Kyeong Ah; Won, Minho; Hong, Janghee; Hur, Gang Min; Seok, Jeong Ho; Shong, Minho; Cho, Myung-Haing; Brazil, Derek P; Hemmings, Brian A; Park, Jongsun

2009-04-15

363

Regulation of microRNA biogenesis.  

PubMed

MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathological processes in animals. The biogenesis of miRNAs is under tight temporal and spatial control, and their dysregulation is associated with many human diseases, particularly cancer. In animals, miRNAs are ?22 nucleotides in length, and they are produced by two RNase III proteins - Drosha and Dicer. miRNA biogenesis is regulated at multiple levels, including at the level of miRNA transcription; its processing by Drosha and Dicer in the nucleus and cytoplasm, respectively; its modification by RNA editing, RNA methylation, uridylation and adenylation; Argonaute loading; and RNA decay. Non-canonical pathways for miRNA biogenesis, including those that are independent of Drosha or Dicer, are also emerging. PMID:25027649

Ha, Minju; Kim, V Narry

2014-08-01

364

Hematologic and hemorheological determinants of resting and exercise-induced hemoglobin oxygen desaturation in children with sickle cell disease  

PubMed Central

The aim of the study was to determine the factors associated with resting and exercise-induced hemoglobin oxygen desaturation. The well-established six-minute walk test was conducted in 107 sickle cell children (50 with sickle hemoglobin C disease and 57 with sickle cell anemia) at steady state. Hemoglobin oxygen saturation was measured before and immediately after the six-minute walk test. Blood samples were obtained on the same day to measure hematologic and hemorheological parameters. Exercise-induced hemoglobin oxygen desaturation was defined as a drop in hemoglobin oxygen saturation of 3% or more at the end of the six-minute walk test compared to resting levels. No children with sickle hemoglobin C disease, but approximately 50% of children with sickle cell anemia showed mild or moderate oxygen desaturation at rest, which was independently associated with the percentage of reticulocytes. Exercise-induced hemoglobin oxygen desaturation was observed in 18% of children with sickle hemoglobin C disease and 34% of children with sickle cell anemia, and was independently associated with the six-minute walk test, acute chest syndrome rate and the strength of red blood cell aggregates in children with sickle cell anemia. No association was found in children with sickle hemoglobin C disease between exercise-indu