Sample records for exercise-induced mitochondrial biogenesis

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

    PubMed

    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

    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

  2. Mitochondrial biogenesis: pharmacological approaches.

    PubMed

    Valero, Teresa

    2014-01-01

    Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1? axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an importan

  3. Biogenesis of mitochondrial proteins

    Microsoft Academic Search

    Roland Lill; Frank E Nargang; Walter Neupert

    1996-01-01

    Numerous components have been identified that participate at various stages in the biogenesis of mitochondria. For many of these components, their specific functions have recently been defined through detailed investigations of the molecular mechanisms underlying protein targeting, translocation across the mitochondrial outer and inner membranes, membrane insertion, suborganellar sorting, and protein folding.

  4. Redox Regulation of Mitochondrial Biogenesis

    PubMed Central

    Piantadosi, Claude A.; Suliman, Hagir B.

    2013-01-01

    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. PMID:23000245

  5. Biogenesis of the mitochondrial TOM complex

    Microsoft Academic Search

    Doron Rapaport

    2002-01-01

    The translocase at the outer membrane of mitochondria (TOM complex) mediates the initial steps of the import of preproteins into the organelle, which are essential for mitochondrial biogenesis and, therefore, for eukaryotic cell viability. The TOM complex is a multisubunit molecular machine with a dynamic structure. The biogenesis of TOM is of special interest because the complex is required for

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

    PubMed Central

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

    2014-01-01

    Adiponectin (Ad) has been proposed to be a regulator of mitochondrial biogenesis in skeletal muscle, and necessary for exercise-induced increases in mitochondrial content. We first confirmed that Ad could acutely increase the expression of mitochondrial proteins during a 10 h incubation in isolated soleus and extensor digitorum longus (EDL) muscles. Next, we further examined the role of Ad as a regulator of mitochondrial content using Ad knockout (AdKO) mice. The AdKO animals showed no differences in resting , respiratory exchange ratio, or in time to exhaustion during exercise when compared to wild-type (WT) mice. There was a reduction in resting palmitate oxidation in isolated soleus from AdKO animals (?23%, P < 0.05) but not EDL, and 5-aminoimidazole-4-carboxamide (AICAR)-stimulated palmitate oxidation was similar in both genotypes regardless of muscle. There were no differences in protein markers of mitochondrial content (COX4, CORE1, CS, 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

  7. Mitochondrial biogenesis in plants during seed germination.

    PubMed

    Law, Simon R; Narsai, Reena; Whelan, James

    2014-11-01

    Mitochondria occupy a central role in the eukaryotic cell. In addition to being major sources of cellular energy, mitochondria are also involved in a diverse range of functions including signalling, the synthesis of many essential organic compounds and a role in programmed cell death. The active proliferation and differentiation of mitochondria is termed mitochondrial biogenesis and necessitates the coordinated communication of mitochondrial status within an integrated cellular network. Two models of mitochondrial biogenesis have been defined previously, the growth and division model and the maturation model. The former describes the growth and division of pre-existing mature organelles through a form of binary fission, while the latter describes the propagation of mitochondria from structurally and biochemically simple promitochondrial structures that upon appropriate stimuli, mature into fully functional mitochondria. In the last decade, a number of studies have utilised seed germination in plants as a platform for the examination of the processes occurring during mitochondrial biogenesis. These studies have revealed many new aspects of the tightly regulated procession of events that define mitochondrial biogenesis during this period of rapid development. A model for mitochondrial biogenesis that supports the maturation of mitochondria from promitochondrial structures has emerged, where mitochondrial signalling plays a crucial role in the early steps of seed germination. PMID:24727594

  8. Mitochondrial biogenesis in exercise and in ageing.

    PubMed

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

    2009-11-30

    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 was appreciated that mitochondria, which are both a target and a source of radicals in cells, are most important organelles to understand ageing. Thus, a common feature between cell physiology of ageing and exercise is that in both situations mitochondria are critical for normal cell functioning. Mitochondrial synthesis is stimulated by the PGC-1alpha-NRF1-TFAM pathway. PGC-1alpha is the first stimulator of mitochondrial biogenesis. NRF1 is an intermediate transcription factor which stimulates the synthesis of TFAM which is a final effector activating the duplication of mitochondrial DNA molecules. This pathway is impaired in ageing. On the contrary, exercise, particularly aerobic exercise, activates mitochondriogenesis in the young animal but its effects on mitochondrial biogenesis in the old animal are doubtful. In this chapter we consider the interrelationship between mitochondrial biogenesis stimulated by exercise and the possible impairment of this pathway in ageing leading to mitochondrial deficiency and eventually muscle sarcopenia. PMID:19716394

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

    PubMed Central

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

    2015-01-01

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

  10. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis.

    PubMed

    Palikaras, Konstantinos; Tavernarakis, Nektarios

    2014-08-01

    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

  11. Mitochondrial Biogenesis and Function in Arabidopsis†

    PubMed Central

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

    2008-01-01

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

  12. Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

    PubMed Central

    Dominy, John E.; Puigserver, Pere

    2013-01-01

    The dynamics of mitochondrial biogenesis and function is a complex interplay of cellular and molecular processes that ultimately shape bioenergetics capacity. Mitochondrial mass, by itself, represents the net balance between rates of biogenesis and degradation. Mitochondrial biogenesis is dependent on different signaling cascades and transcriptional complexes that promote the formation and assembly of mitochondria—a process that is heavily dependent on timely and coordinated transcriptional control of genes encoding for mitochondrial proteins. In this article, we discuss the major signals and transcriptional complexes, programming mitochondrial biogenesis, and bioenergetic activity. This regulatory network represents a new therapeutic window into the treatment of the wide spectrum of mitochondrial and neurodegenerative diseases characterized by dysregulation of mitochondrial dynamics and bioenergetic deficiencies. PMID:23818499

  13. Coordination of Nuclear and Mitochondrial Genome Expression during Mitochondrial Biogenesis in Arabidopsis

    Microsoft Academic Search

    Philippe Giege; Lee J. Sweetlove; Valerie Cognat; Christopher J. Leaverb

    2005-01-01

    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

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

    PubMed Central

    Piantadosi, Claude A.

    2015-01-01

    Abstract Significance: Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Recent Advances: Early-phase inflammatory mediator proteins interact with PRRs to activate NF-?B-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1?, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1?, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. Critical Issues: Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-?B. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. Future Directions: Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation. Antioxid. Redox Signal. 22, 965–976. PMID:25556935

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

    SciTech Connect

    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

    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.

  16. Sirtuin 1 (SIRT1) Deacetylase Activity Is Not Required for Mitochondrial Biogenesis or Peroxisome Proliferator-activated Receptor-? Coactivator-1? (PGC-1?) Deacetylation following Endurance Exercise*

    PubMed Central

    Philp, Andrew; Chen, Ai; Lan, Debin; Meyer, Gretchen A.; Murphy, Anne N.; Knapp, Amy E.; Olfert, I. Mark; McCurdy, Carrie E.; Marcotte, George R.; Hogan, Michael C.; Baar, Keith; Schenk, Simon

    2011-01-01

    The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1? and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1? expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1? expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1? after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1?. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1? or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1? activity after exercise. PMID:21757760

  17. Molecular Genetics of Mitochondrial Biogenesis in Maize.

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  18. Diabetes regulates mitochondrial biogenesis and fission in mouse neurons

    Microsoft Academic Search

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

    2010-01-01

    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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2004-01-01

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

  1. Ssq1, a Mitochondrial Hsp70 Involved in Iron-Sulfur (Fe/S) Center Biogenesis

    E-print Network

    Craig, Elizabeth A

    Ssq1, a Mitochondrial Hsp70 Involved in Iron-Sulfur (Fe/S) Center Biogenesis SIMILARITIES function together to assist in the biogenesis of iron- sulfur (Fe/S) centers in the mitochondrial matrix chaperones work to- gether, along with other proteins, in the processes of iron- sulfur center biogenesis

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

    Microsoft Academic Search

    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

    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

  3. Mitochondrial Biogenesis in the Axons of Vertebrate Peripheral Neurons

    PubMed Central

    Amiri, Mandana; Hollenbeck, Peter J.

    2008-01-01

    Mitochondria are widely distributed via regulated transport in neurons, but their sites of biogenesis remain uncertain. Most mitochondrial proteins are encoded in the nuclear genome, and evidence has suggested that mitochondrial DNA (mtDNA) replication occurs mainly or entirely in the cell body. However, it has also become clear that nuclear-encoded mitochondrial proteins can be translated in the axon and that components of the mitochondrial replication machinery reside there as well. We assessed directly whether mtDNA replication can occur in the axons of chick peripheral neurons labeled with 5-bromo-2?-deoxyuridine (BrdU). In axons that were physically separated from the cell body or had disrupted organelle transport between the cell bodies and axons, a significant fraction of mtDNA synthesis continued. We also detected the mitochondrial fission protein Drp1 in neurons by immunofluorescence or expression of GFP-Drp1. Its presence and distribution on the majority of axonal mitochondria indicated that a substantial number had undergone recent division in the axon. Because the morphology of mitochondria is maintained by the balance of fission and fusion events, we either inhibited Drp1 expression by RNAi or overexpressed the fusion protein Mfn1. Both methods resulted in significantly longer mitochondria in axons, including many at a great distance from the cell body. These data indicate that mitochondria can replicate their DNA, divide, and fuse locally within the axon; thus, the biogenesis of mitochondria is not limited to the cell body. PMID:18666204

  4. Mitochondrial biogenesis as a cellular signaling framework.

    PubMed

    Nisoli, Enzo; Clementi, Emilio; Moncada, Salvador; Carruba, Michele O

    2004-01-01

    The identification, more than 50 years ago, of mitochondria as the site of oxidative energy metabolism has prompted studies that have unraveled the complexity of the numerous biosynthetic and degradative reactions, fundamental to cell function, carried out by these organelles. These activities depend on a distinctive mitochondrial structure, with different enzymes and reactions localized in discrete membranes and aqueous compartments. The characteristic mitochondrial structural organization is the product of both synthesis of macromolecules within the mitochondria and the import of proteins and lipids synthesized outside the organelle. Synthesis and import of mitochondrial components are required for mitochondrial proliferation, but rather than producing new organelles, these processes may facilitate the growth of pre-existing mitochondria. Recent evidence indicates that these events are regulated in a complex way by several agonists and environmental conditions, through activation of specific transcription factors and signaling pathways. Some of these are now being elucidated. Generation of nitric oxide (NO) appears to be a novel player in this scenario, possibly acting as a unifying molecular switch to trigger the whole mitochondriogenic process. PMID:14667924

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

    PubMed

    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

    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

  6. Upregulation of Human Selenoprotein H in murine hippocampal neuronal cells promotes mitochondrial biogenesis and functional performance

    PubMed Central

    Mendelev, Natalia; Mehta, Suresh L.; Witherspoon, Sam; He, Qingping; Sexton, Jonathan Z.; Li, P. Andy

    2010-01-01

    Overexpression of selenoprotein H (SelH) gene provides neuroprotection in neurons against UVB-induced cell death by blocking the mitohcondria-initiated apoptotic cell death pathway. This study examined the effects of SelH on mitochondrial biogenesis and mitochondrial function. The results demonstrated that overexpression of SelH gene in neuronal HT22 cells significantly increased the levels of mitochondrial biogenesis regulators, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor- coactivator-1 alpha (PGC-1?) and mitochondrial transcription factor A (Tfam). Mitochondrial cytochrome c content was elevated, mass was increased and respiration was enhanced. SelH transfection ameliorated ultra violet B (UVB)-induced suppression of mitochondrial biogenesis markers and depolarization of mitochondrial membrane potential. Overexpression of SelH promotes mitochondrial biogenesis and improves mitochondrial functional performance. PMID:20656065

  7. Mitochondrial cytochrome c biogenesis: no longer an enigma.

    PubMed

    Babbitt, Shalon E; Sutherland, Molly C; Francisco, Brian San; Mendez, Deanna L; Kranz, Robert G

    2015-08-01

    Cytochromes c (cyt c) and c1 are heme proteins that are essential for aerobic respiration. Release of cyt c from mitochondria is an important signal in apoptosis initiation. Biogenesis of c-type cytochromes involves covalent attachment of heme to two cysteines (at a conserved CXXCH sequence) in the apocytochrome. Heme attachment is catalyzed in most mitochondria by holocytochrome c synthase (HCCS), which is also necessary for the import of apocytochrome c (apocyt c). Thus, HCCS affects cellular levels of cyt c, impacting mitochondrial physiology and cell death. Here, we review the mechanisms of HCCS function and the roles of heme and residues in the CXXCH motif. Additionally, we consider concepts emerging within the two prokaryotic cytochrome c biogenesis pathways. PMID:26073510

  8. Mitochondrial Biogenesis in the Pulmonary Vasculature During Inhalational Lung Injury and Fibrosis

    Microsoft Academic Search

    Martha S. Carraway; Hagir B. Suliman; Corrine Kliment; Karen E. Welty-Wolf; Tim D. Oury; Claude A. Piantadosi

    2008-01-01

    Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammation and pulmonary fibrosis. By using reporter mice that express green fluorescent protein (GFP) exclusively in mitochondria, we

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

    EPA Science Inventory

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

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

    PubMed

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

    2014-10-27

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

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

    PubMed Central

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

    2014-01-01

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

  12. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

    PubMed

    Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios

    2015-05-28

    Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function. PMID:25896323

  13. The ?2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.

    PubMed

    Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G

    2012-07-01

    Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the ?-adrenoceptor (?-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple ?-AR agonists: isoproterenol (nonselective ?-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective ?(3)-AR agonist), and formoterol (selective ?(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the ?-AR antagonist propranolol and the ?(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor ? coactivator 1?, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1? subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of ?(2)-AR ligands for therapeutic MB. PMID:22490378

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

    PubMed Central

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

    2013-01-01

    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. PMID:24288584

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

    PubMed Central

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

    2014-01-01

    Abstract Aims: Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased guanosine 3?,5?-monophosphate (cGMP), and activation of peroxisome proliferator-activated receptor gamma coactivator-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

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

    SciTech Connect

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

    2012-05-15

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

  17. The protease Omi regulates mitochondrial biogenesis through the GSK3?/PGC-1? pathway

    PubMed Central

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

    2014-01-01

    Loss of the mitochondrial protease activity of Omi causes mitochondrial dysfunction, neurodegeneration with parkinsonian features and premature death in mnd2 (motor neuron degeneration 2) mice. However, the detailed mechanisms underlying this pathology remain largely unknown. Here, we report that Omi participates in the process of mitochondrial biogenesis, which has been linked to several neurodegenerative diseases. The mitochondrial biogenesis is deficit in mnd2 mice, evidenced by severe decreases of mitochondrial components, mitochondrial DNA and mitochondrial density. Omi cleaves glycogen synthase kinase 3? (GSK3?), a kinase promoting PPAR? coactivator-1? (PGC-1?) degradation, to regulate PGC-1?, a factor important for the mitochondrial biogenesis. In mnd2 mice, GSK3? abundance is increased and PGC-1? abundance is decreased significantly. Inhibition of GSK3? by SB216763 or overexpression of PGC-1? can restore mitochondrial biogenesis in mnd2 mice or Omi-knockdown N2a cells. Furthermore, there is a significant improvement of the movement ability of mnd2 mice after SB216763 treatment. Thus, our study identified Omi as a novel regulator of mitochondrial biogenesis, involving in Omi protease-deficient-induced neurodegeneration. PMID:25118933

  18. Mitochondrial Biogenesis and Fission in Axons in Cell Culture and Animal Models of Diabetic Neuropathy

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Liu, Chien-Ting; Brooks, George A

    2012-02-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Wang, Xiaowan; Li, Hailong; Ding, Shinghua

    2014-01-01

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

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

    SciTech Connect

    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

    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.

  3. Exercise-Mediated Wall Shear Stress Increases Mitochondrial Biogenesis in Vascular Endothelium

    PubMed Central

    Kim, Boa; Lee, Hojun; Kawata, Keisuke; Park, Joon-Young

    2014-01-01

    Objective Enhancing structural and functional integrity of mitochondria is an emerging therapeutic option against endothelial dysfunction. In this study, we sought to investigate the effect of fluid shear stress on mitochondrial biogenesis and mitochondrial respiratory function in endothelial cells (ECs) using in vitro and in vivo complementary studies. Methods and Results Human aortic- or umbilical vein-derived ECs were exposed to laminar shear stress (20 dyne/cm2) for various durations using a cone-and-plate shear apparatus. We observed significant increases in the expression of key genes related to mitochondrial biogenesis and mitochondrial quality control as well as mtDNA content and mitochondrial mass under the shear stress conditions. Mitochondrial respiratory function was enhanced when cells were intermittently exposed to laminar shear stress for 72 hrs. Also, shear-exposed cells showed diminished glycolysis and decreased mitochondrial membrane potential (??m). Likewise, in in vivo experiments, mice that were subjected to a voluntary wheel running exercise for 5 weeks showed significantly higher mitochondrial content determined by en face staining in the conduit (greater and lesser curvature of the aortic arch and thoracic aorta) and muscle feed (femoral artery) arteries compared to the sedentary control mice. Interestingly, however, the mitochondrial biogenesis was not observed in the mesenteric artery. This region-specific adaptation is likely due to the differential blood flow redistribution during exercise in the different vessel beds. Conclusion Taken together, our findings suggest that exercise enhances mitochondrial biogenesis in vascular endothelium through a shear stress-dependent mechanism. Our findings may suggest a novel mitochondrial pathway by which a chronic exercise may be beneficial for vascular function. PMID:25375175

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2012-11-15

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

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

    PubMed

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

    2012-06-01

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

  8. Exercise-Induced Urticaria

    MedlinePLUS

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

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

    SciTech Connect

    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

    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.

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

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

    2014-01-01

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

  12. PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation to promote metastasis

    PubMed Central

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

    2014-01-01

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

  13. Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis

    PubMed Central

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

    2011-01-01

    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. PMID:21983013

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

    PubMed Central

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

    2013-01-01

    The role of OPA1, a GTPase dynamin protein mainly involved in the fusion of inner mitochondrial membranes, has been studied in many cell types, but only a few studies have been conducted on adult differentiated tissues such as cardiac or skeletal muscle cells. Yet OPA1 is highly expressed in these cells, and could play different roles, especially in response to an environmental stress like exercise. Endurance exercise increases energy demand in skeletal muscle and repeated activity induces mitochondrial biogenesis and activation of 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

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

    PubMed Central

    Suliman, Hagir B.; Piantadosi, Claude A.

    2014-01-01

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

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

    PubMed

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

    2015-09-01

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

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

    PubMed Central

    Margolis, Lee M.; Pasiakos, Stefan M.

    2013-01-01

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

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

    PubMed Central

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

    2008-01-01

    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. PMID:18477809

  19. High concentration of gadolinium ion modifying isolated rice mitochondrial biogenesis.

    PubMed

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

    2013-12-01

    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

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

    PubMed

    Ngamsiri, Pronrumpa; Watcharasit, Piyajit; Satayavivad, Jutamaad

    2014-01-01

    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

  1. Enhancement of mitochondrial biogenesis with polyphenols: combined effects of resveratrol and equol in human endothelial cells

    PubMed Central

    2013-01-01

    Emerging evidence suggests that combinatorial action of numerous biologically active compounds may be a valuable source in a variety of therapeutic applications. Several nutraceuticals have demonstrated to augment the efficacy of pharmacological approaches or provide physiological benefit to improve age-related decline. Recently, the possibilities of anti-ageing interventions have multiplied also to ameliorate the mitochondrial alterations in ageing-associated diseases. In this report, we approached a novel treatment strategy by combining two bioactive dietary constituents (resveratrol and equol) to determine their effect on mitochondrial function. Taking into account that the biological activities of resveratrol and equol has been observed in a wide range of biological processes, they were selected to examine whether combining them would be more effective to modulate mitochondrial function. In HUVEC cells our results demonstrate that the co-administration of these natural products increased mitochondrial mass and mitochondrial DNA content. Additionally, combined use of both compounds increased SIRT1 enzymatic activity and induced mitochondrial biogenesis factors such as PGC1-?, TFAM and NRF-1. Therefore, identification of this novel synergism may provide a new perspective for future treatments aiming to modulate the mitochondrial activity with implications in maintaining endothelial function which is crucial in the regulation of immune response. Further studies to discover the molecular details of this crosstalk and to identify new combinations of active compounds affecting the mitochondrial function will be extremely beneficial to prevent mitochondrial decline. PMID:23842073

  2. Enhancement of mitochondrial biogenesis with polyphenols: combined effects of resveratrol and equol in human endothelial cells.

    PubMed

    Davinelli, Sergio; Sapere, Nadia; Visentin, Manuela; Zella, Davide; Scapagnini, Giovanni

    2013-01-01

    Emerging evidence suggests that combinatorial action of numerous biologically active compounds may be a valuable source in a variety of therapeutic applications. Several nutraceuticals have demonstrated to augment the efficacy of pharmacological approaches or provide physiological benefit to improve age-related decline. Recently, the possibilities of anti-ageing interventions have multiplied also to ameliorate the mitochondrial alterations in ageing-associated diseases. In this report, we approached a novel treatment strategy by combining two bioactive dietary constituents (resveratrol and equol) to determine their effect on mitochondrial function. Taking into account that the biological activities of resveratrol and equol has been observed in a wide range of biological processes, they were selected to examine whether combining them would be more effective to modulate mitochondrial function. In HUVEC cells our results demonstrate that the co-administration of these natural products increased mitochondrial mass and mitochondrial DNA content. Additionally, combined use of both compounds increased SIRT1 enzymatic activity and induced mitochondrial biogenesis factors such as PGC1-?, TFAM and NRF-1. Therefore, identification of this novel synergism may provide a new perspective for future treatments aiming to modulate the mitochondrial activity with implications in maintaining endothelial function which is crucial in the regulation of immune response. Further studies to discover the molecular details of this crosstalk and to identify new combinations of active compounds affecting the mitochondrial function will be extremely beneficial to prevent mitochondrial decline. PMID:23842073

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

    PubMed

    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

    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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  6. Three weeks of erythropoietin treatment hampers skeletal muscle mitochondrial biogenesis in rats.

    PubMed

    Martinez-Bello, Vladimir E; Sanchis-Gomar, Fabian; Romagnoli, Marco; Derbre, Frederic; Gomez-Cabrera, Mari Carmen; Viña, Jose

    2012-12-01

    The blood O(2)-carrying capacity is maintained by the O(2)-regulated production of erythropoietin (Epo), which stimulates the proliferation and survival of red blood cell progenitors. Epo has been thought to act exclusively on erythroid progenitor cells. However, recent studies have identified the erythropoietin receptor (EpoR) in other cells, such as neurons, astrocytes, microglia, heart, cancer cell lines, and skeletal muscle provides evidence for a potential role of Epo in other tissues. In this study we aimed to determine the effect of recombinant human erythropoietin (rHuEpo) on skeletal muscle adaptations such as mitochondrial biogenesis, myogenesis, and angiogenesis in different muscle fibre types. Fourteen male Wistar rats were randomly divided into two experimental groups, and saline or rHuEpo (300 IU) was administered subcutaneously three times a week for 3 weeks. We evaluated the protein expression of intermediates involved in the mitochondrial biogenesis cascade, the myogenic cascade, and in angiogenesis in the oxidative soleus muscle and in the glycolytic gastrocnemius muscle. Contrary to our expectations, rHuEpo significantly hampered the mitochondrial biogenesis pathway in gastrocnemius muscle (PGC-1?, mTFA and cytochrome c). We did not find any effect of the treatment on cellular signals of myogenesis (MyoD and Myf5) or angiogenesis (VEGF) in either soleus or gastrocnemius muscles. Finally, we found no significant effect on the maximal aerobic velocity at the end of the experiment in the rHuEpo-treated animals. Our findings suggest that 3 weeks of rHuEpo treatment, which generates an increase of oxygen carrying capacity, can affect mitochondrial biogenesis in a muscle fibre-specific dependent manner. PMID:22627788

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

    PubMed Central

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

    2012-01-01

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

  8. Mitochondrial biogenesis related endurance genotype score and sports performance in athletes.

    PubMed

    Eynon, Nir; Ruiz, Jonatan R; Meckel, Yoav; Morán, María; Lucia, Alejandro

    2011-01-01

    We determined the probability of individuals having the 'optimal' mitochondrial biogenesis related endurance polygenic profile, and compared the endurance polygenic profile of Israeli (Caucasian) endurance athletes (n = 74), power athletes (n = 81), and non-athletes (n = 240). We computed a mitochondrial biogenesis related 'endurance genotype score' (EGS, scoring from 0 to 100) from the accumulated combination of six polymorphisms in the PPARGC1A-NRF-TFAM pathway. Some of the variant alleles of the polymorphisms studied were so infrequent, that the probability of possessing an 'optimal' EGS (= 100) was 0% in the entire study population. However, the EGS was significantly higher (P<0.001) in endurance athletes (38.9 ± 17.1) compared with controls (30.6 ± 12.4) or power athletes (29.0 ± 11.2). In summary, although the probability of an individual possessing a theoretically 'optimal' genetic background for endurance sports is very low, in general endurance athletes have a polygenic profile that is more suitable for mitochondrial biogenesis. PMID:20647061

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

    PubMed

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

    2014-02-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    2013-01-01

    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

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

    PubMed Central

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

    2015-01-01

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

  13. The novel nuclear gene DSS-1 of Saccharomyces cerevisiae is necessary for mitochondrial biogenesis.

    PubMed

    Dmochowska, A; Golik, P; Stepien, P P

    1995-07-01

    A previously unknown nuclear gene DSS-1 from Saccharomyces cerevisiae was cloned and sequenced. The gene was isolated as a multicopy suppressor of a disruption of the SUV-3 gene coding for a DEAD/H box protein involved in processing and turnover of mitochondrial transcripts. The DSS-1 gene codes for a 970 amino-acid protein of molecular weight 111 kDa and is necessary for mitochondrial biogenesis. Amino-acid sequence analysis indicates the presence of motifs characteristic for Escherichia coli RNase II, the dis3 protein from Schizosaccharomyces pombe, the cyt4 protein participating in RNA processing and turnover in Neurospora crassa mitochondria, and the vacB protein from Shigella flexneri. We suggest that the DSS-1 protein may be a component of the mitochondrial 3'-5' exoribonuclease complex. PMID:8590460

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

    PubMed Central

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

    2012-01-01

    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 energy metabolism and improve exercise endurance. Here, through the screening of various functional food ingredients, we found that chitooligosaccharide (COS) is an effective inducer of mitochondrial biogenesis. In rodents, COS increased the mitochondrial content in skeletal muscle and enhanced exercise endurance. In cultured myocytes, the expression of major regulators of mitochondrial biogenesis and key components of mitochondrial electron transfer chain was increased upon COS treatment. COS-mediated induction of mitochondrial biogenesis was achieved in part by the activation of silent information regulator two ortholog 1 (Sirt1) and AMP-activated protein kinase (AMPK). Taken together, our data suggest that COS could act as an exercise mimetic by inducing mitochondrial biogenesis and enhancing exercise endurance through the activation of Sirt1 and AMPK. PMID:22808092

  15. Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis.

    PubMed

    Joe, Yeonsoo; Zheng, Min; Kim, Hyo Jeong; Uddin, Md Jamal; Kim, Seul-Ki; Chen, Yingqing; Park, Jeongmin; Cho, Gyeong Jae; Ryter, Stefan W; Chung, Hun Taeg

    2015-07-01

    Hepatic ischemia-reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R and the roles of mitochondria and the Nrf2/heme oxygenase-1 (HO-1) system. Wild-type, Hmox1(-/-), or Nrf2(-/-) mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. Primary hepatocytes were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2-specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury and mitochondrial dysfunction. Cilostazol reduced the serum levels of alanine aminotransferase, TNF-?, and liver myeloperoxidase content relative to control I/R-treated mice. In primary hepatocytes, cilostazol increased the expression of HO-1, and markers of mitochondrial biogenesis, PGC-1?, NRF-1, and TFAM, induced the mitochondrial proteins COX III and COX IV and increased mtDNA and mitochondria content. Pretreatment of primary hepatocytes with ZnPP inhibited cilostazol-induced PGC-1?, NRF-1, and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild-type mice, but not in Hmox1(-/-) or Nrf2(-/-) mice, and failed to protect against liver injury in Nrf2(-/-) mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2- and HO-1-dependent pathway. PMID:25951827

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

    PubMed Central

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

    2010-01-01

    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. PMID:20075336

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

    PubMed Central

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

    2014-01-01

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

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

    SciTech Connect

    Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf; Sharma, Reeta Kumari; Kandimalla, Ramesh J.L. [Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012 (India); Bal, Amanjit [Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh (India); Gill, Kiran Dip, E-mail: kdgill2002@yahoo.co.in [Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012 (India)

    2013-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 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 (10 mg/kg b.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits–NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-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. - Highlights: • Aluminium decreases the mRNA levels of mitochondrial and nuclear encoded subunits. • It decreases the mtDNA copy number and mitochondrial content in rat brain. • It down-regulates the mRNA and protein levels of PGC-1?, NRF-1, NRF-2 and Tfam. • It also disturbs the mitochondrial or nuclear architecture of neurons. • Finally it also decreases mitochondrial number in HC and CS regions of rat brain.

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

    PubMed

    Casuso, Rafael A; Martínez-Amat, Antonio; Hita-Contreras, Fidel; Camiletti-Moirón, Daniel; Aranda, Pilar; Martínez-López, Emilio

    2015-07-01

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

  20. Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle

    PubMed Central

    2014-01-01

    Background Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain. Methods C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro. Results Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid ?-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1? expression in the skeletal muscle. Conclusions Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders. PMID:25114710

  1. Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory Cytokine Expression*

    PubMed Central

    Piantadosi, Claude A.; Withers, Crystal M.; Bartz, Raquel R.; MacGarvey, Nancy Chou; Fu, Ping; Sweeney, Timothy E.; Welty-Wolf, Karen E.; Suliman, Hagir B.

    2011-01-01

    The induction of heme oxygenase-1 (HO-1; Hmox1) by inflammation, for instance in sepsis, is associated both with an anti-inflammatory response and with mitochondrial biogenesis. Here, we tested the idea that HO-1, acting through the Nfe2l2 (Nrf2) transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO-1 induction after LPS stimulated anti-inflammatory IL-10 and IL-1 receptor antagonist (IL-1Ra) expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-? expression. This was accompanied by nuclear Nfe2l2 accumulation and led us to identify abundant Nfe2l2 and other mitochondrial biogenesis transcription factor binding sites in the promoter regions of IL10 and IL1Ra compared with pro-inflammatory genes regulated by NF-??. Mechanistically, HO-1, through its CO product, enabled these transcription factors to bind the core IL10 and IL1Ra promoters, which for IL10 included Nfe2l2, nuclear respiratory factor (NRF)-2 (Gabpa), and MEF2, and for IL1Ra, included NRF-1 and MEF2. In cells, Hmox1 or Nfe2l2 RNA silencing prevented IL-10 and IL-1Ra up-regulation, and HO-1 induction failed post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2?/? mice. Nfe2l2?/? mice compared with WT mice, showed more liver damage, higher mortality, and ineffective CO rescue in sepsis. Nfe2l2?/? mice in sepsis also generated higher hepatic TNF-? mRNA levels, lower NRF-1 and PGC-1? mRNA levels, and no enhancement of anti-inflammatory Il10, Socs3, or bcl-xL gene expression. These findings disclose a highly structured transcriptional network that couples mitochondrial biogenesis to counter-inflammation with major implications for immune suppression in sepsis. PMID:21454555

  2. Biphasic Response of Mitochondrial Biogenesis to Oxidative Stress in Visceral Fat of Diet-Induced Obesity Mice

    PubMed Central

    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

    2014-01-01

    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

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

    PubMed

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

    2014-01-01

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

  4. Mitochondrial biogenesis and degradation are induced by CCCP treatment of porcine oocytes.

    PubMed

    Itami, N; Shiratsuki, S; Shirasuna, K; Kuwayama, T; Iwata, H

    2015-08-01

    In this study, we investigated the mitochondrial quality control system in porcine oocytes during meiotic maturation. Cumulus cell oocyte complexes (COCs) collected from gilt ovaries were treated with 10??M carbonyl cyanide-m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler) for 2?h. The CCCP treatment was found to significantly reduce ATP content, increase the amount of phosphorylated AMP-activated protein kinase and elevate reactive oxygen species levels in oocytes. When the CCCP-treated COCs were cultured further for 44?h in maturation medium, the ATP levels were restored and the parthenogenetic developmental rate of oocytes to the blastocyst stage was comparable with that of untreated COCs. To examine the effects of CCCP treatment of oocytes on the kinetics of mitochondrial DNA copy number (Mt number), COCs treated with 0 or 10??M CCCP were cultured for 44?h, after which the Mt number was determined by RT-PCR. CCCP treatment was found to increase the Mt number in the modified maturation medium in which mitochondrial degradation was inhibited by MG132, whereas CCCP treatment did not affect the Mt number in the maturation medium lacking MG132. The relative gene expression of TFAM was furthermore shown to be significantly higher in CCCP-treated oocytes than in untreated oocytes. Taken together, the finding presented here suggest that when the mitochondria are injured, mitochondrial biogenesis and degradation are induced, and that these processes may contribute to the recuperation of oocytes. PMID:25995440

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

    PubMed

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

    2015-06-20

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

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

    PubMed Central

    2014-01-01

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

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

    PubMed

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

    2015-07-01

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

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

    PubMed

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

    2015-09-01

    The adipokine leptin, known for its key role in the control of energy metabolism, has been shown to be involved in both normal and tumoral mammary growth. One of the hallmarks of cancer is an alteration of tumor metabolism since cancerous cells must rewire metabolism to satisfy the demands of growth and proliferation. Considering the sensibility of breast cancer cells to leptin, the objective of this study was to explore the effects of this adipokine on their metabolism. To this aim, we treated the MCF-7 breast cancer cell line with 50?ng/mL leptin and analyzed several features related to cellular and mitochondrial metabolism. As a result, leptin increased cell proliferation, shifted ATP production from glycolysis to mitochondria and decreased the levels of the glycolytic end-product lactate. We observed an improvement in ADP-dependent oxygen consumption and an amelioration of oxidative stress without changes in total mitochondrial mass or specific oxidative phosphorylation (OXPHOS) complexes. Furthermore, RT-PCR and western blot showed an up-regulation for genes and proteins related to biogenesis and mitochondrial dynamics. This expression signature, together with an increased mitophagy observed by confocal microscopy suggests that leptin may improve mitochondrial quality and function. Taken together, our results propose that leptin may improve bioenergetic efficiency by avoiding the production of reactive oxygen species (ROS) and conferring benefits for growth and survival of MCF-7 breast cancer cells. J. Cell. Biochem. 116: 2039-2048, 2015. © 2015 Wiley Periodicals, Inc. PMID:25752935

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

    PubMed

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

    2012-02-01

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

  10. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis.

    PubMed

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

    2014-07-18

    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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    2014-01-01

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

  13. Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression

    PubMed Central

    Li, Jia; Liu, Xiaolei; Wang, Huayan; Zhang, Weiping; Chan, David C.; Shi, Yuguang

    2012-01-01

    Oxidative stress causes mitochondrial fragmentation and dysfunction in age-related diseases through unknown mechanisms. Cardiolipin (CL) is a phospholipid required for mitochondrial oxidative phosphorylation. The function of CL is determined by its acyl composition, which is significantly altered by the onset of age-related diseases. Here, we examine a role of acyl-CoA:lysocardiolipin acyltransferase lysocardiolipin acyltransferase 1 (ALCAT1), a lysocardiolipin acyltransferase that catalyzes pathological CL remodeling, in mitochondrial biogenesis. We show that overexpression of ALCAT1 causes mitochondrial fragmentation through oxidative stress and depletion of mitofusin mitofusin 2 (MFN2) expression. Strikingly, ALCAT1 overexpression also leads to mtDNA instability and depletion that are reminiscent of MFN2 deficiency. Accordingly, expression of MFN2 completely rescues mitochondrial fusion defect and respiratory dysfunction. Furthermore, ablation of ALCAT1 prevents mitochondrial fragmentation from oxidative stress by up-regulating MFN2 expression, mtDNA copy number, and mtDNA fidelity. Together, these findings reveal an unexpected role of CL remodeling in mitochondrial biogenesis, linking oxidative stress by ALCAT1 to mitochondrial fusion defect. PMID:22509026

  14. Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression.

    PubMed

    Li, Jia; Liu, Xiaolei; Wang, Huayan; Zhang, Weiping; Chan, David C; Shi, Yuguang

    2012-05-01

    Oxidative stress causes mitochondrial fragmentation and dysfunction in age-related diseases through unknown mechanisms. Cardiolipin (CL) is a phospholipid required for mitochondrial oxidative phosphorylation. The function of CL is determined by its acyl composition, which is significantly altered by the onset of age-related diseases. Here, we examine a role of acyl-CoA:lysocardiolipin acyltransferase lysocardiolipin acyltransferase 1 (ALCAT1), a lysocardiolipin acyltransferase that catalyzes pathological CL remodeling, in mitochondrial biogenesis. We show that overexpression of ALCAT1 causes mitochondrial fragmentation through oxidative stress and depletion of mitofusin mitofusin 2 (MFN2) expression. Strikingly, ALCAT1 overexpression also leads to mtDNA instability and depletion that are reminiscent of MFN2 deficiency. Accordingly, expression of MFN2 completely rescues mitochondrial fusion defect and respiratory dysfunction. Furthermore, ablation of ALCAT1 prevents mitochondrial fragmentation from oxidative stress by up-regulating MFN2 expression, mtDNA copy number, and mtDNA fidelity. Together, these findings reveal an unexpected role of CL remodeling in mitochondrial biogenesis, linking oxidative stress by ALCAT1 to mitochondrial fusion defect. PMID:22509026

  15. Exercise-Induced Asthma

    MedlinePLUS

    ... any changes with your child's breathing problems. Recommended Activities for Kids With EIA Exercise is a great idea for ... With Exercise-Induced Asthma For the most part, kids with exercise-induced ... activity, in addition to stretching or flexibility exercises.) Take ...

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

    PubMed Central

    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

    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. PMID:21902452

  17. Dynamic mobilization of PGC-1? mediates mitochondrial biogenesis for the protection of RGC-5 cells by resveratrol during serum deprivation.

    PubMed

    Chen, Shida; Fan, Qian; Li, Ang; Liao, Dongjiang; Ge, Jian; Laties, Alan M; Zhang, Xiulan

    2013-07-01

    Mitochondrial dysfunction contributing to the pathogenesis of glaucomatous neurodegeneration has stimulated considerable interest recently. In this study, we explored the role of peroxisome proliferator activated receptor-? co-activator 1? (PGC-1?) in resveratrol-triggered mitochondrial biogenesis for preventing apoptosis in a retinal ganglion cell line RGC-5. Our results showed that serum deprivation induced cell apoptosis in a time-dependent manner. Applying resveratrol maintained the normal mitochondrial membrane potential, decreased the levels of both total and cleaved caspase-3, and inhibited the release of cytochrome c, which subsequently enhanced cell survival. Moreover, resveratrol stimulated mitochondrial biogenesis by increasing the absolute quantity of mitochondria as well as their DNA copies. Treatment with resveratrol promoted the protein expression of SIRT1, but not PGC-1?; instead, resveratrol facilitated PGC-1? translocation from the cytoplasm to the nucleus and up-regulated NRF1 and TFAM, which were blocked by nicotinamide. Collectively, we demonstrate that the SIRT1-dependent PGC-1? subcellular translocation following resveratrol application potentially attenuates serum deprivation-elicited RGC-5 cell death, thereby raising the possibility of mitigating glaucomatous retinopathy by enhancement of mitochondrial biogenesis. PMID:23525928

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

    PubMed

    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

    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

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

    PubMed

    Rogers, Ryan P; Rogina, Blanka

    2014-04-01

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

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

    PubMed

    Chitra, Loganathan; Boopathy, Rathanam

    2014-02-01

    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

  1. Exercise-induced anaphylaxis

    Microsoft Academic Search

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

    2003-01-01

    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.

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

    PubMed Central

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

    2012-01-01

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

  3. MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome

    PubMed Central

    Rorbach, Joanna; Boesch, Pierre; Gammage, Payam A.; Nicholls, Thomas J. J.; Pearce, Sarah F.; Patel, Dipali; Hauser, Andreas; Perocchi, Fabiana; Minczuk, Michal

    2014-01-01

    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. Ribosome production in all organisms studied thus far entails a complex, multistep pathway involving a number of auxiliary factors. This includes several RNA processing and modification steps required for correct rRNA maturation. Little is known about the maturation of human mitochondrial 16S rRNA and its role in biogenesis of the mitoribosome. Here we investigate two methyltransferases, MRM2 (also known as RRMJ2, encoded by FTSJ2) and MRM3 (also known as RMTL1, encoded by RNMTL1), that are responsible for modification of nucleotides of the 16S rRNA A-loop, an essential component of the peptidyl transferase center. Our studies show that inactivation of MRM2 or MRM3 in human cells by RNA interference results in respiratory incompetence as a consequence of diminished mitochondrial translation. Ineffective translation in MRM2- and MRM3-depleted cells results from aberrant assembly of the large subunit of the mitochondrial ribosome (mt-LSU). Our findings show that MRM2 and MRM3 are human mitochondrial methyltransferases involved in the modification of 16S rRNA and are important factors for the biogenesis and function of the large subunit of the mitochondrial ribosome. PMID:25009282

  4. MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome.

    PubMed

    Rorbach, Joanna; Boesch, Pierre; Gammage, Payam A; Nicholls, Thomas J J; Pearce, Sarah F; Patel, Dipali; Hauser, Andreas; Perocchi, Fabiana; Minczuk, Michal

    2014-09-01

    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. Ribosome production in all organisms studied thus far entails a complex, multistep pathway involving a number of auxiliary factors. This includes several RNA processing and modification steps required for correct rRNA maturation. Little is known about the maturation of human mitochondrial 16S rRNA and its role in biogenesis of the mitoribosome. Here we investigate two methyltransferases, MRM2 (also known as RRMJ2, encoded by FTSJ2) and MRM3 (also known as RMTL1, encoded by RNMTL1), that are responsible for modification of nucleotides of the 16S rRNA A-loop, an essential component of the peptidyl transferase center. Our studies show that inactivation of MRM2 or MRM3 in human cells by RNA interference results in respiratory incompetence as a consequence of diminished mitochondrial translation. Ineffective translation in MRM2- and MRM3-depleted cells results from aberrant assembly of the large subunit of the mitochondrial ribosome (mt-LSU). Our findings show that MRM2 and MRM3 are human mitochondrial methyltransferases involved in the modification of 16S rRNA and are important factors for the biogenesis and function of the large subunit of the mitochondrial ribosome. PMID:25009282

  5. The transmembrane prolines of the mitochondrial ADP/ATP carrier are involved in nucleotide binding and transport and its biogenesis.

    PubMed

    Babot, Marion; Blancard, Corinne; Pelosi, Ludovic; Lauquin, Guy J-M; Trézéguet, Véronique

    2012-03-23

    The mitochondrial ADP/ATP carrier (Ancp) is a paradigm of the mitochondrial carrier family, which allows cross-talk between mitochondria, where cell energy is mainly produced, and cytosol, where cell energy is mainly consumed. The members of this family share numerous structural and functional characteristics. Resolution of the atomic structure of the bovine Ancp, in a complex with one of its specific inhibitors, revealed interesting features and suggested the involvement of some particular residues in the movements of the protein to perform translocation of nucleotides from one side of the membrane to the other. They correspond to three prolines located in the odd-numbered transmembrane helices (TMH), Pro-27, Pro-132, and Pro-229. The corresponding residues of the yeast Ancp (Pro-43, Ser-147, and Pro-247) were mutated into alanine or leucine, one at a time and analysis of the various mutants evidenced a crucial role of Pro-43 and Pro-247 during nucleotide transport. Beside, replacement of Ser-147 with proline does not inactivate Ancp and this is discussed in view of the conservation of the three prolines at equivalent positions in the Ancp sequences. These prolines belong to the signature sequences of the mitochondrial carriers and we propose they play a dual role in the mitochondrial ADP/ATP carrier function and biogenesis. Unexpectedly their mutations cause more general effects on mitochondrial biogenesis and morphology, as evidenced by measurements of respiratory rates, cytochrome contents, and also clearly highlighted by fluorescence microscopy. PMID:22334686

  6. Differential Expression of PGC-1? and Metabolic Sensors Suggest Age-Dependent Induction of Mitochondrial Biogenesis in Friedreich Ataxia Fibroblasts

    PubMed Central

    García-Giménez, José Luis; Gimeno, Amparo; Gonzalez-Cabo, Pilar; Dasí, Francisco; Bolinches-Amorós, Arantxa; Mollá, Belén; Palau, Francesc; Pallardó, Federico V.

    2011-01-01

    Background Friedreich's ataxia (FRDA) is a mitochondrial rare disease, which molecular origin is associated with defect in the expression of frataxin. The pathological consequences are degeneration of nervous system structures and cardiomyopathy with necrosis and fibrosis, among others. Principal Findings Using FRDA fibroblasts we have characterized the oxidative stress status and mitochondrial biogenesis. We observed deficiency of MnSOD, increased ROS levels and low levels of ATP. Expression of PGC-1? and mtTFA was increased and the active form of the upstream signals p38 MAPK and AMPK in fibroblasts from two patients. Interestingly, the expression of energetic factors correlated with the natural history of disease of the patients, the age when skin biopsy was performed and the size of the GAA expanded alleles. Furthermore, idebenone inhibit mitochondriogenic responses in FRDA cells. Conclusions The induction of mitochondrial biogenesis in FRDA may be a consequence of the mitochondrial impairment associated with disease evolution. The increase of ROS and the involvement of the oxidative phosphorylation may be an early event in the cell pathophysiology of frataxin deficiency, whereas increase of mitochondriogenic response might be a later phenomenon associated to the individual age and natural history of the disease, being more evident as the patient age increases and disease evolves. This is a possible explanation of heart disease in FRDA. PMID:21687738

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

    PubMed Central

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

    2014-01-01

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

  8. Sirtuin 3, a New Target of PGC-1?, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis

    PubMed Central

    Kong, Xingxing; Wang, Rui; Xue, Yuan; Liu, Xiaojun; Zhang, Huabing; Chen, Yong; Fang, Fude; Chang, Yongsheng

    2010-01-01

    Background Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1? induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood. Results Here we show that PGC-1? strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1? led to decreased Sirt3 gene expression. PGC-1? activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR) binding element (ERRE) (?407/?399) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERR? bound to the identified ERRE and PGC-1? co-localized with ERR? in the mSirt3 promoter. Knockdown of ERR? reduced the induction of Sirt3 by PGC-1? in C2C12 myotubes. Furthermore, Sirt3 was essential for PGC-1?-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1? in C2C12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1? on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1? on mitochondrial biogenesis in C2C12 myotubes. Conclusion Our results indicate that Sirt3 functions as a downstream target gene of PGC-1? and mediates the PGC-1? effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation. The elucidation of the molecular mechanisms of SIRT3 regulation and its physiological functions may provide a novel target for treating ROS-related disease. PMID:20661474

  9. [Exercise-induced anaphylaxis].

    PubMed

    Wylon, K; Hompes, S; Worm, M

    2013-02-01

    Exercise-induced anaphylaxis is a mast cell dependent reaction, which is induced by allergen exposure in combination with physical activity. Typically, the reaction occurs within 2 hours after allergen exposure followed by physical activity. Not only food allergens but all kinds of allergens including drugs can induce this form of anaphylaxis. The clinical symptoms of exercise-induced anaphylaxis are the same as in any other type of anaphylaxis. Thus not only the skin and mucosa but also other organ systems like the lungs, cardiovascular system and gastrointestinal tract can be affected. The diagnostic work up should cover a detailed clinical history including the assessment of symptoms and possible trigger factors including suspected allergens. Besides classical allergy diagnostics like skin prick tests and specific IgE determination, tryptase should be measured for the differential diagnosis to exclude mast cell dependent diseases. The diagnosis of exercise-induced anaphylaxis is made by the means of a double-blind placebo-controlled provocation test. Both, a sufficient amount of allergen and of physical activity must be achieved for a valid test. After the diagnosis is made, patients should be extensively counseled and provided with an emergency kit including an epinephrine auto injector. PMID:23385620

  10. Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity

    PubMed Central

    Sun, Dongdong; Li, Shuang; Wu, Hao; Zhang, Mingming; Zhang, Xiaotian; Wei, Liping; Qin, Xing; Gao, Erhe

    2015-01-01

    Oncostatin M (OSM) exhibits many unique biological activities by activating O? receptor. However, its role in myocardial I/R injury in diabetic mice remains unknown. The involvement of OSM was assessed in diabetic mice which underwent myocardial I/R injury by OSM treatment or genetic deficiency of OSM receptor O?. Its mechanism on cardiomyocyte apoptosis, mitochondrial biogenesis and insulin sensitivity were further studied. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through inhibition of inositol pyrophosphate 7 (IP7) production, thus activating PI3K/Akt/BAD pathway, decreasing Bax expression while up-regulating Bcl-2 expression and decreasing the ratio of Bax to Bcl-2 in db/db mice. OSM enhanced mitochondrial biogenesis and mitochondrial function in db/db mice subjected to cardiac I/R injury. On the contrary, OSM receptor O? knockout exacerbated cardiac I/R injury, increased IP7 production, enhanced cardiomyocyte apoptosis, impaired mitochondrial biogenesis, glucose homoeostasis and insulin sensitivity in cardiac I/R injured diabetic mice. Inhibition of IP7 production by TNP (IP6K inhibitor) exerted similar effects of OSM. The mechanism of OSM on cardiac I/R injury in diabetic mice is partly associated with IP7/Akt and adenine mononucleotide protein kinase/PGC-1? pathway. OSM protects against cardiac I/R Injury by regulating apoptosis, insulin sensitivity and mitochondrial biogenesis in diabetic mice through inhibition of IP7 production. PMID:25752217

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

    PubMed

    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

    2012-12-01

    Here, we present new genetic and morphological evidence that human tumors consist of two distinct metabolic compartments. First, re-analysis of genome-wide transcriptional profiling data revealed that > 95 gene transcripts associated with mitochondrial biogenesis and/or mitochondrial translation were significantly elevated in human breast cancer cells, as compared with adjacent stromal tissue. Remarkably, nearly 40 of these upregulated gene transcripts were mitochondrial ribosomal proteins (MRPs), functionally associated with mitochondrial translation of protein components of the OXPHOS complex. Second, during validation by immunohistochemistry, we observed that antibodies directed against 15 markers of mitochondrial biogenesis and/or mitochondrial translation (AKAP1, GOLPH3, GOLPH3L, MCT1, MRPL40, MRPS7, MRPS15, MRPS22, NRF1, NRF2, PGC1-?, POLRMT, TFAM, TIMM9 and TOMM70A) selectively labeled epithelial breast cancer cells. These same mitochondrial markers were largely absent or excluded from adjacent tumor stromal cells. Finally, markers of mitochondrial lipid synthesis (GOLPH3) and mitochondrial translation (POLRMT) were associated with poor clinical outcome in human breast cancer patients. Thus, we conclude that human breast cancers contain two distinct metabolic 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. PMID:23172368

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

    The transcriptional coactivator, PGC-1?, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7kb upstream of the canonical PGC-1? promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1? mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1? transcripts. Although the ?2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1? promoter B, it is not yet known what molecular changes occur to facilitate PGC-1? promoter B activation following exercise. We sought to determine whether epigenetic modifications were involved in this exercise response in mouse skeletal muscle. We found that DNA hydroxymethylation correlated to increased basal mRNA levels from PGC-1? promoter A, but that DNA methylation appeared to play no role in the exercise-induced activation of PGC-1? promoter B. The level of the activating histone mark H3K4me3 increased with exercise 2–4 fold across PGC-1? promoter B, but remained unaltered past the canonical PGC-1? transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1? isoforms. PMID:26053857

  15. Mitochondrial Alterations Caused by Defective Peroxisomal Biogenesis in a Mouse Model for Zellweger Syndrome (PEX5 Knockout Mouse)

    PubMed Central

    Baumgart, Eveline; Vanhorebeek, Ilse; Grabenbauer, Markus; Borgers, Marcel; Declercq, Peter E.; Fahimi, H. Dariush; Baes, Myriam

    2001-01-01

    Zellweger syndrome (cerebro-hepato-renal syndrome) is the most severe form of the peroxisomal biogenesis disorders leading to early death of the affected children. To study the pathogenetic mechanisms causing organ dysfunctions in Zellweger syndrome, we have recently developed a knockout-mouse model by disrupting the PEX5 gene, encoding the targeting receptor for most peroxisomal matrix proteins (M Baes, P Gressens, E Baumgart, P Carmeliet, M Casteels, M Fransen, P Evrard, D Fahimi, PE Declercq, D Collen, PP van Veldhoven, GP Mannaerts: A mouse model for Zellweger syndrome. Nat Genet 1997, 17:49–57 1 ). In this study, we present evidence that the absence of functional peroxisomes, causing a general defect in peroxisomal metabolism, leads to proliferation of pleomorphic mitochondria with severe alterations of the mitochondrial ultrastructure, changes in the expression and activities of mitochondrial respiratory chain complexes, and an increase in the heterogeneity of the mitochondrial compartment in various organs and specific cell types (eg, liver, proximal tubules of the kidney, adrenal cortex, heart, skeletal and smooth muscle cells, neutrophils). The changes of mitochondrial respiratory chainenzymes are accompanied by a marked increase ofmitochondrial manganese-superoxide dismutase, asrevealed by in situ hybridization and immunocytochemistry, suggesting increased production of reactive oxygen species in altered mitochondria. This increased oxidative stress induced probably by defective peroxisomal antioxidant mechanisms combined with accumulation of lipid intermediates of peroxisomal ?-oxidation system could contribute significantly to the pathogenesis of multiple organ dysfunctions in Zellweger syndrome. PMID:11583975

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2013-04-01

    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

  19. Exercise-induced anaphylaxis.

    PubMed

    Sheffer, A L; Austen, K F

    1980-08-01

    Sixteen patients were seen because of possibly life-threatening exercise-associated symptoms similar to anaphylactic reactions. Asthma attacks, cholinergic urticaria and angioedema, and cardiac arrythmias are recognized as exertion-related phenomena in predisposed patients but are distinct from the syndrome described here. A syndrome characterized by the exertion-related onset of cutaneous pruritus and warmth, the development of generalized urticaria, and the appearance of such additional manifestations as collapse in 12 patients, gastrointestinal tract symptoms in five patients, and upper respiratory distress in 10 patients has been designated exercise-induced anaphylaxis, because of the striking similarity of this symptom complex to the anaphylactic syndrome elicited by ingestion or injection of a foreign antigenic substance. There is a family history of atopic desease for 11 patients and cold urticaria for two others and a personal history of atopy in six. The size of the wheals, the failure to develop an attack with a warm bath or shower or a fever, and the prominence of syncope rule against the diagnosis of conventional cholinergic urticaria. There is no history or evidence of an encounter with an environmental source of antigen during the exercise period. PMID:7400473

  20. A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase—extensive moonlighting in mitochondrial tRNA biogenesis

    PubMed Central

    Vilardo, Elisa; Nachbagauer, Christa; Buzet, Aurélie; Taschner, Andreas; Holzmann, Johann; Rossmanith, Walter

    2012-01-01

    Transfer RNAs (tRNAs) reach their mature functional form through several steps of processing and modification. Some nucleotide modifications affect the proper folding of tRNAs, and they are crucial in case of the non-canonically structured animal mitochondrial tRNAs, as exemplified by the apparently ubiquitous methylation of purines at position 9. Here, we show that a subcomplex of human mitochondrial RNase P, the endonuclease removing tRNA 5? extensions, is the methyltransferase responsible for m1G9 and m1A9 formation. The ability of the mitochondrial tRNA:m1R9 methyltransferase to modify both purines is uncommon among nucleic acid modification enzymes. In contrast to all the related methyltransferases, the human mitochondrial enzyme, moreover, requires a short-chain dehydrogenase as a partner protein. Human mitochondrial RNase P, thus, constitutes a multifunctional complex, whose subunits moonlight in cascade: a fatty and amino acid degradation enzyme in tRNA methylation and the methyltransferase, in turn, in tRNA 5? end processing. PMID:23042678

  1. Green Tea Polyphenols Stimulate Mitochondrial Biogenesis and Improve Renal Function after Chronic Cyclosporin A Treatment in Rats

    PubMed Central

    Rehman, Hasibur; Krishnasamy, Yasodha; Haque, Khujista; Lemasters, John J.; Schnellmann, Rick G.; Zhong, Zhi

    2013-01-01

    Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-? (AS-?) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-? coactivator (PGC)-1?, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-?, ND3, COX-IV, mtDNA copy number, PGC-1? mRNA and protein, decreased acetylated PGC-1?, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate CsA-induced kidney injury, at least in part, through the stimulation of MB. PMID:23755172

  2. Spatio-Temporal Dynamics of Yeast Mitochondrial Biogenesis: Transcriptional and Post-Transcriptional

    E-print Network

    Boyer, Edmond

    and periodically, contribute to the complex and intricate mitochondrial architecture. This approach revealed, which cover the entire oscillatory period. For instance, assembly factors (32 genes) and translation-transcriptional properties. Thus, mRNAs of modules expressed ``early'' are mostly translated in the vicinity of mitochondria

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2015-05-01

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

  5. The IMMUTANS variegation locus of Arabidopsis defines a mitochondrial alternative oxidase homolog that functions during early chloroplast biogenesis.

    PubMed Central

    Wu, D; Wright, D A; Wetzel, C; Voytas, D F; Rodermel, S

    1999-01-01

    Nuclear gene-induced variegation mutants provide a powerful system to dissect interactions between the genetic systems of the nucleus-cytoplasm, the chloroplast, and the mitochondrion. The immutans (im) variegation mutation of Arabidopsis is nuclear and recessive and results in the production of green- and white-sectored leaves. The green sectors contain cells with normal chloroplasts, whereas the white sectors are heteroplastidic and contain cells with abnormal, pigment-deficient plastids as well as some normal chloroplasts. White sector formation can be promoted by enhanced light intensities, but sectoring becomes irreversible early in leaf development. The white sectors accumulate the carotenoid precursor phytoene. We have positionally cloned IM and found that the gene encodes a 40.5-kD protein with sequence motifs characteristic of alternative oxidase, a mitochondrial protein that functions as a terminal oxidase in the respiratory chains of all plants. However, phylogenetic analyses revealed that the IM protein is only distantly related to these other alternative oxidases, suggesting that IM is a novel member of this protein class. We sequenced three alleles of im, and all are predicted to be null. Our data suggest a model of variegation in which the IM protein functions early in chloroplast biogenesis as a component of a redox chain responsible for phytoene desaturation but that a redundant electron transfer function is capable of compensating for IM activity in some plastids and cells. PMID:9878631

  6. The novel nuclear gene DSS1 of Saccharomyces cerevisiae is necessary for mitochondrial biogenesis

    Microsoft Academic Search

    Aleksandra Dmochowska; Pawel Golik; Piotr P. Stepien

    1995-01-01

    A previously unknown nuclear gene DSS-1 from Saccharomyces cerevisiae was cloned and sequenced. The gene was isolated as a multicopy suppressor of a disruption of the SUV-3 gene coding for a DEAD\\/H box protein involved in processing and turnover of mitochondrial transcripts. The DSS-1 gene codes for a 970 amino-acid protein of molecular weight 111 kDa and is necessary for

  7. Time-course of hormonal induction of mitochondrial glycerophosphate dehydrogenase biogenesis in rat liver.

    PubMed

    Mrácek, T; Jesina, P; Kriváková, P; Bolehovská, R; Cervinková, Z; Drahota, Z; Houstek, J

    2005-11-15

    Thyroid hormones are important regulators of mitochondrial metabolism. Due to their complex mechanism of action, the timescale of different responses varies from minutes to days. In this work, we studied selective T3 induction of the inner mitochondrial membrane enzyme-glycerophosphate dehydrogenase (mGPDH) in liver of euthyroid rats. We correlated the kinetics of the T3 level in blood, the mRNA level in liver, the activity and amount of mGPDH in liver mitochondria after a single dose of T3. The T3 level reached maximum after 1 h (80 nmol/l) and subsequently rapidly decreased. mGPDH mRNA increased also relatively fast, reaching a maximum after 12 h and fell to the control level after 72 h. An increase of mGPDH activity could be already found after 6 h and reached a maximum after 24 h in accordance with the increase in mGPDH content (2.4-fold vs. 2.7-fold induction). After 72 h, the mGPDH activity showed a significant 30% decrease. When the rats received three subsequent doses of T3, the increase of mGPDH activity was 2-fold higher than after a single T3 dose. The results demonstrate that mGPDH displays rapid induction as well as decay upon disappearance of a hormonal stimulus, indicating a rather short half-life of this inner mitochondrial membrane enzyme. PMID:16039782

  8. Transcriptional modulation of mitochondria biogenesis pathway at and above critical speed in mice.

    PubMed

    Mille-Hamard, L; Breuneval, C; Rousseau, A S; Grimaldi, P; Billat, V L

    2015-07-01

    High- or moderate-intensity endurance training leads to mitochondrial biogenesis via the peroxisome proliferator-activated receptor ? co-activator 1? (PGC-1?)/mitochondrial transcription factor A (Tfam) signaling pathway. Although this pathway is stimulated during acute exercise, the relationship between its activity and the intensity of the exercise has not been characterized. In animal studies, individualized running speeds have not previously been assessed. Here, we sought to determine whether this pathway was modulated after a bout of exhaustive exercise at different relative intensities (at and over critical speed (CS)). Our starting hypotheses were that (i) exercise-induced overexpression of PGC-1? in skeletal muscle falls at intensities above CS, and (ii) transcriptional activity of the mitochondrial biogenesis signaling cascade is intensity-sensitive at and above CS. To test these hypothesis, male Friend Virus B-Type mice were divided into a control group and three exercise groups (exercising at CS, peak velocity (vPeak) and 150 % CS, respectively). mRNA expression levels for genes involved in mitochondrial biogenesis signaling were analyzed in the quadriceps muscle. PGC-1? was overexpressed at all exercise intensities. We also identified that, PGC-1? mRNA expression was negatively correlated with exercise intensity and blood lactate levels but not with maximal oxygen uptake, vPeak, or CS. Expression of the PGC-1? co-activator peroxisome proliferator-activated receptor ? was negatively correlated with the exercise intensity. In contrast, expression levels of Tfam were dissociated from exercise intensity. Our data indicate that at the intensities used in endurance training, the expression of mitochondrial biogenesis genes is finely modulated by the relative intensity of exhaustive exercise. PMID:25912548

  9. Adolescents and Exercise Induced Asthma

    ERIC Educational Resources Information Center

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

    2008-01-01

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

  10. Chronic anthracycline cardiotoxicity: molecular and functional analysis with focus on nuclear factor erythroid 2-related factor 2 and mitochondrial biogenesis pathways.

    PubMed

    Jirkovsky, Eduard; Popelová, Olga; Kriváková-Stanková, Pavla; Vávrová, Anna; Hroch, Milos; Hasková, Pavlína; Brcáková-Dolezelová, Eva; Micuda, Stanislav; Adamcová, Michaela; Sim?nek, Tomás; Cervinková, Zuzana; Gersl, Vladimír; Sterba, Martin

    2012-11-01

    Anthracycline anticancer drugs (e.g., doxorubicin or daunorubicin) can induce chronic cardiotoxicity and heart failure (HF), both of which are believed to be based on oxidative injury and mitochondrial damage. In this study, molecular and functional changes induced by chronic anthracycline treatment with progression into HF in post-treatment follow-up were analyzed with special emphasis on nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-? coactivator-1? (PGC1?) pathways. Chronic cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg, weekly for 10 weeks), and the animals were followed for another 10 weeks. Echocardiography revealed a significant drop in left ventricular (LV) systolic function during the treatment with marked progression to LV dilation and congestive HF in the follow-up. Although daunorubicin-induced LV lipoperoxidation was found, it was only loosely associated with cardiac performance. Furthermore, although LV oxidized glutathione content was increased, the oxidized-to-reduced glutathione ratio itself remained unchanged. Neither Nrf2, the master regulator of antioxidant response, nor the majority of its target genes showed up-regulation in the study. However, down-regulation of manganese superoxide dismutase and NAD(P)H dehydrogenase [quinone] 1 were observed together with heme oxygenase 1 up-regulation. Although marked perturbations in mitochondrial functions were found, no induction of PGC1?-controlled mitochondrial biogenesis pathway was revealed. Instead, especially in the post-treatment period, an impaired regulation of this pathway was observed along with down-regulation of the expression of mitochondrial genes. These results imply that global oxidative stress need not be a factor responsible for the development of anthracycline-induced HF, whereas suppression of mitochondrial biogenesis might be involved. PMID:22915767

  11. Indoxyl Sulfate-Induced Oxidative Stress, Mitochondrial Dysfunction, and Impaired Biogenesis Are Partly Protected by Vitamin C and N-Acetylcysteine

    PubMed Central

    Lee, Wen-Chin; Li, Lung-Chih; Chen, Jin-Bor; Chang, Hsueh-Wei

    2015-01-01

    Indoxyl sulfate (IS) contributes to oxidative stress and endothelial dysfunction in chronic kidney disease patients. However, the role of mitochondria in IS-induced oxidative stress is not very clear. In this study, we examined whether mitochondria play a pivotal role in modulating the effects of antioxidants during IS treatment. In the context of human umbilical vein endothelial cells, we found that IS had a dose-dependent antiproliferative effect. In addition, we used flow cytometry to demonstrate that the level of reactive oxygen species increased in a dose-dependent manner after treatment with IS. High doses of IS also corresponded to increased mitochondrial depolarization and decreased mitochondrial DNA copy number and mitochondrial mass. However, these effects could be reversed by the addition of antioxidants, namely, vitamin C and N-acetylcysteine. Thus, our results suggest that IS-induced oxidative stress and antiproliferative effect can be attributed to mitochondrial dysfunction and impaired biogenesis and that these processes can be protected by treatment with antioxidants. PMID:25839054

  12. OM2, a Novel Oligomannuronate-Chromium(III) Complex, Promotes Mitochondrial Biogenesis and Lipid Metabolism in 3T3-L1 Adipocytes via the AMPK-PGC1? Pathway

    PubMed Central

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

    2015-01-01

    Background In our previous studies, we prepared novel oligomannuronate-chromium(III) complexes (OM2, OM4) from marine alginate, and found that these compounds sensitize insulin action better than oligomannuronate(OM), chromium, and metformin in C2C12 skeletal muscle cells. In the present study, we studied their effects on mitochondrial biogenesis, lipid metabolism, and the underlying molecular mechanisms in differentiated 3T3-L1 adipocytes. Methodology/Principal Findings We firstly used the pGL3-PGC1? and pGL3-ATGL promoter plasmids to compare their effects on PGC1? and ATGL transcription activities. Then mitochondrial biogenesis was quantified by transmission electron microscopy and MitoTracker staining. Mitochondrial oxygen consumption and fatty acid oxidation were measured by an oxygen biosensor system and ³H-labelled water scintillation. The mitochondrial DNA and mRNA involved in mitochondrial biogenesis and lipid oxidation were evaluated by real-time PCR. AMPK together with other protein expression levels were measured by western blotting. The inhibitor compound C and siRNA of PGC1? were used to inhibit the OM2-induced AMPK-PGC1? signaling pathway. And we found that OM2 stimulated AMPK-PGC1? pathway in the 3T3-L1 adipocytes, which were correlated with induced mitochondrial biogenesis, improved mitochondrial function, and reduced lipid accumulation by enhanced fatty acid ?-oxidation and augmented ATGL protein expression. Conclusions/Significance Our data indicated that the marine oligosaccharide-derived OM2 might represent a novel class of molecules that could be useful for type 2 diabetes prevention and treatment by up-regulating AMPK-PGC1? signaling pathway. PMID:26176781

  13. Jac1, a mitochondrial J-type chaperone, is involved in the biogenesis of Fe S clusters in

    E-print Network

    Craig, Elizabeth A

    S clusters. In fact, a minor Hsp70 of the yeast mitochondrial matrix, Ssq1, has been linked to iron me and or mitochondrial iron metabolism. Here, we report evidence that Jac1, a J-type chaperone of the mitochondrial in activity of Fe S containing mitochon- drial proteins and an accumulation of iron in mitochondria. Fe

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

    PubMed Central

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

    2012-01-01

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

  15. Nutrition Controls Mitochondrial Biogenesis in the Drosophila Adipose Tissue through Delg and Cyclin D/Cdk4

    PubMed Central

    Baltzer, Claudia; Tiefenböck, Stefanie K.; Marti, Mark; Frei, Christian

    2009-01-01

    Mitochondria are cellular organelles that perform critical metabolic functions: they generate energy from nutrients but also provide metabolites for de novo synthesis of fatty acids and several amino acids. Thus mitochondrial mass and activity must be coordinated with nutrient availability, yet this remains poorly understood. Here, we demonstrate that Drosophila larvae grown in low yeast food have strong defects in mitochondrial abundance and respiration activity in the larval fat body. This correlates with reduced expression of genes encoding mitochondrial proteins, particularly genes involved in oxidative phosphorylation. Second, genes involved in glutamine metabolism are also expressed in a nutrient-dependent manner, suggesting a coordination of amino acid synthesis with mitochondrial abundance and activity. Moreover, we show that Delg (CG6338), the Drosophila homologue to the alpha subunit of mammalian transcription factor NRF-2/GABP, is required for proper expression of most genes encoding mitochondrial proteins. Our data demonstrate that Delg is critical to adjust mitochondrial abundance in respect to Cyclin D/Cdk4, a growth-promoting complex and glutamine metabolism according to nutrient availability. However, in contrast to nutrients, Delg is not involved in the regulation of mitochondrial activity in the fat body. These findings are the first genetic evidence that the regulation of mitochondrial mass can be uncoupled from mitochondrial activity. PMID:19742324

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

    PubMed Central

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

    2012-01-01

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

  17. PGC-1? transcriptional response and mitochondrial adaptation to acute exercise is maintained in skeletal muscle of sedentary elderly males.

    PubMed

    Cobley, J N; Bartlett, J D; Kayani, A; Murray, S W; Louhelainen, J; Donovan, T; Waldron, S; Gregson, W; Burniston, J G; Morton, J P; Close, G L

    2012-12-01

    The aim of the present study was to examine the effects of ageing and training status on (1) markers of skeletal muscle mitochondrial content and (2) the ability to activate the acute signalling pathways associated with regulating exercise-induced mitochondrial biogenesis. Muscle biopsies were obtained from the vastus lateralis muscle of young untrained (24 ± 4 years, n = 6; YU), young trained (22 ± 3 years, n = 6; YT), old untrained (65 ± 6 years, n = 6; OU) and old trained (64 ± 3 years, n = 6; OT) healthy males before and after (3 h and 3 days post-exercise) completion of high-intensity interval cycling exercise. In resting muscle, lifelong training preserved mtDNA, PGC-1? and COXIV protein content such that muscles from OT individuals were comparable to muscles from both YU and YT individuals, whereas lifelong sedentary behaviour reduced such markers of mitochondrial content. Regardless of age or training status, acute exercise induced comparable increases in p38MAPK phosphorylation immediately post-exercise, PGC-1? and COXIV mRNA expression at 3 h post-exercise and COXIV protein at 3 days post-exercise. Data demonstrate that lifelong endurance training preserves skeletal muscle PGC-1? content and that despite the mitochondrial dysfunction typically observed with sedentary ageing, muscles from sedentary elderly individuals retain the capacity to activate the acute signalling pathways associated with regulating the early processes of mitochondrial biogenesis. We consider our data to have immediate translational potential as they highlight the potential therapeutic effects of exercise to induce skeletal muscle mitochondrial biogenesis persist late in adulthood, even after a lifetime of physical inactivity. PMID:23187721

  18. Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro.

    PubMed

    An, F-M; Chen, S; Xu, Z; Yin, L; Wang, Y; Liu, A-R; Yao, W-B; Gao, X-D

    2015-08-01

    Our previous study has proved that glucagon-like peptide-1 (GLP-1), which is developed to treat type 2 diabetes, has a significant effect on neuroprotection against advanced glycation end product (AGE)-induced neuronal insult in vitro models of diabetes-related Alzheimer's disease (AD). However, the molecular mechanisms remain to be elucidated and it is not clear whether GLP-1 receptor mediates the down-regulation effects on AGE-induced AD-like changes in vivo. This study aims to explore the effect and mechanisms of GLP-1 receptor agonists (GLP-1RA) against the AGE-dependent signaling pathway both in vitro and in vivo. In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1?g/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3? (GSK-3?) to reverse tau hyperphosphorylation directly. Collectively, our results suggest that GLP-1RA protects neurons against AGE-induced tau hyperphosphorylation via regulating GSK-3? and PGC-1? two cooperative signaling pathways. PMID:25987199

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

    PubMed

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

    2014-04-01

    Mitochondrial transcription factor A (TFAM) is one of the key regulators of the transcription of mtDNA. In diabetes, despite increase in gene transcripts of TFAM, its protein levels in the mitochondria are decreased and mitochondria copy numbers become subnormal. The aim of this study is to investigate the mechanism(s) responsible for decreased mitochondrial TFAM in diabetes. Using retinal endothelial cells, we have investigated the effect of overexpression of cytosolic chaperone, Hsp70, and TFAM on glucose-induced decrease in mitochondrial TFAM levels, and the transcription of mtDNA-encoded genes, NADH dehydrogenase subunit 6 (ND6) and cytochrome b (Cytb). To investigate the role of posttranslational modifications in subnormal mitochondrial TFAM, ubiquitination of TFAM was 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

  20. Nuclear–mitochondrial interaction

    Microsoft Academic Search

    G. Cannino; C. M. Di Liegro; A. M. Rinaldi

    2007-01-01

    The biogenesis of mitochondria depends on the coordinated expression of nuclear and mitochondrial genomes. Consequently, the control of mitochondrial biogenesis and function depends on extremely complex processes requiring a variety of well orchestrated regulatory mechanisms. It is clear that the interplay of transcription factors and coactivators contributes to the expression of both nuclear and mitochondrial respiratory genes. In addition, the

  1. Hypoglycemic effect of catalpol on high-fat diet/streptozotocin-induced diabetic mice by increasing skeletal muscle mitochondrial biogenesis.

    PubMed

    Li, Xia; Xu, Zhimeng; Jiang, Zhenzhou; Sun, Lixin; Ji, Jinzi; Miao, Jingshan; Zhang, Xueji; Li, Xiaojie; Huang, Shan; Wang, Tao; Zhang, Luyong

    2014-09-01

    Catalpol, an iridoid glycoside, exists in the root of Radix Rehmanniae. Some studies have shown that catalpol has a remarkable hypoglycemic effect in the streptozotocin-induced diabetic model, but the underlying mechanism for this effect has not been fully elucidated. Because mitochondrial dysfunction plays a vital role in the pathology of diabetes and because improving mitochondrial function may offer a new approach for the treatment of diabetes, this study was designed. Catalpol was orally administered together with metformin to high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice daily for 4 weeks. Body weight (BW), fasting blood glucose (FBG) level, and glucose disposal (IPGTT) were measured during or after the treatment. The results showed a dose-dependent reduction of FBG level with no apparent changes in BW through four successive weeks of catalpol administration. Catalpol treatment substantially reduced serum total cholesterol and triglyceride levels in the diabetic mice. In addition, catalpol efficiently increased mitochondrial ATP production and reversed the decrease of mitochondrial membrane potential and mtDNA copy number in skeletal muscle tissue. Furthermore, catalpol (200 mg/kg) rescued mitochondrial ultrastructure in skeletal muscle, as detected with transmission electron microscopy. The relative mRNA level of peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) ? was significantly decreased in muscle tissue of diabetic mice, while this effect was reversed by catalpol, resulting in a dose-dependent up-regulation. Taken together, we found that catalpol was capable of lowering FBG level via improving mitochondrial function in skeletal muscle of HFD/STZ-induced diabetic mice. PMID:25178463

  2. Yeast Mitochondrial Biogenesis: A Role for the PUF RNA-Binding Protein Puf3p in mRNA Localization

    Microsoft Academic Search

    Yann Saint-Georges; Mathilde Garcia; Thierry Delaveau; Laurent Jourdren; Stephane Le Crom; Sophie Lemoine; Veronique Tanty; Frederic Devaux; Claude Jacq; Jürg Bähler

    2008-01-01

    The asymmetric localization of mRNA plays an important role in coordinating posttranscriptional events in eukaryotic cells. We investigated the peripheral mitochondrial localization of nuclear-encoded mRNAs (MLR) in various conditions in which the mRNA binding protein context and the translation efficiency were altered. We identified Puf3p, a Pumilio family RNA-binding protein, as the first trans-acting factor controlling the MLR phenomenon. This

  3. The airway microvasculature and exercise induced asthma.

    PubMed Central

    Anderson, S D; Daviskas, E

    1992-01-01

    It has been proposed that exercise induced asthma is a result of "rapid expansion of the blood volume of peribronchial plexi" (McFadden ER, Lancet 1990;335:880-3). This hypothesis proposes that the development of exercise induced asthma depends on the thermal gradient in the airways at the end of hyperpnoea. The events that result in exercise induced asthma are vasoconstriction and airway cooling followed by reactive hyperaemia. We agree that the airway microcirculation has the potential for contributing to the pathophysiology of exercise induced asthma. We do, however, question whether reactive hyperaemia, in response to airway cooling, is the mechanism whereby hyperpnoea provokes airways obstruction in asthmatic patients. Further, we question whether vasoconstriction accompanies dry air breathing and whether an abnormal temperature gradient and rapid rewarming of the airways are prerequisites for exercise induced asthma. From published experiments we conclude that dry air breathing is associated with vasodilation and increase in airway blood flow rather than vasoconstriction and a decrease in blood flow to the airways. We propose that the stimulus for the increase in airway blood flow is an increase in osmolarity of the airway submucosa. This osmotic change is caused by the movement of water to the airway lumen in response to evaporative water loss during hyperpnoea. The increase in airway blood flow may occur directly or indirectly by the osmotic release of mediators. Exercise induced asthma is most likely to be due to the contraction of bronchial smooth muscle caused by the same mediators. Whether it is enhanced or inhibited by alterations in airway blood flow is not yet established in man. PMID:1440473

  4. 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 Central

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

    2014-01-01

    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

  5. 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

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

    2014-04-01

    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

  6. Genes involved in mitochondrial biogenesis\\/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

    Microsoft Academic Search

    M. I. Hernández-Alvarez; C. Chiellini; M. Manco; D. Naon; M. Liesa; M. Palacín; G. Mingrone; A. Zorzano

    2009-01-01

    Aims\\/hypothesis  The mechanisms allowing normalisation of insulin sensitivity and reversal of type 2 diabetes after bilio-pancreatic diversion\\u000a (BPD) have not been elucidated. We studied whether the expression of genes relevant to mitochondrial biogenesis\\/function is\\u000a induced in response to BPD and whether the response differs between morbidly obese patients with normal glucose tolerance\\u000a (NGT) and patients with type 2 diabetes.\\u000a \\u000a \\u000a \\u000a Methods  The effect

  7. Assessment of Mitochondrial Biogenesis and mTORC1 Signaling During Chronic Rapamycin Feeding in Male and Female Mice

    PubMed Central

    2013-01-01

    Chronic inhibition of the protein synthesis regulator mTORC1 through rapamycin extends life span in mice, with longer extension in females than in males. Whether rapamycin treatment inhibits protein synthesis or whether it does so differently between sexes has not been examined. UM-HET3 mice were fed a control or rapamycin-supplemented (Rap) diet for 12 weeks. Protein synthesis in mixed, cytosolic (cyto), and mitochondrial (mito) fractions and DNA synthesis and mTORC1 signaling were determined in skeletal muscle, heart, and liver. In both sexes, mito protein synthesis was maintained in skeletal muscle from Rap despite decreases in mixed and cyto fractions, DNA synthesis, and rpS6 phosphorylation. In the heart, no change in protein synthesis occurred despite the decreased DNA synthesis. In the heart and liver, Rap males were more sensitive to mTORC1 inhibition than Rap females. In conclusion, we show changes in protein synthesis and mTORC1 signaling that differ by sex and tissue. PMID:23657975

  8. Increased fatigue resistance linked to Ca2+-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice

    PubMed Central

    Bruton, Joseph D; Aydin, Jan; Yamada, Takashi; Shabalina, Irina G; Ivarsson, Niklas; Zhang, Shi-Jin; Wada, Masanobu; Tavi, Pasi; Nedergaard, Jan; Katz, Abram; Westerblad, Håkan

    2010-01-01

    Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold-exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24°C) or cold-acclimated (4°C) for 4–5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (?50%), tetanic [Ca2+]i (?40%), and sarcoplasmic reticulum (SR) Ca2+ leak (?fourfold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold-acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations. PMID:20837639

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

    PubMed

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

    2014-05-01

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

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

    PubMed Central

    Welter, A.E.; Dominguez, J.M.; Behnke, B.J.; Adhihetty, P.J.

    2015-01-01

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

  11. Peroxisome Proliferator-activated Receptor ? Co-activator 1-? as a Critical Co-activator of the Murine Hepatic Oxidative Stress Response and Mitochondrial Biogenesis in Staphylococcus aureus Sepsis*

    PubMed Central

    Cherry, Anne D.; Suliman, Hagir B.; Bartz, Raquel R.; Piantadosi, Claude A.

    2014-01-01

    A key transcriptional regulator of cell metabolism, the peroxisome proliferator-activated receptor ? co-activator 1-? (PPARGC-1-? or PGC-1?), also regulates mitochondrial biogenesis, but its role in antioxidant gene regulation is not well understood. Here, we asked whether genetic heterozygosity of PGC-1? modulates gene expression for the mitochondrial antioxidant enzyme SOD-2 during hepatic inflammatory stress. Using Staphylococcus aureus peritonitis in mice, we found significant Sod2 gene induction in WT mice, whereas PGC-1? heterozygotes (PGC-1?+/?) failed to augment Sod2 mRNA and protein levels. Impaired Sod2 regulation in PGC-1?+/? mice was accompanied by oxidative stress shown by elevated mitochondrial GSSG/GSH and protein carbonyls. In silico analysis of the mouse proximal Sod2 promoter region revealed consensus binding sites for the Nfe2l2 (Nrf2) transcription factor. Chromatin immunoprecipitation demonstrated diminished Nfe2l2 protein binding to the antioxidant response element promoter site proximal to the Sod2 start site in PGC-1? heterozygous mice, implicating PGC-1? in facilitation of Nfe2l2 DNA binding. Nuclear protein co-immunoprecipitation demonstrated an interaction between hepatic Nfe2l2 and PGC-1? in WT mice that was greatly reduced in PGC-1?+/? mice. The data indicate that PGC-1? promotes mitochondrial antioxidant enzyme expression through Nfe2l2-mediated SOD-2 expression in sepsis. The presence of this new PGC-1?-dependent signaling axis indicates that PGC-1? opposes mitochondrial oxidative stress by means of selective induction of one or more antioxidant response element-driven genes. By implication, exploitation of this axis could lead to new pharmacological interventions to improve the antioxidant defenses during oxidative stress-induced mitochondrial damage. PMID:24253037

  12. Exercise-induced anaphylaxis: A clinical view

    PubMed Central

    2012-01-01

    Exercise-induced anaphylaxis (EIA) is a distinct form of physical allergy. The development of anaphylaxis during exertion often requires the concomitant exposure to triggering factors such as intake of foods (food dependent exercise-induced anaphylaxis) or drugs prior to exercise, extreme environmental conditions. EIA is a rare, but serious disorder, which is often undetected or inadequately treated. This article summarizes current evidences on pathophysiology, diagnosis and management. We reviewed recent advances in factors triggering the release of mediators from mast cells which seems to play a pathogenetic role. A correct diagnosis is essential to avoid unnecessary restricted diet, to allow physical activity in subjects with EIA dependent from triggering factors such as food, and to manage attacks. An algorithm for diagnosing EIA based on medical history, IgE tests and exercise challenge test has been provided. In the long-term management of EIA, there is a need for educating patients and care-givers to avoid exposure to precipitating factors and to recognize and treat episodes. Future researches on existing questions are discussed. PMID:22980517

  13. Suppression of mitochondrial biogenesis through toll-like receptor 4-dependent mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling in endotoxin-induced acute kidney injury.

    PubMed

    Smith, Joshua A; Stallons, L Jay; Collier, Justin B; Chavin, Kenneth D; Schnellmann, Rick G

    2015-02-01

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

  14. Activation of the Iron Regulon by the Yeast Aft1\\/Aft2 Transcription Factors Depends on Mitochondrial but Not Cytosolic Iron-Sulfur Protein Biogenesis

    Microsoft Academic Search

    Julian C. Rutherford; Luis Ojeda; Janneke Balk; Ulrich Muhlenhoff; Roland Lill; Dennis R. Winge

    2005-01-01

    Two transcriptional activators, Aft1 and Aft2, regulate iron homeostasis in Saccharomyces cerevisiae. These factors induce the expression of iron regulon genes in iron-deficient yeast but are inactivated in iron-replete cells. Iron inhibition of Aft1\\/Aft2 is abrogated in cells defective for Fe-S cluster biogenesis within the mito- chondrial matrix (Chen, O. S., Crisp, R. J., Valachovic, M., Bard, M., Winge, D.

  15. Mechanisms and Management of Exercise-Induced Bronchoconstriction

    Microsoft Academic Search

    John D. Brannan; Paul M. O'Byrne

    The term “exercise-induced asthma” has been used to describe the transient narrowing of the airways and the subsequent increase\\u000a in airway resistance, which can occur during, though more commonly following, vigorous exercise [1]. Exercise is a trigger\\u000a for bronchoconstriction in individuals with asthma, but is not considered an independent risk factor for the development of\\u000a asthma. The term “exercise-induced asthma”

  16. Asthma Bronchiale and Exercise-Induced Bronchoconstriction.

    PubMed

    Jayasinghe, Harshani; Kopsaftis, Zoe; Carson, Kristin

    2015-01-01

    Exercising regularly has a wide range of beneficial health effects; in particular, it has been well documented to help in the management of chronic illnesses including asthma. However, in some individuals, exertion can also trigger an exacerbation of asthmatic episodes and subsequent acute attacks of breathlessness, coughing, tightness of the chest and wheezing. This physiological process is called exercise-induced bronchoconstriction (EIB) whereby post-exercise forced expiratory volume in 1 s is reduced by 10-15% from baseline. While EIB is highly prevalent in asthmatics and presents with similar respiratory symptoms, asthma and EIB are not mutually exclusive. The aim of this review is to present a broad overview of both conditions in order to enhance the understanding of the similarities and differences distinguishing them as two separate entities. The pathophysiology and mechanisms underlying asthma are well described with research now focussing on defining phenotypes for targeted management strategies. Conversely, the mechanistic understanding of EIB remains largely under-described. Diagnostic pathways for both are established and similar, as are pharmacologic and non-pharmacologic treatments and management approaches, which have enhanced success with early detection. Given the potential for exacerbation of asthma, exercise avoidance is common but counterproductive as current evidence indicates that it is well tolerated and improves quality of life. Literature supporting the benefit of exercise for EIB sufferers is at present favourable, yet extremely limited; therefore, future research should be directed in this area as well as towards further developing the understanding of the pathophysiology and mechanisms underpinning both EIB and asthma. © 2015 S. Karger AG, Basel. PMID:26068579

  17. Management of Exercise-Induced Bronchospasm in Children

    PubMed Central

    Hendeles, Leslie; Asmus, Michael J.; Chesrown, Sarah

    2003-01-01

    Bronchospasm precipitated by exercise is often indistinguishable from bronchospasm produced by other stimuli. Symptoms result from airflow limitation and include wheezing, cough, chest tightness, dyspnea and sometimes hypoxemia. The prevalence of exercise-induced bronchospasm varies from 30%-90%, but virtually all patients with current asthma will experience a decrease in lung function if the exercise is sufficiently vigorous, especially in cold, dry environmental conditions. Exercise-induced bronchospasm is more prevalent in children than in adults, probably because children are physically more active. It is also more prevalent among elite winter sports athletes. The pathogenesis of exercise-induced bronchospasm involves a defect in respiratory heat exchange that probably triggers mast cell and eosinophil release of bronchoconstricting mediators. The goal of therapy is prevention of symptoms. This may be accomplished by pre-treating patients with isolated exercise-induced bronchospasm using an inhaled rapid-onset ?2-adrenergic agonist before a scheduled activity or by treating the underlying inflammation when exercise-induced bronchospasm is part of the clinical syndrome of persistent asthma. In the later instance, either an inhaled corticosteroid, an oral leukotriene modifier, or a combination of both, depending on severity, may be required to prevent exercise-induced bronchospasm associated with activities of daily living. In addition, some of these patients may still require pre-treatment with a short-acting inhaled ?2-agonist before a scheduled vigorous activity, especially in very cold ambient temperatures. Because the duration of bronchoprotection decreases with daily use (tachyphylaxis), long acting ?2-adrenergic agonists (e.g., formoterol, salmeterol) have a limited role in treating exercise-induced bronchospasm. PMID:23300391

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

    PubMed Central

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

    2014-01-01

    Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPT-FOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control. PMID:24659933

  19. Current topics in bioenergetics: Structure, biogenesis, and assembly of energy transducing enzyme systems. Volume 15

    SciTech Connect

    Lee, C.P.

    1987-01-01

    This book contains 11 chapters. The chapter titles are: Structure of NADH-Ubiquinone Reductase (Complex I); Structure of the Succinate-Ubiquinone Oxidoreductase (Complex II); Structure of Mitochondrial Ubiquinol-Cytochrome-c Redutase (Complex III); Structure of Cytochrome-c Oxidase; Evolution of a Regulatory Enzyme: Cytochrome-c Oxidase (Complex IV); The Assembly of F/sub 1/F/sub 0/-ATPase in Escherichia coli; Biogenesis of Mitochondrial Energy Transducing Complexes; Biogenesis of Mammalian Mitochondria; Structure and Biogenesis of Chloroplast Coupling Factor (CF/sub 0/CF/sub 1/)-ATPase; Mitochondrial Gene Products; and Overview: Bioenergetics between Chemistry, Genetics, and Physics.

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

    PubMed Central

    Philp, Andrew; Schenk, Simon

    2013-01-01

    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. PMID:23792490

  1. Nox4 Is Dispensable for Exercise Induced Muscle Fibre Switch

    PubMed Central

    Vogel, Juri; Figueiredo de Rezende, Flávia; Rohrbach, Susanne; Zhang, Min; Schröder, Katrin

    2015-01-01

    Introduction By producing H2O2, the NADPH oxidase Nox4 is involved in differentiation of mesenchymal cells. Exercise alters the composition of slow and fast twitch fibres in skeletal. Here we hypothesized that Nox4 contributes to exercise-induced adaptation such as changes in muscle metabolism or muscle fibre specification and studied this in wildtype and Nox4-/- mice. Results Exercise, as induced by voluntary running in a running wheel or forced running on a treadmill induced a switch from fast twitch to intermediate fibres. However the induced muscle fibre switch was similar between Nox4-/- and wildtype mice. The same held true for exercise-induced expression of PGC1? or AMPK activation. Both are increased in response to exercise, but with no difference was observed between wildtype and Nox4-/- mice. Conclusion Thus, exercise-induced muscle fibre switch is Nox4-independent. PMID:26083642

  2. Rosa rugosa Aqueous Extract Alleviates Endurance Exercise-Induced Stress.

    PubMed

    Seo, Eunjin; You, Yanghee; Yoon, Ho-Geun; Kim, Boemjeong; Kim, Kyungmi; Lee, Yoo-Hyun; Lee, Jeongmin; Chung, Jin Woong; Shim, Sangin; Jun, Woojin

    2015-06-01

    This study was performed to investigate the effect of water extract from Rosa rugosa (RRW) on endurance exercise-induced stress in mice. The mice were orally administered with distilled water or RRW, respectively. The endurance capacity was evaluated by exhaustive swimming using an adjustable-current water pool. Mice administered RRW swam longer before becoming exhausted. Also, RRW administration resulted in less lipid peroxidation, lower muscular antioxidant enzyme activities, and lower cortisol level. The results suggest that RRW can prevent exercise-induced stress by decreasing oxidative stress levels. PMID:25674938

  3. 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...

  4. Diagnosis and Management of Exercise-Induced Asthma.

    ERIC Educational Resources Information Center

    Rupp, Ned T.

    1996-01-01

    Exercise-induced asthma (EIA) affects 12-15% of the population. This comprehensive guide suggests that nearly all individuals with EIA can be active, highlighting both pharmacologic and nonpharmacologic management of asthma and stressing the importance of rigorous patient education in controlling underlying asthma and EIA. (SM)

  5. Human Mitochondrial Protein Database

    National Institute of Standards and Technology Data Gateway

    SRD 131 Human Mitochondrial Protein Database (Web, free access)   The Human Mitochondrial Protein Database (HMPDb) provides comprehensive data on mitochondrial and human nuclear encoded proteins involved in mitochondrial biogenesis and function. This database consolidates information from SwissProt, LocusLink, Protein Data Bank (PDB), GenBank, Genome Database (GDB), Online Mendelian Inheritance in Man (OMIM), Human Mitochondrial Genome Database (mtDB), MITOMAP, Neuromuscular Disease Center and Human 2-D PAGE Databases. This database is intended as a tool not only to aid in studying the mitochondrion but in studying the associated diseases.

  6. Current topics in bioenergetics: Structure, biogenesis, and assembly of energy transducing enzyme systems. Volume 15

    Microsoft Academic Search

    1987-01-01

    This book contains 11 chapters. The chapter titles are: Structure of NADH-Ubiquinone Reductase (Complex I); Structure of the Succinate-Ubiquinone Oxidoreductase (Complex II); Structure of Mitochondrial Ubiquinol-Cytochrome-c Redutase (Complex III); Structure of Cytochrome-c Oxidase; Evolution of a Regulatory Enzyme: Cytochrome-c Oxidase (Complex IV); The Assembly of FâFâ-ATPase in Escherichia coli; Biogenesis of Mitochondrial Energy Transducing Complexes; Biogenesis of Mammalian Mitochondria; Structure

  7. Exercise-Induced Deep Vein Thrombosis of the Upper Extremity

    Microsoft Academic Search

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

    2006-01-01

    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

  8. Exercise-induced neuromuscular dysfunction under reflex conditions

    Microsoft Academic Search

    Thomas Kaufman; Jeanmarie R. Burke; Mark J. Davis; Larry J. Durstine

    2001-01-01

    .   The purpose of this research was to describe further the effects of exercise-induced muscle damage on reflex sensitivity.\\u000a The subjects were eight physically active, but untrained males, between the ages of 18 and 29 years. The effects of eccentric\\u000a and concentric exercise on patellar tendon reflex responses were determined. The 8 week experiment consisted of two, 5 day,\\u000a test protocols with a

  9. Exercise-induced pulmonary perfusion redistribution in heaves.

    PubMed

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

    2002-09-01

    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

  10. A case of mite-ingestion-associated exercise- induced anaphylaxis mimicking wheat-dependent exercise-induced anaphylaxis.

    PubMed

    Adachi, Yoko S; Itazawa, Toshiko; Okabe, Yoshie; Higuchi, Osamu; Ito, Yasunori; Adachi, Yuichi

    2013-01-01

    We present a case of mite-ingestion-associated exercise-induced anaphylaxis mimicking wheat-dependent exercise-induced anaphylaxis (WDEIA). A 17-year-old boy was referred for an episode of anaphylaxis while jogging, 1.5 h after having eaten okonomiyaki (a Japanese pancake). Laboratory measures revealed a slightly elevated specific immunoglobulin E (IgE) antibody against omega-5 gliadin (0.41 kUA/l) and a marked elevation of specific IgE antibody against house-dust mite, Dermatophagoides farinae (142 kUA/l). A detailed interview revealed that, in spite of the referring doctor's advice to discontinue postprandial exercises, he continued his jogging routine after consuming foods containing wheat and also that his younger brother, who had mild intermittent asthma, had suffered a mild asthma attack 2 h after eating the same food. We therefore examined the okonimiyaki mix, which had been stored for several months after opening the package until this episode, under a microscope, and we found an abundant number of live mites, D. farinae. Finally, a diagnosis of mite-ingestion-associated exercise-induced anaphylaxis was made. This clinical entity should be excluded when making a diagnosis of WDEIA. PMID:23921625

  11. Molecular Genetics of Mitochondrial Disorders

    ERIC Educational Resources Information Center

    Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA…

  12. NAMPT regulates mitochondria biogenesis via NAD metabolism and calcium binding proteins during skeletal muscle contraction

    PubMed Central

    Kim, Jeong Seok; Yoon, Chung-Su; Park, Dae Ryoung

    2014-01-01

    [Purpose] The purpose of this study was to investigate the effect that muscle contraction induced NAD metabolism via NAMPT has on mitochondrial biogenesis. [Methods] Primary skeletal muscle cells were isolated from the gastrocnemius in C57BL/6 mice. The muscle cells were stimulated by electrical current at 1Hz for 3 minutes in conditions of normal or NAD metabolism related inhibitor treatment. NAD/NADH level, Sirt1 and mitochondria biogenesis related signal factor’s changes were examined in normal or NAD metabolism related inhibitor treated cells. [Results] Electrical stimulation (ES) induced muscle contractions significantly increased NAD/NADH levels, NAMPT inhibitor FK-866 inhibited ES-induced NAD formation, which caused SIRT1 expression and PGC-1? deacetylation to decrease. Moreover, NAMPT inhibition decreased mitochondrial biogenesis related mRNA, COX-1 and Tfam levels. Along with AMPK inhibitor, compound C decreases SIRT1 expression, PGC-1? deacetylation and muscle contraction induced mitochondrial biogenesis related mRNA increment. These results indicated that the AMPK-NAMPT signal is a key player for muscle contraction induced SIRT1 expression and PGC-1? deacetylation, which influences mitochondrial biogenesis. Inhibition of the AMPK upregulator, Camkk?, STO-609 decreased AMPK phosphorylation and SIRT1 expression but did not decrease PGC-1? deacetylation. However, CAMKII inhibition via AIP decreased PGC-1? deacetylation. [Conclusion] In conclusion, the results indicate that NAMPT plays an important role in NAD metabolism and mitochondrial biogenesis. However, mitochondrial biogenesis is also controlled by different calcium binding protein signals including Camkk? and CAMKII. [Keyword] Muscle contraction, NAD metabolism, SIRT1, PGC-1 ?, mitochondria biogenesis. PMID:25566462

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

    PubMed Central

    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

    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. PMID:20507973

  14. Autophagosome biogenesis requires SNAREs

    PubMed Central

    Nair, Usha; Klionsky, Daniel J.

    2011-01-01

    We recently showed that phagophore biogenesis requires SNAREs. Our data indicate that the exocytic Q/t-SNAREs Sso1/2 and Sec9 are required for one of the earliest steps in autophagosome biogenesis, the homotypic fusion of Atg9-containing vesicles. We propose that this step precedes the formation of Atg9-containing tubulovesicular clusters (TVCs) that is a key step in perivacuolar, phagophore assembly. We also found that the endosomal Q/t-SNARE Tlg2 and the R/v-SNAREs Sec22 and Ykt6 interact with Sso1-Sec9, and are required for normal Atg9 trafficking. Thus, autophagosome biogenesis appears to involve multiple SNARE-mediated fusion events. These findings provide novel insights into the mechanism of autophagosome construction. PMID:22024744

  15. Autophagosome biogenesis requires SNAREs.

    PubMed

    Nair, Usha; Klionsky, Daniel J

    2011-12-01

    We recently showed that phagophore biogenesis requires SNAREs. Our data indicate that the exocytic Q/t-SNAREs Sso1/2 and Sec9 are required for one of the earliest steps in autophagosome biogenesis, the homotypic fusion of Atg9-containing vesicles. We propose that this step precedes the formation of Atg9-containing tubulovesicular clusters (TVCs) that is a key step in perivacuolar, phagophore assembly. We also found that the endosomal Q/t-SNARE Tlg2 and the R/v-SNAREs Sec22 and Ykt6 interact with Sso1-Sec9, and are required for normal Atg9 trafficking. Thus, autophagosome biogenesis appears to involve multiple SNARE-mediated fusion events. These findings provide novel insights into the mechanism of autophagosome construction. PMID:22024744

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

    PubMed Central

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

    1986-01-01

    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. PMID:2874824

  17. Effect of simulated weightlessness on exercise-induced anaerobic threshold

    NASA Technical Reports Server (NTRS)

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

    1986-01-01

    The effect of simulated weightlessness, induced by ten days of continuous bedrest (BR) in the -6 deg head-down position, on the exercise-induced anaerobic threshold (AT) was determined by comparing specific ventilatory and gas-exchange measurements during an incremental ergometer test performed before and after BR. The primary index for determining the exercise-induced AT values of each subject was visual identification of the workrate or oxygen uptake (VO2) at which the ratio of the expired minute ventilation volume (VE) to VO2 exhibited a systematic increase without a concomitant increase in the VE/VCO2 value. Following BR, the mean VO2max of the subjects decreased by 7.0 percent, and the AT decreased from a mean of 1.26 L/min VO2 before BR to 0.95 L/min VO2 after BR. The decrease in AT was manifested by a decrease in both absolute and relative workrates. The change in AT correlated significantly with the change in plasma volume but not with the change in VO2max. The results suggest that the reduction in AT cannot be completely explained by the reduction in VO2, and that the AT decrease is associated with the reduction in intravascular fluid volume.

  18. Exercise-induced hyperthermia and hormonal responses to exercise.

    PubMed

    Radomski, M W; Cross, M; Buguet, A

    1998-05-01

    Changes in plasma hormonal concentrations during exercise have been ascribed to the type, duration, and intensity of exercise, physical fitness of subjects, oxygen availability and debt, and acid-base balance. However, relatively few studies have examined the possible role of exercise-induced hyperthermia. This paper reviews previous studies on this subject and describes a series of experiments carried out in our laboratories to define the role of changes in body temperature in the release of hormones during exercise. In a first series of experiments, we studied the relationship between thermoregulatory and growth hormone responses to severe exercise at 23 degrees C for 2 h in fit euhydrated subjects, controlling the core temperature increase to a maximum of 40 degrees C by varying wind speed. Exponential relationships were found between increases in core temperature and plasma growth hormone, prolactin, and catecholamines during exercise, suggesting the existence of a thermal threshold for stimulation of hormonal release during exercise. The effect of endurance exercise with and without a thermal clamp (immersion in cold and warm water) on hormonal and leukocyte responses was examined. Again, a significant exponential relationship was found between increases in core temperature and hormonal responses. Thermal clamping significantly diminished the hormonal and the leukocytic responses to exercise, suggesting that an exercise-induced thermal threshold of approximately 38 degrees C exists where hormonal responses are observed. Therefore, core temperature increases may be integrated in the controlling system of hormonal and leukocytic responses to exercise. PMID:9839081

  19. Exercise-induced bronchoconstriction and atopy in Tunisian athletes

    PubMed Central

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

    2009-01-01

    Background This study is a cross sectional analysis, aiming to evaluate if atopy is as a risk factor for exercise induced bronchoconstriction (EIB) among Tunisian athletes. Methods Atopy was defined by a skin prick test result and EIB was defined as a decrease of at least 15% in forced expiratory volume in one second (FEV1) after 8-min running at 80–85% HRmaxTheo. The study population was composed of 326 athletes (age: 20.8 ± 2.7 yrs – mean ± SD; 138 women and 188 men) of whom 107 were elite athletes. Results Atopy was found in 26.9% (88/326) of the athletes. Post exercise spirometry revealed the presence of EIB in 9.8% of the athletes including 13% of the elite athletes. Frequency of atopy in athletes with EIB was significantly higher than in athletes without EIB [62.5% vs 23.1%, respectively]. Conclusion This study showed that atopic Tunisian athletes presented a higher risk of developing exercise induced bronchoconstriction than non-atopic athletes. PMID:19196480

  20. Exploring the Relationship between Exercise-Induced Arousal and Cognition Using Fractionated Response Time

    ERIC Educational Resources Information Center

    Chang, Yu-Kai; Etnier, Jennifer L.; Barella, Lisa A.

    2009-01-01

    Although a generally positive effect of acute exercise on cognitive performance has been demonstrated, the specific nature of the relationship between exercise-induced arousal and cognitive performance remains unclear. This study was designed to identify the relationship between exercise-induced arousal and cognitive performance for the central…

  1. Mitochondrial DNA transcription regulation and nucleoid organization

    Microsoft Academic Search

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

    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

  2. Exercise-Induced Syncope in a Sedentary Woman

    PubMed Central

    Rickard, John W.; Zakaria, Sammy

    2014-01-01

    Vasovagal (neurocardiogenic) syncope, a subtype of reflex syncope, has many well-known triggers. However, we found no previous report of vasovagal exercise-induced syncope in a sedentary person. We present the case of a 35-year-old sedentary woman who experienced vasovagal syncope as she underwent an exercise stress test. Results of evaluations, including resting and stress electrocardiography and echocardiography, were normal. Her presentation is highly unusual: syncope has typically not been associated with exercise except in young athletes, people with structural heart abnormalities, or people with a prolonged QT syndrome. To our knowledge, this is the first report of vasovagal syncope associated with exercise in a sedentary patient who had normal cardiac and electrophysiologic function. We suggest possible physiologic mechanisms and diagnostic strategies. PMID:25593529

  3. Moyamoya disease presenting with paroxysmal exercise-induced dyskinesia.

    PubMed

    Lyoo, Chul Hyoung; Kim, Dong Joon; Chang, Hyuk; Lee, Myung Sik

    2007-10-01

    We report a patient with moyamoya disease presenting with paroxysmal exercise-induced dyskinesia (PED). A 31-year-old lathe man developed recurrent attacks of paroxysmal hemichorea. The attacks always affected his left limbs and occurred either after several hours of working or while playing football. The duration of attacks ranged from 30 min to 4h. Attacks were not provoked by sudden movements, consumption of coffee or alcohol, hyperventilation, emotional stress, exposure to cold or passive movement. An MRI of the brain showed no parenchymal lesions. However, (99m)Tc-ethylcysteine dimer SPECT study showed hypoperfusion in the right striatum. Digital subtraction angiography showed stenosis of the right internal carotid and middle cerebral artery with prominent basal collaterals, which was compatible with moyamoya disease. Imaging studies of the cerebral arteries should be done in patients with clinical features of PED in order to detect possible cases of moyamoya disease. PMID:16952479

  4. Exercise-induced bronchospasm: coding and billing for physician services.

    PubMed

    Pohlig, Carol

    2009-01-01

    Physician reporting of the service to insurance companies for reimbursement is multifaceted and perplexing to those who do not understand the factors to consider. Test selection should be individualized based on the patient's history and/or needs. Federal regulations concerning physician supervision of diagnostic tests mandate different levels of physician supervision based on the type and complexity of the test. Many factors play a key role in physician claim submission. These include testing location, component services, coding edits, and additional visits. Medical necessity of the service(s) must also be demonstrated for payer consideration and reimbursement. The following article reviews various tests for exercise-induced bronchospasm and focuses on issues to assist the physician in reporting the services accurately and appropriately. PMID:19136408

  5. Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease.

    PubMed

    Perez-Schindler, Joaquin; Philp, Andrew

    2015-10-01

    Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease. PMID:26186742

  6. Maintenance of exercise-induced benefits in physical functioning and bone among elderly women

    Microsoft Academic Search

    S. Karinkanta; A. Heinonen; H. Sievänen; K. Uusi-Rasi; M. Fogelholm; P. Kannus

    2009-01-01

    Summary  This study showed that about a half of the exercise-induced gain in dynamic balance and bone strength was maintained one year\\u000a after cessation of the supervised high-intensity training of home-dwelling elderly women. However, to maintain exercise-induced\\u000a gains in lower limb muscle force and physical functioning, continued training seems necessary.\\u000a \\u000a \\u000a \\u000a Introduction  Maintenance of exercise-induced benefits in physical functioning and bone structure was

  7. Resistance to exercise-induced weight loss: compensatory behavioral adaptations

    PubMed Central

    Melanson, Edward L.; Keadle, Sarah Kozey; Donnelly, Joseph E.; Braun, Barry; King, Neil A.

    2013-01-01

    In many interventions that are based on an exercise program intended to induce weight loss, the mean weight loss observed is modest and sometimes far less than the individual expected. The individual responses are also widely variable, with some individuals losing a substantial amount of weight, others maintaining weight, and a few actually gaining weight. The media have focused on the sub-population that loses little weight, contributing to a public perception that exercise has limited utility to cause weight loss. The purpose of the symposium was to present recent, novel data that help explain how compensatory behaviors contribute to a wide discrepancy in exercise-induced weight loss. The presentations provide evidence that some individuals adopt compensatory behaviors, i.e. increased energy intake and/or reduced activity, that offset the exercise energy expenditure and limit weight loss. The challenge for both scientists and clinicians is to develop effective tools to identify which individuals are susceptible to such behaviors, and to develop strategies to minimize their impact. PMID:23470300

  8. Food-dependent exercise-induced anaphylaxis to pistachio.

    PubMed

    Porcel, S; Sánchez, A B; Rodríguez, E; Fletes, C; Alvarado, M; Jiménez, S; Hernández, J

    2006-01-01

    We report the case of a 16-year-old male who, 30 minutes after beginning to play football with previous ingestion of pistachio nuts, experienced an anaphylactic reaction. Prick-by-prick test with roasted pistachios was negative. Specific IgE antibodies to pistachio, cashew nuts and mango were negative. An open oral challenge test with pistachio in resting conditions was negative. Treadmill ergonometric stress in a fasting state and 60 minutes after a meal without pistachio gave negative results. A specific food exercise challenge 60 minutes after ingestion of 50 g pistachio nuts was positive, showing mild diffuse erythema and small wheals in face and thorax. To the best of our knowledge, this is the first described case of specific food dependent exercise-induced anaphylaxis to pistachio. Negative allergologic tests is an unusual condition, since most cases appear to be IgE-mediated. In this case, a positive specific food exercise challenge test provided a definite diagnosis. PMID:16599253

  9. Provocation by eucapnic voluntary hyperpnoea to identify exercise induced bronchoconstriction.

    PubMed

    Anderson, S D; Argyros, G J; Magnussen, H; Holzer, K

    2001-10-01

    The International Olympic Committee Medical Commission (IOC-MC) requires notification for use of a beta(2) agonist at the Winter Olympic Games in Salt Lake City. This notification will be required seven days before the event and must be accompanied by objective evidence that justifies the need to use one. The IOC-MC has expressed the viewpoint that, at present, eucapnic voluntary hyperpnoea (EVH) is the optimal laboratory challenge to confirm that an athlete has exercise induced bronchoconstriction (EIB). The EVH test recommended was specifically designed to identify EIB. EVH has been performed in thousands of subjects in both the laboratory and the field. The test requires the subject to hyperventilate dry air containing 5% carbon dioxide at room temperature for six minutes at a target ventilation of 30 times the subject's forced expiratory volume in one second (FEV(1)). The test conditions can be modified to simulate the conditions that give the athlete their symptoms with exercise. A reduction in FEV(1) of 10% or more of the value before the test is considered positive. PMID:11579071

  10. New Insights into to Pathogenesis of Exercise-induced Bronchoconstriction

    PubMed Central

    Hallstrand, Teal S.

    2012-01-01

    Purpose of review Exercise-induced bronchoconstriction (EIB) refers to acute airflow obstruction that is triggered by a period of physical exertion. Here we review recent findings about the epidemiology of EIB, immunopathology leading to EIB, and the latest understanding of the pathogenesis of EIB. Recent findings Longitudinal studies demonstrated that airway hyperresponsiveness to exercise or cold air at an early age are among the strongest predictors of persistent asthma. Patients that are susceptible to EIB have epithelial disruption and increased levels of inflammatory eicosanoids such as cysteinyl leukotrienes (CysLT)s. The leukocytes implicated in production of eicosanoids in the airways include both a unique mast cell population as well as eosinophils. A secreted phospholipase A2 (sPLA2) enzyme that serves as a regulator of CysLT formation is present in increased quantities in asthma. Transglutaminase 2 (TGM2) is expressed at increased levels in asthma and serves as a regulator of sPLA2-X. Further, sPLA2-X acts on target cells such as eosinophils to initiate cellular eicosanoid synthesis. Summary Recent studies have advanced our understanding of EIB as a syndrome that is caused by the increased production of inflammatory eicosanoids. The airway epithelium may be an important regulator of the production of inflammatory eicosanoids by leukocytes. Abstract word count: 199 PMID:22157157

  11. Diaphragmatic breathing reduces exercise-induced oxidative stress.

    PubMed

    Martarelli, Daniele; Cocchioni, Mario; Scuri, Stefania; Pompei, Pierluigi

    2011-01-01

    Diaphragmatic breathing is relaxing and therapeutic, reduces stress, and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices. Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant; therefore, in this study, we investigated the effects of diaphragmatic breathing on exercise-induced oxidative stress and the putative role of cortisol and melatonin hormones in this stress pathway. We monitored 16 athletes during an exhaustive training session. After the exercise, athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1?h relaxing performing diaphragmatic breathing and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals. PMID:19875429

  12. Exercise-induced anterior tibial compartment compression syndrome in the elderly

    PubMed Central

    Sweeney, R. C.; Chadwick, C. J.; Bagnall, W. E.

    1981-01-01

    Exercise-induced anterior tibial compartment compression syndrome occurs predominantly in young males. The authors report a case in a 79-year-old female as a complication of rehabilitation. PMID:7301708

  13. Heat and Water Loss from the Airways and Exercise-Induced Asthma

    Microsoft Academic Search

    W. Y. Chen; D. J. Horton

    1977-01-01

    Exercise-induced asthma was studied in 8 asthmatics using various conditions of inspired air during exercise. The exercise consisted of walking on a treadmill for 10 min, with a speed and grade elevation adjusted to achieve the target heart rate of approximately 90 % of predicted maximum. Pulmonary function tests were performed pre- and post-exercise to determine exercise-induced asthma. With inspired

  14. Air quality and temperature effects on exercise-induced bronchoconstriction.

    PubMed

    Rundell, Kenneth W; Anderson, Sandra D; Sue-Chu, Malcolm; Bougault, Valerie; Boulet, Louis-Philippe

    2015-03-01

    Exercise-induced bronchoconstriction (EIB) is exaggerated constriction of the airways usually soon after cessation of exercise. This is most often a response to airway dehydration in the presence of airway inflammation in a person with a responsive bronchial smooth muscle. Severity is related to water content of inspired air and level of ventilation achieved and sustained. Repetitive hyperpnea of dry air during training is associated with airway inflammatory changes and remodeling. A response during exercise that is related to pollution or allergen is considered EIB. Ozone and particulate matter are the most widespread pollutants of concern for the exercising population; chronic exposure can lead to new-onset asthma and EIB. Freshly generated emissions particulate matter less than 100 nm is most harmful. Evidence for acute and long-term effects from exercise while inhaling high levels of ozone and/or particulate matter exists. Much evidence supports a relationship between development of airway disorders and exercise in the chlorinated pool. Swimmers typically do not respond in the pool; however, a large percentage responds to a dry air exercise challenge. Studies support oxidative stress mediated pathology for pollutants and a more severe acute response occurs in the asthmatic. Winter sport athletes and swimmers have a higher prevalence of EIB, asthma and airway remodeling than other athletes and the general population. Because of fossil fuel powered ice resurfacers in ice rinks, ice rink athletes have shown high rates of EIB and asthma. For the athlete training in the urban environment, training during low traffic hours and in low traffic areas is suggested. © 2015 American Physiological Society. Compr Physiol 5: 579-610, 2015. PMID:25880506

  15. Biogenesis of thylakoid membranes.

    PubMed

    Rast, Anna; Heinz, Steffen; Nickelsen, Jörg

    2015-09-01

    Thylakoids mediate photosynthetic electron transfer and represent one of the most elaborate energy-transducing membrane systems. Despite our detailed knowledge of its structure and function, much remains to be learned about how the machinery is put together. The concerted synthesis and assembly of lipids, proteins and low-molecular-weight cofactors like pigments and transition metal ions require a high level of spatiotemporal coordination. While increasing numbers of assembly factors are being functionally characterized, the principles that govern how thylakoid membrane maturation is organized in space are just starting to emerge. In both cyanobacteria and chloroplasts, distinct production lines for the fabrication of photosynthetic complexes, in particular photosystem II, have been identified. This article is part of a Special Issue entitled: Chloroplast Biogenesis. PMID:25615584

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

    Microsoft Academic Search

    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

    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

  17. Binding of Yeast Frataxin to the Scaffold for Fe-S Cluster Biogenesis, Isu*

    E-print Network

    Craig, Elizabeth A

    Binding of Yeast Frataxin to the Scaffold for Fe-S Cluster Biogenesis, Isu* Received, a conserved iron-binding protein of the mitochondrial matrix, thought to supply iron for formation of Fe-S clusters on the scaffold protein Isu. Frataxin binds Isu in an iron-dependent manner in vitro. However

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

    PubMed Central

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

    2012-01-01

    This review offers an overview of the influence of reactive species produced during exercise and their effect on exercise adaptation. Reactive species and free radicals are unstable molecules that oxidize other molecules in order to become stable. Although they play important roles in our body, they can also lead to oxidative stress impairing diverse cellular functions. During exercise, reactive species can be produced mainly, but not exclusively, by the following mechanisms: electron leak at the mitochondrial electron transport chain, ischemia/reperfusion and activation of endothelial xanthine oxidase, inflammatory response, and autooxidation of catecholamines. Chronic exercise also leads to the upregulation of the body's antioxidant defence mechanism, which helps minimize the oxidative stress that may occur after an acute bout of exercise. Recent studies show a beneficial role of the reactive species, produced during a bout of exercise, that lead to important training adaptations: angiogenesis, mitochondria biogenesis, and muscle hypertrophy. The adaptations occur depending on the mechanic, and consequently biochemical, stimulus within the muscle. This is a new area of study that promises important findings in the sphere of molecular and cellular mechanisms involved in the relationship between oxidative stress and exercise. PMID:22701757

  19. Exercise-Induced Arterial Adaptations in Elite Judo Athletes

    PubMed Central

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

    2009-01-01

    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 included brachial, radial, ulnar, popliteal, anterior and posterior tibial arteries. The experimental parameters were recorded with the use of Duplex ultrasound at rest. Diastolic diameter and blood mean flow velocity of the examined arteries in Judo athletes were found to be both significantly increased (p < 0.05) compared to the findings of the control groups. In male Judo athletes the brachial (p < 0.001), radial (p < 0.001), and anterior tibial artery (p < 0.001) presented the highest difference on the diastolic diameter, compared with the control male group. In female Judo athletes, ulnar (p < 0.001), radial (p < 0.001), and brachial (p < 0.001) arteries illustrated the highest diastolic diameter. The highest blood mean flow velocity was recorded in ulnar (p < 0.001) and popliteal arteries (p < 0.001) of the Judo athletes groups. Recording differences between the two genders, male participants presented larger arteries than females. Conclusively, Judo has been found to be a highly demanding physical sport, involving upper and lower limbs leading to significant arterial adaptations. Obtaining vascular parameters provide a useful tool to the medical team, not only in the direction of enhancement of the efficacy of physical training, but in unknown so far parameters that may influence athletic performance of both male and female elite Judokas. Key points Judo athletes demonstrated a general homogenous increase of the arterial functionality of the upper and lower limbs compared to the control groups. Diastolic diameter found to be significantly increased in male and female Judo athletes, highlighting the effects of exercise training on the vascular system. Judo athletes had had statistically significant increase of the blood mean flow velocity in all examined arteries, compared with the relevant control group. The current study underscores the impact of Judo training on the structure and the function of the arterial system. Clinically, the increased arterial parameters in elite Judo athletes may be essential elements for improved athletic performance. Sports medicine practitioners should give special concern to the vascular functionality for several physiological and medical tests. PMID:24150007

  20. Mitochondrial donation Mitochondrial donation

    E-print Network

    Newcastle upon Tyne, University of

    Mitochondrial donation Q&A: Mitochondrial donation #12;Mitochondrial donation What is mitochondrial DNA disease, and multiple different organs can be affected as mitochondria are present in all tissues? Mitochondrial DNA disease commonly affects multiple different organs, with symptoms including loss of movement

  1. Pharmacological approaches to restore mitochondrial function

    PubMed Central

    Andreux, Pénélope A.; Houtkooper, Riekelt H.; Auwerx, Johan

    2014-01-01

    Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders, but is also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson’s disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models, as well as multicellular organisms, have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for a range of diseases, which has spurred active drug discovery efforts in this area. PMID:23666487

  2. Exercise training and immune crosstalk in breast cancer microenvironment: exploring the paradigms of exercise-induced immune modulation and exercise-induced myokines

    PubMed Central

    Goh, Jorming; Niksirat, Negin; Campbell, Kristin L

    2014-01-01

    Observational research suggests that exercise may reduce the risk of breast cancer and improve survival. One proposed mechanism for the protective effect of aerobic exercise related to cancer risk and outcomes, but has not been examined definitively, is the immune response to aerobic exercise. Two prevailing paradigms are proposed. The first considers the host immune response as modifiable by aerobic exercise training. This exercise-modulated immune-tumor crosstalk in the mammary microenvironment may alter the balance between tumor initiation and progression versus tumor suppression. The second paradigm considers the beneficial role of exercise-induced, skeletal muscle-derived cytokines, termed “myokines”. These myokines exert endocrine-like effects on multiple organs, including the mammary glands. In this systematic review, we i) define the role of macrophages and T-cells in breast cancer initiation and progression; ii) address the two paradigms that support exercise-induced immunomodulation; iii) systematically assessed the literature for exercise intervention that assessed biomarkers relevant to both paradigms in human intervention trials of aerobic exercise training, in healthy women and women with breast cancer; iv) incorporated pre-clinical animal studies and non-RCTs for background discussion of putative mechanisms, through which aerobic exercise training modulates the immunological crosstalk, or the myokine-tumor interaction in the tumor microenvironment; and v) speculated on the potential biomarkers and mechanisms that define an exercise-induced, anti-tumor “signature”, with a view toward developing relevant biomarkers for future aerobic exercise intervention trials. PMID:25360210

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

    Microsoft Academic Search

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

    1988-01-01

    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

  4. MicroRNA-23a has minimal effect on endurance exercise-induced adaptation of mouse skeletal muscle.

    PubMed

    Wada, Shogo; Kato, Yoshio; Sawada, Shuji; Aizawa, Katsuji; Park, Jong-Hoon; Russell, Aaron P; Ushida, Takashi; Akimoto, Takayuki

    2015-02-01

    Skeletal muscles contain several subtypes of myofibers that differ in contractile and metabolic properties. Transcriptional control of fiber-type specification and adaptation has been intensively investigated over the past several decades. Recently, microRNA (miRNA)-mediated posttranscriptional gene regulation has attracted increasing attention. MiR-23a targets key molecules regulating contractile and metabolic properties of skeletal muscle, such as myosin heavy-chains and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1?). In the present study, we analyzed the skeletal muscle phenotype of miR-23a transgenic (miR-23a Tg) mice to explore whether forced expression of miR-23a affects markers of mitochondrial content, muscle fiber composition, and muscle adaptations induced by 4 weeks of voluntary wheel running. When compared with wild-type mice, protein markers of mitochondrial content, including PGC-1?, and cytochrome c oxidase complex IV (COX IV), were significantly decreased in the slow soleus muscle, but not the fast plantaris muscle of miR-23a Tg mice. There was a decrease in type IId/x fibers only in the soleus muscle of the Tg mice. Following 4 weeks of voluntary wheel running, there was no difference in the endurance exercise capacity as well as in several muscle adaptive responses including an increase in muscle mass, capillary density, or the protein content of myosin heavy-chain IIa, PGC-1?, COX IV, and cytochrome c. These results show that miR-23a targets PGC-1? and regulates basal metabolic properties of slow but not fast twitch muscles. Elevated levels of miR-23a did not impact on whole body endurance capacity or exercise-induced muscle adaptations in the fast plantaris muscle. PMID:24756198

  5. The Roles of Testosterone and Alpha-Amylase in Exercise-Induced Sexual Arousal in Women

    E-print Network

    Meston, Cindy

    The Roles of Testosterone and Alpha-Amylase in Exercise-Induced Sexual Arousal in Women Lisa Dawn-report questionnaire, and genital arousal was measured by a vaginal photoplethysmograph. Testosterone and a-amylase (a. There was a significant increase in a-amylase across the study in the exercise condition, but not in the no

  6. The effects of exercise-induced muscle damage on maximal intensity intermittent exercise performance

    Microsoft Academic Search

    Craig Twist; Roger Eston

    2005-01-01

    Exercise-induced muscle damage (EIMD) is a common occurrence following activities with a high eccentric component. Alterations to the torque–velocity relationship following EIMD would appear to have serious implications for athletic performance, particularly as they relate to impairment of maximal intensity exercise. However, this has been studied infrequently. The purpose of this study was to assess the effects of EIMD on

  7. Thyroid Hormone and Estrogen Regulate Exercise-Induced Growth Hormone Release

    PubMed Central

    Ignacio, Daniele Leão; da S. Silvestre, Diego H.; Cavalcanti-de-Albuquerque, João Paulo Albuquerque; Louzada, Ruy Andrade

    2015-01-01

    Growth hormone (GH) regulates whole body metabolism, and physical exercise is the most potent stimulus to induce its secretion in humans. The mechanisms underlying GH secretion after exercise remain to be defined. The aim of this study was to elucidate the role of estrogen and pituitary type 1 deiodinase (D1) activation on exercise-induced GH secretion. Ten days after bilateral ovariectomy, animals were submitted to 20 min of treadmill exercise at 75% of maximum aerobic capacity and tissues were harvested immediately or 30 min after exercise. Non-exercised animals were used as controls. A significant increase in D1 activity occurred immediately after exercise (~60%) in sham-operated animals and GH was higher (~6-fold) 30 min after exercise. Estrogen deficient rats exhibited basal levels of GH and D1 activity comparable to those found in control rats. However, after exercise both D1 activity and serum GH levels were blunted compared to sedentary rats. To understand the potential cause-effect of D1 activation in exercise-induced GH release, we pharmacologically blocked D1 activity by propylthiouracil (PTU) injection into intact rats and submitted them to the acute exercise session. D1 inhibition blocked exercise-induced GH secretion, although basal levels were unaltered. In conclusion, estrogen deficiency impairs the induction of thyroid hormone activating enzyme D1 in the pituitary, and GH release by acute exercise. Also, acute D1 activation is essential for exercise-induced GH response. PMID:25874614

  8. Green Tea Catechin Consumption Enhances Exercise-Induced Abdominal Fat Loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aim: This study evaluated the influence of a green tea catechin beverage on body composition and fat distribution in overweight and obese adults during exercised-induced weight loss. Methods: Participants (N=132) were randomly assigned to receive a 500 mL beverage containing approximately 625 mg of...

  9. Simple Screening Test for Exercise-Induced Bronchospasm in the Middle School Athlete

    ERIC Educational Resources Information Center

    Weiss, Tyler J.; Baker, Rachel H.; Weiss, Jason B.; Weiss, Michelle M.

    2013-01-01

    This article recommends and provides results from a simple screening test that could be incorporated into a standardized school evaluation for all children participating in sports and physical education classes. The test can be employed by physical educators utilizing their own gym to identify children who demonstrate signs of exercise-induced…

  10. Cellulose biogenesis in Dictyostelium discoideum

    SciTech Connect

    Blanton, R.L.

    1993-12-31

    Organisms that synthesize cellulose can be found amongst the bacteria, protistans, fungi, and animals, but it is in plants that the importance of cellulose in function (as the major structural constituent of plant cell walls) and economic use (as wood and fiber) can be best appreciated. The structure of cellulose and its biosynthesis have been the subjects of intense investigation. One of the most important insights gained from these studies is that the synthesis of cellulose by living organisms involves much more than simply the polymerization of glucose into a (1{r_arrow}4)-{beta}-linked polymer. The number of glucoses in a polymer (the degree of polymerization), the crystalline form assumed by the glucan chains when they crystallize to form a microfibril, and the dimensions and orientation of the microfibrils are all subject to cellular control. Instead of cellulose biosynthesis, a more appropriate term might be cellulose biogenesis, to emphasize the involvement of cellular structures and mechanisms in controlling polymerization and directing crystallization and deposition. Dictyostelium discoideum is uniquely suitable for the study of cellulose biogenesis because of its amenability to experimental study and manipulation and the extent of our knowledge of its basic cellular mechanisms (as will be evident from the rest of this volume). In this chapter, I will summarize what is known about cellulose biogenesis in D. discoideum, emphasizing its potential to illuminate our understanding both of D. discoideum development and plant cellulose biogenesis.

  11. Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.

    PubMed

    Singh, François; Charles, Anne-Laure; Schlagowski, Anna-Isabel; Bouitbir, Jamal; Bonifacio, Annalisa; Piquard, François; Krähenbühl, Stephan; Geny, Bernard; Zoll, Joffrey

    2015-07-01

    Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H2O2 production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100?M) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon. PMID:25769432

  12. Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway

    PubMed Central

    Maday, Sandra; Holzbaur, Erika L. F.

    2014-01-01

    Summary Autophagy is an essential degradative pathway in neurons, yetlittle is known about the mechanisms driving this process in highly polarized cells. Here, we use dual-color live-cell imaging to investigate the neuron-specific mechanisms of constitutiveautophagosome biogenesis in primary DRG and hippocampal cultures. Under basal conditions autophagosomes are continuously generated in the axon tip. There is an ordered assembly of proteins recruited with stereotypical kinetics onto the developing autophagosome. Plasma- or mitochondrial-derived membraneswere not incorporated into nascent autophagosomes in the distal axon. Rather, autophagosomes are generated at DFCP1-positive subdomains of the endoplasmic reticulum, distinct from ER exit sites. Biogenesis events arehighly enriched distally; autophagosomes form infrequently in dendrites, the cell soma or mid-axon, consistent with a highly compartmentalized pathway for constitutive autophagy in primary neurons. This distal biogenesis may facilitate the degradation of damaged mitochondria and long-lived cytoplasmic proteins that reach the axon tip via slow axonal transport. PMID:25026034

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

    PubMed Central

    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

    2014-01-01

    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. PMID:24814483

  14. Biogenesis of Mitochondria: Dual Role of Tom7 in Modulating Assembly of the Preprotein Translocase of the Outer Membrane

    Microsoft Academic Search

    Thomas Becker; Lena-Sophie Wenz; Nicolas Thornton; David Stroud; Chris Meisinger; Nils Wiedemann; Nikolaus Pfanner

    2011-01-01

    Biogenesis of the translocase of the outer mitochondrial membrane (TOM complex) involves the assembly of the central ?-barrel forming protein Tom40 with six different subunits that are embedded in the membrane via ?-helical transmembrane segments. The sorting and assembly machinery (SAM complex) of the outer membrane plays a central role in this process. The SAM complex mediates the membrane integration

  15. Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis.

    PubMed

    Hangen, Emilie; Féraud, Olivier; Lachkar, Sylvie; Mou, Haiwei; Doti, Nunzianna; Fimia, Gian Maria; Lam, Ngoc-Vy; Zhu, Changlian; Godin, Isabelle; Muller, Kevin; Chatzi, Afroditi; Nuebel, Esther; Ciccosanti, Fabiola; Flamant, Stéphane; Bénit, Paule; Perfettini, Jean-Luc; Sauvat, Allan; Bennaceur-Griscelli, Annelise; Ser-Le Roux, Karine; Gonin, Patrick; Tokatlidis, Kostas; Rustin, Pierre; Piacentini, Mauro; Ruvo, Menotti; Blomgren, Klas; Kroemer, Guido; Modjtahedi, Nazanine

    2015-06-18

    Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis. PMID:26004228

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

    PubMed

    Zhonghui, Zhao; Xiaowei, Zheng; Fang, Fang

    2014-04-01

    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. PMID:24600303

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

    PubMed

    Batson, Glenna

    2013-01-01

    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

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

    PubMed Central

    Zhonghui, Zhao; Xiaowei, Zheng; Fang, Fang

    2013-01-01

    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. PMID:24600303

  19. MitoTimer: a novel protein for monitoring mitochondrial turnover in the heart.

    PubMed

    Gottlieb, Roberta A; Stotland, Aleksandr

    2015-03-01

    Mitochondrial quality control refers to the coordinated cellular systems involved in maintaining a population of healthy mitochondria. In addition to mitochondrial protein chaperones (Hsp10, Hsp60, and others) and proteases (Lon, AAA proteases) needed for refolding or degrading individual proteins, mitochondrial integrity is maintained through the regulation of protein import via the TOM/TIM complex and protein redistribution across the network via fusion and fission and through mitophagy and biogenesis, key determinants of mitochondrial turnover. A growing number of studies point to the importance of mitochondrial dynamics (fusion/fission) and mitochondrial autophagy in the heart. Mitochondrial biogenesis must keep pace with mitophagy in order to maintain a stable number of mitochondria. In this review, we will discuss the use of MitoTimer as a tool to monitor mitochondrial turnover. PMID:25479961

  20. Acute exercise induces gastrointestinal leakage of allergen in lysozyme-sensitized mice

    Microsoft Academic Search

    Hiromi Yano; Yasuko Kato; Tsukasa Matsuda

    2002-01-01

    .   Food-dependent exercise-induced anaphylaxis (FDEIAn) is a leading cause of physical allergies. However, the mechanisms involved\\u000a in the development of FDEIAn are not yet clearly understood. In this study, to investigate the leakage of allergen from the\\u000a gastrointestinal tract into the circulation, lysozyme (LYZ)-sensitized B10.A mice, which have been shown to exhibit an especially\\u000a high concentration of plasma antigen-specific immunoglobulin-E

  1. Suppression of exercise-induced angina by magnesium sulfate in patients with variant angina

    SciTech Connect

    Kugiyama, K.; Yasue, H.; Okumura, K.; Goto, K.; Minoda, K.; Miyagi, H.; Matsuyama, K.; Kojima, A.; Koga, Y.; Takahashi, M.

    1988-11-01

    The effects of intravenous magnesium on exercise-induced angina were examined in 15 patients with variant angina and in 13 patients with stable effort angina and were compared with those of placebo. Symptom-limited bicycle exercise and thallium-201 myocardial scintigraphy were performed after intravenous administration of 0.27 mmol/kg body weight of magnesium sulfate and after placebo on different days. In all patients, serum magnesium levels after administration of magnesium sulfate were about twofold higher than levels after placebo. Exercise-induced angina associated with transient ST segment elevation occurred in 11 patients with variant angina receiving placebo and in only 2 of these patients receiving magnesium (p less than 0.005). On the other hand, exercise-induced angina was not suppressed by magnesium in any patient with stable effort angina. In these patients there was no significant difference in exercise duration after administration of placebo versus after administration of magnesium. The size of the perfusion defect as measured by thallium-201 scintigraphy was significantly less in patients with variant angina receiving magnesium than that in those receiving placebo (p less than 0.001), whereas it was not significantly different in patients with stable effort angina receiving placebo versus magnesium. In conclusion, exercise-induced angina is suppressed by intravenous magnesium in patients with variant angina but not in patients with stable effort angina. This beneficial effect of magnesium in patients with variant angina is most likely due to improvement of regional myocardial blood flow by suppression of coronary artery spasm.

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

    Microsoft Academic Search

    Kazunori Nosaka; Priscilla M. Clarkson

    1997-01-01

    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

  3. Prevalence of exercise-induced cough in schoolchildren: a pilot study.

    PubMed

    Cichalewski, ?ukasz; Majak, Pawe?; Jerzy?ska, Joanna; Stelmach, W?odzimierz; Kaczmarek, Adam; Malewska, Kamila; Smejda, Katarzyna; Stelmach, Iwona

    2015-01-01

    Association between exercise-induced bronchoconstriction (EIB) and physical activity has not been investigated in a natural school environment in a general pediatric population. Our objective was to determine the prevalence of exercise-induced symptoms (cough, wheeze, chest tightness, dyspnea) and bronchospasm among schoolchildren during physical education (PE). A total of 557 schoolchildren from seven public schools were enrolled. Information regarding demographic characteristic, previously diagnosed asthma was obtained. All children attended 45-minute PE lesson with similar exercise intensity. Pulmonary function tests were performed before and immediately after PE lesson. The diagnosis of EIB was defined as a forced expiratory volume in one second (FEV1) decrease from baseline of more than or equal to 10% with exercise. Cough and dyspnea after exercise were recorded. A total of 557 participants were included into the analysis. After PE lesson, 15.3% children suffered from cough, 0.9% reported dyspnea, and 10.1% had more than 10% fall in FEV1 from baseline. Among all participants, 5.9% had doctors' diagnosed asthma, 4.8% of them were treated with inhaled corticosteroids (ICS). Among children with cough, 21.5% had asthma and 17.6% experienced EIB. Among asthmatics, 48.6% suffered from cough and 18.2% had more than 10% fall in FEV1 from baseline after PE lesson. EIB was not affected by age, gender, body mass index, asthma diagnosis, and ICS use. Only cough (odds ratio: 2.21, 95% confidence interval: 1.16-4.23; p = 0.0161) was independently associated with EIB. This study showed a high prevalence of exercise-induced cough and/or 10% fall in FEV1 during activity lesson in a natural school environment in a large urban population of schoolchildren. Our results call for another studies addressing the impact of environment on exercise-induced symptoms. PMID:25562558

  4. Dietary supplementation of Vitamin E protects heart tissue from exercise-induced oxidant stress

    Microsoft Academic Search

    Charles T. Kumar; Veera K. Reddy; M. Prasad; K. Thyagaraju; P. Reddanna

    1992-01-01

    Exhaustive endurance exercise in adult female albino rats (C-Ex) increased the generation of free radicals (R ·) in the myocardium, probably through enhanced oxidative mechanisms. Free radical mediated lipid peroxidation measured in the form of tissue MDA content also increased in C-Ex animals, suggesting the exercise-induced oxidative stress in these animals. Dietary supplementation of Vit E, for a period of

  5. Exercise?induced muscle cramp: A prospective biochemical study in marathon runners

    Microsoft Academic Search

    R. J. Maughan

    1986-01-01

    Exercise?induced muscle cramp has been considered to result from disturbances of fluid and electrolyte balance resulting from excessive sweat loss. Serum biochemical and haematological measurements were made on 82 male marathon runners before and after a 42.2?km race. Fifteen (18%) of the runners reported an attack of muscle cramp which occurred after 35 ± 6 km (mean±s.d.) had been covered.

  6. Exercise-induced skeletal muscle damage and adaptation following repeated bouts of eccentric muscle contractions

    Microsoft Academic Search

    S. J. Brown; R. B. Child; S. H. Day; A. E. Donnelly

    1997-01-01

    Repeated bouts of eccentric muscle contractions were used to examine indirect indices of exercise-induced muscle damage and adaptation in human skeletal muscle. Twenty-four subjects (18 females, 6 males) aged 20.0–1.4 years (mean - S.D.) performed an initial bout of either 10 (n = 7), 30 (n = 9) or 50 (n = 8) maximum voluntary eccentric contractions of the knee

  7. Evidence of exercise-induced muscle damage following a simulated rugby league match

    Microsoft Academic Search

    Craig Twist; Dave Sykes

    2011-01-01

    This study investigated symptoms of exercise-induced muscle damage following a simulated rugby league game. Ten male participants were assessed before, immediately after (0 h), and 24 and 48 h after the simulated game. Perceived muscle soreness was higher at all time points (P=0.001) and creatine kinase values were increased at 24 h following the simulated game (P=0.001). Peak knee extensor

  8. Early explosive force reduction associated with exercise-induced muscle damage

    Microsoft Academic Search

    D. García-López; J. A. de Paz; R. Jiménez-Jiménez; G. Bresciani; F. De Souza-Teixeira; J. A. Herrero; I. Alvear-Ordenes; J. González-Gallego

    2006-01-01

    This study was aimed to analyze the loss of muscle explosive force in the early phase of eccentric exercise-induced damage,\\u000a and its possible relationships with muscle soreness and blood creatine kinase (CK) levels. Squat jump (SJ) and counter-movement\\u000a jump (CMJ) heights decreased in response to an eccentric exercise (120 eccentric actions of the knee extensors), with reductions\\u000a that persisted at

  9. Acute exercise induces biphasic increase in respiratory mRNA in skeletal muscle

    SciTech Connect

    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

    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.

  10. The basic chemistry of exercise-induced DNA oxidation: oxidative damage, redox signaling, and their interplay

    PubMed Central

    Cobley, James N.; Margaritelis, Nikos V.; Morton, James P.; Close, Graeme L.; Nikolaidis, Michalis G.; Malone, John K.

    2015-01-01

    Acute exercise increases reactive oxygen and nitrogen species generation. This phenomenon is associated with two major outcomes: (1) redox signaling and (2) macromolecule damage. Mechanistic knowledge of how exercise-induced redox signaling and macromolecule damage are interlinked is limited. This review focuses on the interplay between exercise-induced redox signaling and DNA damage, using hydroxyl radical (·OH) and hydrogen peroxide (H2O2) as exemplars. It is postulated that the biological fate of H2O2 links the two processes and thus represents a bifurcation point between redox signaling and damage. Indeed, H2O2 can participate in two electron signaling reactions but its diffusion and chemical properties permit DNA oxidation following reaction with transition metals and ·OH generation. It is also considered that the sensing of DNA oxidation by repair proteins constitutes a non-canonical redox signaling mechanism. Further layers of interaction are provided by the redox regulation of DNA repair proteins and their capacity to modulate intracellular H2O2 levels. Overall, exercise-induced redox signaling and DNA damage may be interlinked to a greater extent than was previously thought but this requires further investigation. PMID:26136689

  11. All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes.

    PubMed

    Tourniaire, Franck; Musinovic, Hana; Gouranton, Erwan; Astier, Julien; Marcotorchino, Julie; Arreguin, Andrea; Bernot, Denis; Palou, Andreu; Bonet, M Luisa; Ribot, Joan; Landrier, Jean-François

    2015-06-01

    A positive effect of all-trans retinoic acid (ATRA) on white adipose tissue (WAT) oxidative and thermogenic capacity has been described and linked to an in vivo fat-lowering effect of ATRA in mice. However, little is known about the effects of ATRA on mitochondria in white fat. Our objective has been to characterize the effect of ATRA on mitochondria biogenesis and oxidative phosphorylation (OXPHOS) capacity in mature white adipocytes. Transcriptome analysis, oxygraphy, analysis of mitochondrial DNA (mtDNA), and flow cytometry-based analysis of mitochondria density were performed in mature 3T3-L1 adipocytes after 24 h incubation with ATRA (2 µM) or vehicle. Selected genes linked to mitochondria biogenesis and function and mitochondria immunostaining were analyzed in WAT tissues of ATRA-treated as compared with vehicle-treated mice. ATRA upregulated the expression of a large set of genes linked to mtDNA replication and transcription, mitochondrial biogenesis, and OXPHOS in adipocytes, as indicated by transcriptome analysis. Oxygen consumption rate, mtDNA content, and staining of mitochondria were increased in the ATRA-treated adipocytes. Similar results were obtained in WAT depots of ATRA-treated mice. We conclude that ATRA impacts mitochondria in adipocytes, leading to increased OXPHOS capacity and mitochondrial content in these cells. PMID:25914170

  12. Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension.

    PubMed

    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

    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

  13. Exercise-induced normalization of right precordial negative T waves in arrhythmogenic right ventricular cardiomyopathy.

    PubMed

    Zorzi, Alessandro; ElMaghawry, Mohamed; Rigato, Ilaria; Cardoso Bianchini, Fernando; Crespi Ponta, Georgiane; Michieli, Pierantonio; Migliore, Federico; Perazzolo Marra, Martina; Bauce, Barbara; Basso, Cristina; Schiavon, Maurizio; Thiene, Gaetano; Iliceto, Sabino; Corrado, Domenico

    2013-08-01

    Negative T waves (NTWs) in right precordial leads (V? to V?) may be observed on the electrocardiogram (ECG) of healthy subjects but can also represent the hallmark of an underlying arrhythmogenic right ventricular cardiomyopathy (ARVC). It has been a consistent observation that NTWs usually become upright with exercise in healthy subjects without underlying heart disease. No systematic study has evaluated exercise-induced changes of NTWs in ARVC. We assessed the prevalence and relation to the clinical phenotype of exercise-induced right precordial NTWs changes in 35 patients with ARVC (19 men, mean age 22.2 ± 6.2 years). Forty-one healthy subjects with right precordial NTWs served as controls. At peak of exercise (mean power 149 ± 43 W, mean heart rate 83.6 ± 12.6% of target), NTWs persisted in 3 patients with ARVC (9%), completely normalized in 12 (34%), and partially reverted in 20 (57%). Patients with ARVC with or without NTWs normalization showed a similar clinical phenotype. The overall prevalence of right precordial T waves changes during exercise (normalization plus partial reversal) did not differ between patients with ARVC and controls (92% vs 88%, p = 1.0), whereas there was a statistically nonsignificant trend toward a greater prevalence of complete normalization in controls (56% vs 34%, p = 0.06). In conclusion, our study demonstrated that right precordial NTWs partially or completely revert with exercise in most patients with ARVC, and NTWs normalization is unrelated to the clinical phenotype. Exercise-induced NTWs changes are inaccurate in differentiating between ARVC patients and benign repolarization abnormalities. PMID:23647791

  14. Personality Does not Influence Exercise-Induced Mood Enhancement Among Female Exercisers

    PubMed Central

    Lane, Andrew M.; Milton, Karen E.; Terry, Peter C.

    2005-01-01

    The present study investigated the influence of personality on exercise-induced mood changes. It was hypothesised that (a) exercise would be associated with significant mood enhancement across all personality types, (b) extroversion would be associated with positive mood and neuroticism with negative mood both pre- and post-exercise, and (c) personality measures would interact with exercise-induced mood changes. Participants were 90 female exercisers (M = 25.8 yr, SD = 9.0 yr) who completed the Eysenck Personality Inventory (EPI) once and the Brunel Mood Scale (BRUMS) before and after a 60-minute exercise session. Median splits were used to group participants into four personality types: stable introverts (n = 25), stable extroverts (n = 20), neurotic introverts (n = 26), and neurotic extroverts (n = 19). Repeated measures MANOVA showed significant mood enhancement following exercise across all personality types. Neuroticism was associated with negative mood scores pre- and post-exercise but the effect of extroversion on reported mood was relatively weak. There was no significant interaction effect between exercise-induced mood enhancement and personality. In conclusion, findings lend support to the notion that exercise is associated with improved mood. However, findings show that personality did not influence this effect, although neuroticism was associated with negative mood. Key Points Research in general psychology has found that stable personality trait are associated changes in mood states. Ninety females exercisers completed a personality test and mood scales before and after exercise. Results indicated mood changes were not associated with personality, although neuroticism was associated with negative mood. PMID:24453525

  15. Therapeutic prospects for mitochondrial disease

    PubMed Central

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

    2010-01-01

    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. PMID:20556877

  16. Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer’s and Parkinson’s diseases

    Microsoft Academic Search

    Tomohiro Nakamura; Stuart A. Lipton

    2010-01-01

    Normal mitochondrial dynamics consist of fission and fusion events giving rise to new mitochondria, a process termed mitochondrial\\u000a biogenesis. However, several neurodegenerative disorders manifest aberrant mitochondrial dynamics, resulting in morphological\\u000a abnormalities often associated with deficits in mitochondrial mobility and cell bioenergetics. Rarely, dysfunctional mitochondrial\\u000a occur in a familial pattern due to genetic mutations, but much more commonly patients manifest sporadic

  17. The influence of ice slurry ingestion on maximal voluntary contraction following exercise-induced hyperthermia

    Microsoft Academic Search

    Rodney SiegelJoseph; Joseph Maté; Greig Watson; Kazunori Nosaka; Paul B. Laursen

    The purpose of this study was to determine whether ingestion of a small bolus of ice slurry (1.25 g kg?1) could attenuate the reduction in maximal voluntary isometric contraction (MVC) torque output during a 2-min sustained task\\u000a following exercise-induced hyperthermia. On two separate occasions, 10 males (age: 24 ± 3 years, $$ \\\\dot{V}{\\\\text{O}}_{{ 2 {\\\\text{peak}}}} $$: 49.8 ± 4.7 ml kg?1 min?1) ran to exhaustion at their first ventilatory threshold

  18. Protective and biogenesis effects of sodium hydrosulfide on brain mitochondria after cardiac arrest and resuscitation.

    PubMed

    Pan, Hao; Xie, Xuemeng; Chen, Di; Zhang, Jincheng; Zhou, Yaguang; Yang, Guangtian

    2014-10-15

    Mitochondrial dysfunction plays a critical role in brain injury after cardiac arrest and cardiopulmonary resuscitation (CPR). Recent studies demonstrated that hydrogen sulfide (H2S) donor compounds preserve mitochondrial morphology and function during ischemia-reperfusion injury. In this study, we sought to explore the effects of sodium hydrosulfide (NaHS) on brain mitochondria 24h after cardiac arrest and resuscitation. Male Sprague-Dawley rats were subjected to 6min cardiac arrest and then resuscitated successfully. Rats received NaHS (0.5mg/kg) or vehicle (0.9% NaCl, 1.67ml/kg) 1min before the start of CPR intravenously, followed by a continuous infusion of NaHS (1.5mg/kg/h) or vehicle (5ml/kg/h) for 3h. Neurological deficit was evaluated 24h after resuscitation and then cortex was collected for assessments. As a result, we found that rats treated with NaHS revealed an improved neurological outcome and cortex mitochondrial morphology 24h after resuscitation. We also observed that NaHS therapy reduced intracellular reactive oxygen species generation and calcium overload, inhibited mitochondrial permeability transition pores, preserved mitochondrial membrane potential, elevated ATP level and ameliorated the cytochrome c abnormal distribution. Further studies indicated that NaHS administration increased mitochondrial biogenesis in cortex at the same time. Our findings suggested that administration of NaHS 1min prior CPR and followed by a continuous infusion ameliorated neurological dysfunction 24h after resuscitation, possibly through mitochondria preservation as well as by promoting mitochondrial biogenesis. PMID:25066114

  19. Mitochondrial biogenesis: which part of ``NO'' do we understand?

    E-print Network

    Leary, Scot

    -cyclase-dependent signaling pathway that ac- tivates PGC1a (peroxisome proliferator-activated recep- tor g coactivator-1a-sensitive isoforms (neuronal NOS and endothelial NOS [eNOS]), while the third is an inducible isoform (inducible NOS

  20. Biogenesis of light harvesting proteins.

    PubMed

    Dall'Osto, Luca; Bressan, Mauro; Bassi, Roberto

    2015-09-01

    The LHC family includes nuclear-encoded, integral thylakoid membrane proteins, most of which coordinate chlorophyll and xanthophyll chromophores. By assembling with the core complexes of both photosystems, LHCs form a flexible peripheral moiety for enhancing light-harvesting cross-section, regulating its efficiency and providing protection against photo-oxidative stress. Upon its first appearance, LHC proteins underwent evolutionary diversification into a large protein family with a complex genetic redundancy. Such differentiation appears as a crucial event in the adaptation of photosynthetic organisms to changing environmental conditions and land colonization. The structure of photosystems, including nuclear- and chloroplast-encoded subunits, presented the cell with a number of challenges for the control of the light harvesting function. Indeed, LHC-encoding messages are translated in the cytosol, and pre-proteins imported into the chloroplast, processed to their mature size and targeted to the thylakoids where are assembled with chromophores. Thus, a tight coordination between nuclear and plastid gene expression, in response to environmental stimuli, is required to adjust LHC composition during photoacclimation. In recent years, remarkable progress has been achieved in elucidating structure, function and regulatory pathways involving LHCs; however, a number of molecular details still await elucidation. In this review, we will provide an overview on the current knowledge on LHC biogenesis, ranging from organization of pigment-protein complexes to the modulation of gene expression, import and targeting to the photosynthetic membranes, and regulation of LHC assembly and turnover. Genes controlling these events are potential candidate for biotechnological applications aimed at optimizing light use efficiency of photosynthetic organisms. This article is part of a Special Issue entitled: Chloroplast biogenesis. PMID:25687893

  1. Exercise-Induced Norepinephrine Decreases Circulating Hematopoietic Stem and Progenitor Cell Colony-Forming Capacity

    PubMed Central

    Mangge, Harald; Pekovits, Karin; Fuchs, Robert; Allard, Nathalie; Schinagl, Lukas; Hofmann, Peter; Dohr, Gottfried; Wallner-Liebmann, Sandra; Domej, Wolfgang; Müller, Wolfram

    2014-01-01

    A recent study showed that ergometry increased circulating hematopoietic stem and progenitor cell (CPC) numbers, but reduced hematopoietic colony forming capacity/functionality under normoxia and normobaric hypoxia. Herein we investigated whether an exercise-induced elevated plasma free/bound norepinephrine (NE) concentration could be responsible for directly influencing CPC functionality. Venous blood was taken from ten healthy male subjects (25.3+/?4.4 yrs) before and 4 times after ergometry under normoxia and normobaric hypoxia (FiO2<0.15). The circulating hematopoietic stem and progenitor cell numbers were correlated with free/bound NE, free/bound epinephrine (EPI), cortisol (Co) and interleukin-6 (IL-6). Additionally, the influence of exercise-induced NE and blood lactate (La) on CPC functionality was analyzed in a randomly selected group of subjects (n?=?6) in vitro under normoxia by secondary colony-forming unit granulocyte macrophage assays. Concentrations of free NE, EPI, Co and IL-6 were significantly increased post-exercise under normoxia/hypoxia. Ergometry-induced free NE concentrations found in vivo showed a significant impairment of CPC functionality in vitro under normoxia. Thus, ergometry-induced free NE was thought to trigger CPC mobilization 10 minutes post-exercise, but as previously shown impairs CPC proliferative capacity/functionality at the same time. The obtained results suggest that an ergometry-induced free NE concentration has a direct negative effect on CPC functionality. Cortisol may further influence CPC dynamics and functionality. PMID:25180783

  2. Exercise-induced norepinephrine decreases circulating hematopoietic stem and progenitor cell colony-forming capacity.

    PubMed

    Kröpfl, Julia M; Stelzer, Ingeborg; Mangge, Harald; Pekovits, Karin; Fuchs, Robert; Allard, Nathalie; Schinagl, Lukas; Hofmann, Peter; Dohr, Gottfried; Wallner-Liebmann, Sandra; Domej, Wolfgang; Müller, Wolfram

    2014-01-01

    A recent study showed that ergometry increased circulating hematopoietic stem and progenitor cell (CPC) numbers, but reduced hematopoietic colony forming capacity/functionality under normoxia and normobaric hypoxia. Herein we investigated whether an exercise-induced elevated plasma free/bound norepinephrine (NE) concentration could be responsible for directly influencing CPC functionality. Venous blood was taken from ten healthy male subjects (25.3+/-4.4 yrs) before and 4 times after ergometry under normoxia and normobaric hypoxia (FiO2<0.15). The circulating hematopoietic stem and progenitor cell numbers were correlated with free/bound NE, free/bound epinephrine (EPI), cortisol (Co) and interleukin-6 (IL-6). Additionally, the influence of exercise-induced NE and blood lactate (La) on CPC functionality was analyzed in a randomly selected group of subjects (n?=?6) in vitro under normoxia by secondary colony-forming unit granulocyte macrophage assays. Concentrations of free NE, EPI, Co and IL-6 were significantly increased post-exercise under normoxia/hypoxia. Ergometry-induced free NE concentrations found in vivo showed a significant impairment of CPC functionality in vitro under normoxia. Thus, ergometry-induced free NE was thought to trigger CPC mobilization 10 minutes post-exercise, but as previously shown impairs CPC proliferative capacity/functionality at the same time. The obtained results suggest that an ergometry-induced free NE concentration has a direct negative effect on CPC functionality. Cortisol may further influence CPC dynamics and functionality. PMID:25180783

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

    PubMed

    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

    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

  4. EXERCISE-INDUCED MODULATION OF PAIN IN ADULTS WITH AND WITHOUT PAINFUL DIABETIC NEUROPATHY

    PubMed Central

    Knauf, Matthew T.; Koltyn, Kelli F.

    2015-01-01

    The purpose of this study was to examine exercise-induced pain modulation in diabetic adults with painful diabetic neuropathy (PDN) compared to diabetic adults without PDN. Eighteen adults diagnosed with Type 2 diabetes with and without PDN (mean age of 49 yrs) completed two sessions. During the familiarization session, participants completed questionnaires, were familiarized with the pain testing protocols, and completed maximal isometric contractions. During the exercise session, experimental pain testing was completed before and following exercise consisting of three minutes of isometric exercise performed at 25% MVC. Ratings of perceived exertion (RPE) and muscle pain (MP) were assessed every 30 seconds during exercise. Results indicated RPE and MP during exercise were significantly higher (p < 0.05) for diabetic adults with PDN vs diabetic adults without PDN. Diabetic adults with PDN did not experience changes in thermal pain ratings following exercise while diabetic adults without PDN reported significantly lower pain ratings following exercise. It is concluded that diabetic adults with PDN experienced high levels of muscle pain during exercise and a lack of exercise-induced hypoalgesia following exercise in comparison to diabetic adults without PDN who experienced lower levels of muscle pain during exercise and a hypoalgesic response following exercise. PMID:24632113

  5. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus

    PubMed Central

    Pereira, Ana C.; Huddleston, Dan E.; Brickman, Adam M.; Sosunov, Alexander A.; Hen, Rene; McKhann, Guy M.; Sloan, Richard; Gage, Fred H.; Brown, Truman R.; Small, Scott A.

    2007-01-01

    With continued debate over the functional significance of adult neurogenesis, identifying an in vivo correlate of neurogenesis has become an important goal. Here we rely on the coupling between neurogenesis and angiogenesis and test whether MRI measurements of cerebral blood volume (CBV) provide an imaging correlate of neurogenesis. First, we used an MRI approach to generate CBV maps over time in the hippocampal formation of exercising mice. Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus CBV, the only subregion that supports adult neurogenesis. Moreover, exercise-induced increases in dentate gyrus CBV were found to correlate with postmortem measurements of neurogenesis. Second, using similar MRI technologies, we generated CBV maps over time in the hippocampal formation of exercising humans. As in mice, exercise was found to have a primary effect on dentate gyrus CBV, and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging. PMID:17374720

  6. Duration of action of sodium cromoglycate on exercise induced asthma: comparison of 2 formulations.

    PubMed

    Bar-Yishay, E; Gur, I; Levy, M; Volozni, D; Godfrey, S

    1983-08-01

    Thirteen asthmatic children aged 9-14 years participated in a double blind randomised trial to compare the effectiveness and duration of action of 2 formulations of sodium cromoglycate; one a 20 mg capsule of powdered sodium cromoglycate delivered by turbo inhaler (spinhaler), and the other 1 mg of aerosolised sodium cromoglycate delivered by pressurised cannister inhaler (aerosol). The children performed exercise tests on each of 3 days in a 10 day period--15 minutes, 2 hours, and 6 hours after inhalation of powder, aerosol, or a placebo. Two patients were not protected from exercise induced asthma by either formulation of sodium cromoglycate. Among the remaining patients both formulations gave good protection from exercise induced asthma 15 minutes after inhalation, and the effect of both wore off steadily over the next 6 hours. The spinhaler gave appreciably better protection than the aerosol at 15 minutes after inhalation, and was the only formulation to provide good protection at 2 hours and 6 hours. The more limited effectiveness of the aerosol may be explained by the lower dose of sodium cromoglycate and the more complicated inhalation technique required. PMID:6412638

  7. Simulation of Exercise-Induced Syncope in a Heart Model with Severe Aortic Valve Stenosis

    PubMed Central

    Sever, Matjaž; Ribari?, Samo; Kordaš, Marjan

    2012-01-01

    Severe aortic valve stenosis (AVS) can cause an exercise-induced reflex syncope (RS). The precise mechanism of this syncope is not known. The changes in hemodynamics are variable, including arrhythmias and myocardial ischemia, and one of the few consistent changes is a sudden fall in systemic and pulmonary arterial pressures (suggesting a reduced vascular resistance) followed by a decline in heart rate. The contribution of the cardioinhibitory and vasodepressor components of the RS to hemodynamics was evaluated by a computer model. This lumped-parameter computer simulation was based on equivalent electronic circuits (EECs) that reflect the hemodynamic conditions of a heart with severe AVS and a concomitantly decreased contractility as a long-term detrimental consequence of compensatory left ventricular hypertrophy. In addition, the EECs model simulated the resetting of the sympathetic nervous tone in the heart and systemic circuit during exercise and exercise-induced syncope, the fluctuating intra-thoracic pressure during respiration, and the passive relaxation of ventricle during diastole. The results of this simulation were consistent with the published case reports of exertional syncope in patients with AVS. The value of the EEC model is its ability to quantify the effect of a selective and gradable change in heart rate, ventricular contractility, or systemic vascular resistance on the hemodynamics during an exertional syncope in patients with severe AVS. PMID:23251225

  8. Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency.

    PubMed

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

    2010-06-01

    Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult-onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of L-Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP-cyclohydrolase 1 (GCH-1) gene. We propose that GCH-1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals. PMID:20187889

  9. Early explosive force reduction associated with exercise-induced muscle damage.

    PubMed

    García-López, D; de Paz, J A; Jiménez-Jiménez, R; Bresciani, G; De Souza-Teixeira, F; Herrero, J A; Alvear-Ordenes, I; González-Gallego, J

    2006-09-01

    This study was aimed to analyze the loss of muscle explosive force in the early phase of eccentric exercise-induced damage, and its possible relationships with muscle soreness and blood creatine kinase (CK) levels. Squat jump (SJ) and countermovement jump (CMJ) heights decreased in response to an eccentric exercise (120 eccentric actions of the knee extensors), with reductions that persisted at least for 24 h. The SJ/CMJ ratio was not significantly modified. Blood CK levels changed significantly over time and CK activity was significantly higher at 6 and at 24 h when compared to values obtained immediately after the eccentric exercise. Muscle soreness perceived at 6 h was slightly higher than that experienced just after finalizing the exercise and reached a clearly upper value at 24 h. A highly significant relationship between SJ and CMJ height loss was observed. CK activity at 24 h was significantly related to the SJ height loss at 6 h and to both the SJ height loss and the CMJ height loss immediately after the exercise. In summary, eccentric exercise induced a reduction in the explosive force generating capacity that affected in a similar way the pure concentric jump (SJ) and the jump eliciting the stretch-shortening cycle (CMJ). Results obtained suggest that CK activity is a better predictor of explosive force reduction than soreness, at least when values close to the peak are used. PMID:17451157

  10. Biogenesis of the Gram-Negative Bacterial

    E-print Network

    Mekalanos, John

    Biogenesis of the Gram-Negative Bacterial Outer Membrane Martine P. Bos, Viviane Robert, and Jan lipopolysaccharide, outer membrane proteins, lipoproteins, phospholipids Abstract The cell envelope of gram . . . . . . . . . . . . . . . . . 206 PERSPECTIVES . . . . . . . . . . . . . . . . . . . 206 INTRODUCTION The cell envelope of gram

  11. Opposing roles of mitochondrial and nuclear PARP1 in the regulation of mitochondrial and nuclear DNA integrity: implications for the regulation of mitochondrial function

    PubMed Central

    Szczesny, Bartosz; Brunyanszki, Attila; Olah, Gabor; Mitra, Sankar; Szabo, Csaba

    2014-01-01

    The positive role of PARP1 in regulation of various nuclear DNA transactions is well established. Although a mitochondrial localization of PARP1 has been suggested, its role in the maintenance of the mitochondrial DNA is currently unknown. Here we investigated the role of PARP1 in the repair of the mitochondrial DNA in the baseline and oxidative stress conditions. We used wild-type A549 cells or cells depleted of PARP1. Our data show that intra-mitochondrial PARP1 interacts with a key mitochondrial-specific DNA base excision repair (BER) enzymes, namely EXOG and DNA polymerase gamma (Pol?), which under oxidative stress become poly(ADP-ribose)lated (PARylated). Interaction between mitochondrial BER enzymes was significantly affected in the presence of PARP1. Moreover, the repair of the oxidative-induced damage to the mitochondrial DNA in PARP1-depleted cells was found to be more robust compared to control counterpart. In addition, mitochondrial biogenesis was enhanced in PARP1-depleted cells, including mitochondrial DNA copy number and mitochondrial membrane potential. This observation was further confirmed by analysis of lung tissue isolated from WT and PARP1 KO mice. In summary, we conclude that mitochondrial PARP1, in opposite to nuclear PARP1, exerts a negative effect on several mitochondrial-specific transactions including the repair of the mitochondrial DNA. PMID:25378300

  12. Opposing roles of mitochondrial and nuclear PARP1 in the regulation of mitochondrial and nuclear DNA integrity: implications for the regulation of mitochondrial function.

    PubMed

    Szczesny, Bartosz; Brunyanszki, Attila; Olah, Gabor; Mitra, Sankar; Szabo, Csaba

    2014-12-01

    The positive role of PARP1 in regulation of various nuclear DNA transactions is well established. Although a mitochondrial localization of PARP1 has been suggested, its role in the maintenance of the mitochondrial DNA is currently unknown. Here we investigated the role of PARP1 in the repair of the mitochondrial DNA in the baseline and oxidative stress conditions. We used wild-type A549 cells or cells depleted of PARP1. Our data show that intra-mitochondrial PARP1 interacts with a key mitochondrial-specific DNA base excision repair (BER) enzymes, namely EXOG and DNA polymerase gamma (Pol?), which under oxidative stress become poly(ADP-ribose)lated (PARylated). Interaction between mitochondrial BER enzymes was significantly affected in the presence of PARP1. Moreover, the repair of the oxidative-induced damage to the mitochondrial DNA in PARP1-depleted cells was found to be more robust compared to control counterpart. In addition, mitochondrial biogenesis was enhanced in PARP1-depleted cells, including mitochondrial DNA copy number and mitochondrial membrane potential. This observation was further confirmed by analysis of lung tissue isolated from WT and PARP1 KO mice. In summary, we conclude that mitochondrial PARP1, in opposite to nuclear PARP1, exerts a negative effect on several mitochondrial-specific transactions including the repair of the mitochondrial DNA. PMID:25378300

  13. Mitochondrial Dysfunction: Different Routes to Alzheimer's Disease Therapy

    PubMed Central

    Picone, Pasquale; Nuzzo, Domenico; Caruana, Luca; Scafidi, Valeria; Di Carlo, Marta

    2014-01-01

    Mitochondria are dynamic ATP-generating organelle which contribute to many cellular functions including bioenergetics processes, intracellular calcium regulation, alteration of reduction-oxidation potential of cells, free radical scavenging, and activation of caspase mediated cell death. Mitochondrial functions can be negatively affected by amyloid ? peptide (A?), an important component in Alzheimer's disease (AD) pathogenesis, and A? can interact with mitochondria and cause mitochondrial dysfunction. One of the most accepted hypotheses for AD onset implicates that mitochondrial dysfunction and oxidative stress are one of the primary events in the insurgence of the pathology. Here, we examine structural and functional mitochondrial changes in presence of A?. In particular we review data concerning A? import into mitochondrion and its involvement in mitochondrial oxidative stress, bioenergetics, biogenesis, trafficking, mitochondrial permeability transition pore (mPTP) formation, and mitochondrial protein interaction. Moreover, the development of AD therapy targeting mitochondria is also discussed. PMID:25221640

  14. New roles for mitochondrial proteases in health, ageing and disease.

    PubMed

    Quirós, Pedro M; Langer, Thomas; López-Otín, Carlos

    2015-06-01

    Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'. PMID:25970558

  15. Mitochondrial dysfunction leads to nuclear genome instability: A link through iron-sulfur clusters

    PubMed Central

    Veatch, Joshua R.; McMurray, Michael A.; Nelson, Zara W.; Gottschling, Daniel E.

    2009-01-01

    Summary Mutations and deletions in the mitochondrial genome (mtDNA), as well as instability of the nuclear genome, are involved in multiple human diseases. Here we report that in Saccharomyces cerevisiae, loss of mtDNA leads to nuclear genome instability, through a process of cell cycle arrest and selection we define as a cellular crisis. This crisis is not mediated by the absence of respiration, but instead correlates with a reduction in the mitochondrial membrane potential. Analysis of cells undergoing this crisis identified a defect in iron-sulfur cluster (ISC) biogenesis, which requires normal mitochondrial function. We found that down-regulation of non-mitochondrial ISC protein biogenesis was sufficient to cause increased genomic instability in cells with intact mitochondrial function. These results suggest mitochondrial dysfunction stimulates nuclear genome instability by inhibiting the production of ISC-containing protein(s), which are required for maintenance of nuclear genome integrity. PMID:19563757

  16. Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits

    Microsoft Academic Search

    R. O. Vogel; C. E. J. Dieteren; L. P. W. J. van den Heuvel; P. H. G. M. Willems; J. A. M. Smeitink; W. J. H. Koopman; L. G. J. Nijtmans

    2007-01-01

    Biogenesis of human mitochondrial complex I (CI) requires the coordinated assembly of 45 subunits derived from both the mitochondrial and nuclear genome. The presence of CI subcomplexes in CI-deficient cells suggests that assembly occurs in distinct steps. However, discriminating between products of assembly or instability is problematic. Using an inducible NDUFS3-green fluorescent protein (GFP) expression system in HEK293 cells, we

  17. Disruption of microRNA Biogenesis Confers Resistance to ER Stress-Induced Cell Death Upstream of the Mitochondrion

    PubMed Central

    Cawley, Karen; Logue, Susan E.; Gorman, Adrienne M.; Zeng, Qingping; Patterson, John; Gupta, Sanjeev; Samali, Afshin

    2013-01-01

    Global downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA biogenesis promotes tumor development is not clearly understood. Here we show that loss of miRNA biogenesis increased resistance to endoplasmic reticulum (ER) stress-induced cell death. We observed that HCT116 cells with a DICER hypomorphic mutation (Exn5/Exn5) or where DICER or DROSHA were knocked down were resistant to ER stress-induced cell death. Extensive analysis revealed little difference in the unfolded protein response (UPR) of WT compared to Exn5/Exn5 HCT116 cells upon ER stress treatment. However, analysis of the intrinsic apoptotic pathway showed that resistance occurred upstream of the mitochondria. In particular, BAX activation and dissipation of mitochondrial membrane potential was attenuated, and there was altered expression of BCL-2 family proteins. These observations demonstrate a key role for miRNAs as critical modulators of the ER stress response. In our model, downregulation of miRNA biogenesis delays ER stress-induced apoptosis. This suggests that disrupted miRNA biogenesis may contribute to cancer progression by inhibiting ER stress-induced cell death. PMID:23977393

  18. Forkhead BoxO transcription factors restrain exercise-induced angiogenesis.

    PubMed

    Slopack, Dara; Roudier, Emilie; Liu, Sammy T K; Nwadozi, Emmanuel; Birot, Olivier; Haas, Tara L

    2014-09-15

    The physiological process of exercise-induced angiogenesis involves the orchestrated upregulation of angiogenic factors together with repression of angiostatic factors. The Forkhead Box 'O' (FoxO) transcription factors promote an angiostatic environment in pathological contexts. We hypothesized that endothelial FoxO1 and FoxO3a also play an integral role in restricting the angiogenic response to aerobic exercise training. A single exercise bout significantly increased levels of FoxO1 and FoxO3a mRNA (5.5- and 1.7-fold, respectively) and protein (1.7- and 2.2-fold, respectively) within the muscles of mice 2 h post-exercise compared to sedentary. Training abolished the exercise-induced increases in both FoxO1 and FoxO3a mRNA and proteins, and resulted in significantly lower nuclear levels of FoxO1 and FoxO3a protein (0.5- and 0.4-fold, respectively, relative to sedentary). Thrombospondin 1 (THBS1) protein level closely mirrored the expression pattern of FoxO proteins. The 1.7-fold increase in THBS1 protein following acute exercise no longer occurred after 10 days of repeated exercise. Endothelial cell-directed conditional deletion of FoxO1/3a/4 in mice prevented the increase in THBS1 mRNA following a single exercise bout. Mice harbouring the endothelial FoxO deletion also demonstrated a significant 20% increase in capillary to muscle fibre ratio after only 7 days of training while 14 days of training was required to elicit a similar increase in wildtype littermates. Our results demonstrate that the downregulation of FoxO1 and FoxO3a proteins facilitates angiogenesis in response to repeated exercise. In conclusion, FoxO proteins can delay exercise-induced angiogenesis, and thus are critical regulators of the physiological angiogenic response in skeletal muscle. PMID:25063823

  19. Mitochondrial abnormalities in temporal lobe of autistic brain.

    PubMed

    Tang, Guomei; Gutierrez Rios, Puri; Kuo, Sheng-Han; Akman, Hasan Orhan; Rosoklija, Gorazd; Tanji, Kurenai; Dwork, Andrew; Schon, Eric A; Dimauro, Salvatore; Goldman, James; Sulzer, David

    2013-06-01

    Autism spectrum disorder (ASD) consists of a group of complex developmental disabilities characterized by impaired social interactions, deficits in communication and repetitive behavior. Multiple lines of evidence implicate mitochondrial dysfunction in ASD. In postmortem BA21 temporal cortex, a region that exhibits synaptic pathology in ASD, we found that compared to controls, ASD patients exhibited altered protein levels of mitochondria respiratory chain protein complexes, decreased Complex I and IV activities, decreased mitochondrial antioxidant enzyme SOD2, and greater oxidative DNA damage. Mitochondrial membrane mass was higher in ASD brain, as indicated by higher protein levels of mitochondrial membrane proteins Tom20, Tim23 and porin. No differences were observed in either mitochondrial DNA or levels of the mitochondrial gene transcription factor TFAM or cofactor PGC1?, indicating that a mechanism other than alterations in mitochondrial genome or mitochondrial biogenesis underlies these mitochondrial abnormalities. We further identified higher levels of the mitochondrial fission proteins (Fis1 and Drp1) and decreased levels of the fusion proteins (Mfn1, Mfn2 and Opa1) in ASD patients, indicating altered mitochondrial dynamics in ASD brain. Many of these changes were evident in cortical pyramidal neurons, and were observed in ASD children but were less pronounced or absent in adult patients. Together, these findings provide evidence that mitochondrial function and intracellular redox status are compromised in pyramidal neurons in ASD brain and that mitochondrial dysfunction occurs during early childhood when ASD symptoms appear. PMID:23333625

  20. Candida albicans Sun41p, a Putative Glycosidase, Is Involved in Morphogenesis, Cell Wall Biogenesis, and Biofilm Formation

    Microsoft Academic Search

    Ekkehard Hiller; Sonja Heine; Herwig Brunner; Steffen Rupp

    2007-01-01

    The SUN gene family has been defined in Saccharomyces cerevisiae and comprises a fungus-specific family of proteins which show high similarity in their C-terminal domains. Genes of this family are involved in different cellular processes, like DNA replication, aging, mitochondrial biogenesis, and cytokinesis. In Candida albicans the SUN family comprises two genes, SUN41 and SIM1. We demonstrate that C. albicans

  1. Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice.

    PubMed

    Betts, Corinne A; Saleh, Amer F; Carr, Carolyn A; Hammond, Suzan M; Coenen-Stass, Anna M L; Godfrey, Caroline; McClorey, Graham; Varela, Miguel A; Roberts, Thomas C; Clarke, Kieran; Gait, Michael J; Wood, Matthew J A

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice. PMID:25758104

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

    PubMed

    Diwakar, Amit; Schmidt, Gregory A

    2014-04-01

    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

  3. An open-label study examining the effect of pharmacological treatment on mannitol- and exercise-induced airway hyperresponsiveness in asthmatic children and adolescents with exercise-induced bronchoconstriction

    PubMed Central

    2014-01-01

    Background Mannitol- and exercise bronchial provocation tests are both used to diagnose exercise-induced bronchoconstriction. The study aim was to compare the short-term treatment response to budesonide and montelukast on airway hyperresponsiveness to mannitol challenge test and to exercise challenge test in children and adolescents with exercise-induced bronchoconstriction. Methods Patients were recruited from a paediatric asthma rehabilitation clinic located in the Swiss Alps. Individuals with exercise-induced bronchoconstriction and a positive result in the exercise challenge test underwent mannitol challenge test on day 0. All subjects then received a treatment with 400 ?g budesonide and bronchodilators as needed for 7 days, after which exercise- and mannitol-challenge tests were repeated (day 7). Montelukast was then added to the previous treatment and both tests were repeated again after 7 days (day 14). Results Of 26 children and adolescents with exercise-induced bronchoconstriction, 14 had a positive exercise challenge test at baseline and were included in the intervention study. Seven of 14 (50%) also had a positive mannitol challenge test. There was a strong correlation between airway responsiveness to exercise and to mannitol at baseline (r?=?0.560, p?=?0.037). Treatment with budesonide and montelukast decreased airway hyperresponsiveness to exercise challenge test and to a lesser degree to mannitol challenge test. The fall in forced expiratory volume in one second during exercise challenge test was 21.7% on day 0 compared to 6.7% on day 14 (p?=?0.001) and the mannitol challenge test dose response ratio was 0.036%/mg on day 0 compared to 0.013%/mg on day 14 (p?=?0.067). Conclusion Short-term treatment with an inhaled corticosteroid and an additional leukotriene receptor antagonist in children and adolescents with exercise-induced bronchoconstriction decreases airway hyperresponsiveness to exercise and to mannitol. PMID:25084607

  4. Influence of prior anterograde shear rate exposure on exercise-induced brachial artery dilation

    PubMed Central

    Ade, Carl J; Brown, Michael G; Ederer, Austin K; Hardy, Rachel N; Reiter, Landon K; Didier, Kaylin D

    2015-01-01

    Shear rate can elicit substantial adaptations to vascular endothelial function. Recent studies indicate that prior exposure to anterograde flow and shear increases endothelium-dependent flow-mediated dilation at rest and that anterograde shear can create an anti-atherosclerotic and provasodilatory state. The primary aim of the present study was therefore to determine the effects of prior exposure to anterograde shear on exercise-induced brachial artery dilation, total forearm blood flow (FBF), and vascular conductance (FVC) during dynamic handgrip exercise. Eight men completed a constant-load exercise test corresponding to 10% maximal voluntary contraction, prior to (baseline) and following a 40 min shear rate intervention (post-SRI) achieved via unilateral forearm heating, which has previously been shown to increase anterograde shear rate in the brachial artery. During the SRI, anterograde shear rate increased 60.9 ± 29.2 sec?1 above baseline (P < 0.05). Post-SRI, the exercise-induced brachial artery vasodilation was significantly increased compared to baseline (4.1 ± 0.7 vs. 4.3 ± 0.6 mm, P < 0.05). Post-SRI FBF mean response time (33.2 ± 16.0 vs. 23.0 ± 11.8 sec, P < 0.05) and FVC mean response time (31.1 ± 12.8 20.2 ± 10.7 sec, P < 0.05) at exercise onset were accelerated compared to baseline. These findings demonstrate that prior exposure to anterograde shear rate increases the vascular responses to exercise and supports the possible beneficial effects of anterograde shear rate in vivo. PMID:26009637

  5. The influence of ice slurry ingestion on maximal voluntary contraction following exercise-induced hyperthermia.

    PubMed

    Siegel, Rodney; Maté, Joseph; Watson, Greig; Nosaka, Kazunori; Laursen, Paul B

    2011-10-01

    The purpose of this study was to determine whether ingestion of a small bolus of ice slurry (1.25 g kg(-1)) could attenuate the reduction in maximal voluntary isometric contraction (MVC) torque output during a 2-min sustained task following exercise-induced hyperthermia. On two separate occasions, 10 males (age: 24 ± 3 years, .VO(2peak): 49.8 ± 4.7 ml kg(-1) min(-1)) ran to exhaustion at their first ventilatory threshold in a hot environment (34.1 ± 0.1°C, 49.5 ± 3.6% RH). Prior to and after exercise, subjects performed a 2-min sustained MVC of the right elbow flexors in a thermoneutral environment (24.6 ± 0.8°C, 37.2 ± 4.5% RH). The post exercise MVC was performed immediately following the ingestion of either 1.25 g kg(-1) of ice slurry (-1°C; ICE) or warm fluid (40°C; CON), in a counterbalanced and randomised order. Run time to exhaustion (42.4 ± 9.5 vs. 41.7 ± 8.7 min; p = 0.530), and rectal (39.08 ± 0.30 vs. 39.08 ± 0.30°C; p = 0.934) and skin temperatures (35.26 ± 0.65 vs. 35.28 ± 0.67°C; p = 0.922) and heart rate (189 ± 5 vs. 189 ± 6 beats min(-1); p = 0.830) at the end of the run were similar between trials. Torque output during the post-exercise 2-min sustained MVC was significantly higher (p = 0.001) following ICE (30.75 ± 16.40 Nm) compared with CON (28.69 ± 14.88 Nm). These results suggest that ice slurry ingestion attenuated the effects of exercise-induced hyperthermia on MVC, possibly via internal thermoreceptive and/or temperature-related sensory mechanisms. PMID:21360201

  6. Increased dietary protein attenuates C-reactive protein and creatine kinase responses to exercise-induced energy deficit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We determined if dietary protein (P) modulates responses of C-reactive protein (CRP) and creatine kinase (CK), biomarkers of inflammation and muscle damage, during exercise-induced energy deficit (DEF). Thirteen healthy men (22 +/- 1 y, VO2peak 60 +/- 2 ml.kg-1.min-1) balanced energy expenditure (EE...

  7. The Free-Running Asthma Screening Test: An Approach to Screening for Exercise-Induced Asthma in Rural Alabama.

    ERIC Educational Resources Information Center

    Heaman, Doris J.; Estes, Jenny

    1997-01-01

    This study documented the prevalence of exercise-induced asthma (EIA) in rural elementary schools, examining the use of a free-running asthma screening test and peak expiratory flow-rate measurement for school screening. Results indicated that 5.7% of the students had EIA. Absenteeism and poverty were related to EIA. (SM)

  8. A Systematic Review of the Literature on Screening for Exercise-Induced Asthma: Considerations for School Nurses

    ERIC Educational Resources Information Center

    Worrell, Kelly; Shaw, Michele R.; Postma, Julie; Katz, Janet R.

    2015-01-01

    Asthma is a major cause of illness, missed school days, and hospitalization in children. One type of asthma common in children is exercise-induced asthma (EIA). EIA causes airway narrowing with symptoms of cough and shortness of breath during exercise. The purpose of this article is to review the literature relevant to screening children and…

  9. The life of plant mitochondrial complex I.

    PubMed

    Braun, Hans-Peter; Binder, Stefan; Brennicke, Axel; Eubel, Holger; Fernie, Alisdair R; Finkemeier, Iris; Klodmann, Jennifer; König, Ann-Christine; Kühn, Kristina; Meyer, Etienne; Obata, Toshihiro; Schwarzländer, Markus; Takenaka, Mizuki; Zehrmann, Anja

    2014-11-01

    The mitochondrial NADH dehydrogenase complex (complex I) of the respiratory chain has several remarkable features in plants: (i) particularly many of its subunits are encoded by the mitochondrial genome, (ii) its mitochondrial transcripts undergo extensive maturation processes (e.g. RNA editing, trans-splicing), (iii) its assembly follows unique routes, (iv) it includes an additional functional domain which contains carbonic anhydrases and (v) it is, indirectly, involved in photosynthesis. Comprising about 50 distinct protein subunits, complex I of plants is very large. However, an even larger number of proteins are required to synthesize these subunits and assemble the enzyme complex. This review aims to follow the complete "life cycle" of plant complex I from various molecular perspectives. We provide arguments that complex I represents an ideal model system for studying the interplay of respiration and photosynthesis, the cooperation of mitochondria and the nucleus during organelle biogenesis and the evolution of the mitochondrial oxidative phosphorylation system. PMID:24561573

  10. Insights into chloroplast biogenesis and development.

    PubMed

    Pogson, Barry J; Ganguly, Diep; Albrecht-Borth, Verónica

    2015-09-01

    In recent years many advances have been made to obtain insight into chloroplast biogenesis and development. In plants several plastids types exist such as the proplastid (which is the progenitor of all plastids), leucoplasts (group of colourless plastids important for storage including elaioplasts (lipids), amyloplasts (starch) or proteinoplasts (proteins)), chromoplasts (yellow to orange-coloured due to carotenoids, in flowers or in old leaves as gerontoplasts), and the green chloroplasts. Chloroplasts are indispensable for plant development; not only by performing photosynthesis and thus rendering the plant photoautotrophic, but also for biochemical processes (which in some instances can also take place in other plastids types), such as the synthesis of pigments, lipids, and plant hormones and sensing environmental stimuli. Although we understand many aspects of these processes there are gaps in our understanding of the establishment of functional chloroplasts and their regulation. Why is that so? Even though chloroplast function is comparable in all plants and most of the algae, ferns and moss, detailed analyses have revealed many differences, specifically with respect to its biogenesis. As an update to our prior review on the genetic analysis of chloroplast biogenesis and development [1] herein we will focus on recent advances in Angiosperms (monocotyledonous and dicotyledonous plants) that provide novel insights and highlight the challenges and prospects for unravelling the regulation of chloroplast biogenesis specifically during the establishment of the young plants. This article is part of a Special Issue entitled: Chloroplast Biogenesis. PMID:25667967

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

    PubMed Central

    Waltz, Xavier; Romana, Marc; Lalanne-Mistrih, Marie-Laure; Machado, Roberto F.; Lamarre, Yann; Tarer, Vanessa; Hardy-Dessources, Marie-Dominique; Tressières, Benoît; Divialle-Doumdo, Lydia; Petras, Marie; Maillard, Frederic; Etienne-Julan, Maryse; Connes, Philippe

    2013-01-01

    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-induced hemoglobin oxygen desaturation and the measured parameters. Hemoglobin oxygen desaturation at rest was common in children with sickle cell anemia but not in children with sickle hemoglobin C disease, and was mainly associated with greater hemolysis. Physiological strain during exercise and red blood cell aggregation properties may predict the occurrence of exercise-induced hemoglobin oxygen desaturation in children with sickle cell anemia. PMID:23539539

  12. Mitochondrial dynamics in the mouse liver infected by Schistosoma mansoni.

    PubMed

    Chen, Tina Tu-Wen; Wu, Lawrence Shih Hsin; Hsu, Paul Wei-Che; Pang, Cheng-Yoong; Lee, Kin-Mu; Cheng, Po-Ching; Peng, Shih-Yi

    2015-08-01

    Mitochondrial dynamics is crucial for regulation of cell homeostasis. Schistosoma mansoni is one of the most common parasites known to cause liver disease. Mice infected by S. mansoni show acute symptoms of schistosomiasis after 8 weeks. Hence, in this study, we attempted to assess the direct effects of S. mansoni infection on mice liver, and to explore the expression of mitochondrial morphology, dynamics, and function. Our recent findings show that S. mansoni infection changes mitochondrial morphology and affects mitochondrial functions, which attenuates mitochondrial membrane potential and ATP generation. S. mansoni-infected mice increases mitochondrial numbers by upregulating of genes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor c co-activator 1? (PGC1?) and mitochondrial transcription factor A (Tfam). This may promote mitochondria generation for accelerating the recovery of mitochondrial functions. Moreover, S. mansoni would disrupt mitochondrial dynamics including induced mitochondrial fission and promoted mitochondrial fragmentation in mice liver. More importantly, S. mansoni further stimulated upregulation both extrinsic and intrinsic apoptosis pathway in infected mice liver. The intrinsic pathway was triggered by cytochrome c release. Additionally, NF?B (nuclear factor-kappa B, p65) could play a protective role to inhibit apoptosis through reducing active caspase-3 expression. Therefore, our results confirmed the liver damage mechanism of experimental schistosomiasis in mice model. PMID:25910628

  13. Mitochondrial homeostasis molecules: regulation by a trio of recessive Parkinson's disease genes.

    PubMed

    Han, Ji-Young; Kim, Ji-Soo; Son, Jin H

    2014-12-01

    Mitochondria are small organelles that produce the majority of cellular energy as ATP. Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD), and rare familial forms of PD provide valuable insight into the pathogenic mechanism underlying mitochondrial impairment, even though the majority of PD cases are sporadic. The regulation of mitochondria is crucial for the maintenance of energy-demanding neuronal functions in the brain. Mitochondrial biogenesis and mitophagic degradation are the major regulatory pathways that preserve optimal mitochondrial content, structure and function. In this mini-review, we provide an overview of the mitochondrial quality control mechanisms, emphasizing regulatory molecules in mitophagy and biogenesis that specifically interact with the protein products of three major recessive familial PD genes, PINK1, Parkin and DJ-1. PMID:25548534

  14. Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders

    PubMed Central

    Aiyar, Raeka S.; Bohnert, Maria; Duvezin-Caubet, Stéphane; Voisset, Cécile; Gagneur, Julien; Fritsch, Emilie S.; Couplan, Elodie; von der Malsburg, Karina; Funaya, Charlotta; Soubigou, Flavie; Courtin, Florence; Suresh, Sundari; Kucharczyk, Roza; Evrard, Justine; Antony, Claude; St.Onge, Robert P.; Blondel, Marc; di Rago, Jean-Paul; van der Laan, Martin; Steinmetz, Lars M.

    2014-01-01

    Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce. Identifying molecular intervention points that can be therapeutically targeted remains a major challenge, which we confronted via a screening assay we developed. Using yeast models of mitochondrial ATP synthase disorders, we screened a drug repurposing library, and applied genomic and biochemical techniques to identify pathways of interest. Here we demonstrate that modulating the sorting of nuclear-encoded proteins into mitochondria, mediated by the TIM23 complex, proves therapeutic in both yeast and patient-derived cells exhibiting ATP synthase deficiency. Targeting TIM23-dependent protein sorting improves an array of phenotypes associated with ATP synthase disorders, including biogenesis and activity of the oxidative phosphorylation machinery. Our study establishes mitochondrial protein sorting as an intervention point for ATP synthase disorders, and because of the central role of this pathway in mitochondrial biogenesis, it holds broad value for the treatment of mitochondrial diseases. PMID:25519239

  15. Dynamic adaptation of liver mitochondria to chronic alcohol feeding in mice: biogenesis, remodeling, and functional alterations.

    PubMed

    Han, Derick; Ybanez, Maria D; Johnson, Heather S; McDonald, Jeniece N; Mesropyan, Lusine; Sancheti, Harsh; Martin, Gary; Martin, Alanna; Lim, Atalie M; Dara, Lily; Cadenas, Enrique; Tsukamoto, Hidekazu; Kaplowitz, Neil

    2012-12-01

    Liver mitochondria undergo dynamic alterations following chronic alcohol feeding to mice. Intragastric alcohol feeding to mice resulted in 1) increased state III respiration (109% compared with control) in isolated liver mitochondria, probably due to increased levels of complexes I, IV, and V being incorporated into the respiratory chain; 2) increased mitochondrial NAD(+) and NADH levels (?2-fold), with no change in the redox status; 3) alteration in mitochondrial morphology, with increased numbers of elongated mitochondria; and 4) enhanced mitochondrial biogenesis in the liver, which corresponded with an up-regulation of PGC-1? (peroxisome proliferator-activated receptor ? coactivator-1?). Oral alcohol feeding to mice, which is associated with less liver injury and steatosis, slightly enhanced respiration in isolated liver mitochondria (30.8% compared with control), lower than the striking increase caused by intragastric alcohol feeding. Mitochondrial respiration increased with both oral and intragastric alcohol feeding despite extensive N-acetylation of mitochondrial proteins. The alcohol-induced mitochondrial alterations are probably an adaptive response to enhance alcohol metabolism in the liver. Isolated liver mitochondria from alcohol-treated mice had a greater rate of acetaldehyde metabolism and respiration when treated with acetaldehyde than control. Aldehyde dehydrogenase-2 levels were unaltered in response to alcohol, suggesting that the greater acetaldehyde metabolism by isolated mitochondria from alcohol-treated mice was due to increased mitochondrial respiration that regenerated NAD(+), the rate-limiting substrate in alcohol/acetaldehyde metabolism. Overall, our work suggests that mitochondrial plasticity in the liver may be an important adaptive response to the metabolic stress caused by alcohol intake and could potentially play a role in many other vital functions performed by the liver. PMID:23086958

  16. Posttranslational regulation of the scaffold for Fe-S cluster biogenesis, Isu.

    PubMed

    Andrew, Amy J; Song, Ji-Yoon; Schilke, Brenda; Craig, Elizabeth A

    2008-12-01

    Isu, the scaffold protein on which Fe-S clusters are built in the mitochondrial matrix, plays a central role in the biogenesis of Fe-S cluster proteins. We report that the reduction in the activity of several components of the cluster biogenesis system, including the specialized Hsp70 Ssq1, causes a 15-20-fold up-regulation of Isu. This up-regulation results from changes at both the transcriptional and posttranslational level: an increase in ISU mRNA levels and in stability of ISU protein. Its biological importance is demonstrated by the fact that cells lacking Ssq1 grow poorly when Isu levels are prevented from rising above those found in wild-type cells. Of the biogenesis factors tested, Nfs1, the sulfur donor, was unique. Little increase in Isu levels occurred when Nfs1 was depleted. However, its presence was required for the up-regulation caused by reduction in activity of other components. Our results are consistent with the existence of a mechanism to increase the stability of Isu, and thus its level, that is dependent on the presence of the cysteine desulfurase Nfs1. PMID:18843040

  17. Dense-Core Secretory Granule Biogenesis

    NSDL National Science Digital Library

    Taeyoon Kim (National Institutes of Health Section on Cellular Neurobiology, National Institute of Child Health and Human Development)

    2006-04-01

    The dense-core secretory granule is a key organelle for secretion of hormones and neuropeptides in endocrine cells and neurons, in response to stimulation. Cholesterol and granins are critical for the assembly of these organelles at the trans-Golgi network, and their biogenesis is regulated quantitatively by posttranscriptional and posttranslational mechanisms.

  18. Food-dependent exercise-induced anaphylaxis to lentil and anaphylaxis to chickpea in a 17-year-old boy.

    PubMed

    Orhan, F; Karakas, T

    2008-01-01

    We report the case of a 17-year-old boy who experienced 4 episodes of exercise-induced anaphylactic reaction after ingestion of lentil and 2 episodes of anaphylaxis following ingestion of chickpea. His medical history revealed that he had allergic rhinitis with positive results after skin prick tests (SPT) with mites. His SPTs and specific immunoglobulin E antibody testing with lentil and chickpea were positive. Oral challenge with chickpea was not performed due to patient refusal. Treadmill exercise challenge tests in the fasting state and 1 hour after a meal not containing lentil were negative. However, an exercise challenge test 1 hour after intake of lentil soup resulted in pruritus of the hands, forearms, shoulders, and back, urticarial lesions on the face and shoulders, mild angioedema of the lips, and mild hoarseness and cough. To our knowledge, this is the first case of food-dependent exercise-induced anaphylaxis due to lentil. PMID:19123439

  19. Cold- and exercise-induced peak metabolic rates in tropical birds

    PubMed Central

    Wiersma, Popko; Chappell, Mark A.; Williams, Joseph B.

    2007-01-01

    Compared with temperate birds, tropical birds have low reproductive rates, slow development as nestlings, and long lifespans. These “slow” life history traits are thought to be associated with reduced energy expenditure, or a slow “pace of life.” To test predictions from this hypothesis, we measured exercise-induced peak metabolic rates (PMRE) in 45 species of tropical lowland forest birds and compared these data with PMRE for three temperate species. We also compared cold-induced PMR (PMRC) with PMRE in the same individuals of 19 tropical species. Tropical birds had a 39% lower PMRE than did the temperate species. In tropical birds, PMRC and PMRE scaled similarly with body mass (Mb), but PMRE was 47% higher than PMRC. PMRE averaged 6.44 × basal metabolic rate (BMR) and PMRC averaged 4.52 × BMR. The slope of the equation relating PMRE to Mb exceeded the slope for the equation for BMR vs. Mb, whereas slopes for the equations of PMRC and BMR vs. Mb did not differ. Mb-adjusted residuals of PMRE were positively correlated with residual BMR, whereas residual PMRC and residual BMR were not correlated. PMRE and PMRC were not correlated after we corrected for Mb. Temperate birds maintained their body temperature at an 8.6°C lower average air temperature than did tropical species. The lower PMRE values in tropical species suggest that their suite of life history traits on the slow end of the life history continuum are associated with reduced metabolic rates. PMID:18093954

  20. Wheat-dependent exercise-induced anaphylaxis sensitized with hydrolyzed wheat protein in soap.

    PubMed

    Chinuki, Yuko; Morita, Eishin

    2012-12-01

    Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy typically induced by exercise after ingestion of wheat products. Wheat ?-5 gliadin is a major allergen associated with conventional WDEIA, and detection of serum immunoglobulin E (IgE) specific to recombinant ?-5 gliadin is a reliable method for its diagnosis. Recently, an increased incidence of a new subtype of WDEIA, which is likely to be sensitized via a percutaneous and/or rhinoconjunctival route to hydrolyzed wheat protein (HWP), has been observed. All of the patients with this new subtype had used the same brand of soap, which contained HWP. Approximately half of these patients developed contact allergy several months later and subsequently developed WDEIA. In each of these patients, contact allergy with soap exposure preceded food ingestion-induced reactions. Other patients directly developed generalized symptoms upon ingestion of wheat products. The predominant observed symptom of the new WDEIA subtype was angioedema of the eyelids; a number of patients developed anaphylaxis. This new subtype of WDEIA has little serum ?-5 gliadin-specific serum IgE. PMID:23093796

  1. Exercise-induced changes in blood minerals, associated proteins and hormones in women athletes.

    PubMed

    Deuster, P A; Kyle, S B; Singh, A; Moser, P B; Bernier, L L; Yu-Yahiro, J A; Schoomaker, E B

    1991-12-01

    The acute effects of prolonged exercise on the body's distribution of trace minerals in women athletes has not been examined. To this end, plasma concentrations of zinc, copper, and iron; erythrocyte zinc (EZn) and copper (ECu); and the associated proteins, ceruloplasmin and transferrin were measured in 38 highly trained women runners under resting conditions and again after running a competitive 26.2 mile marathon. The hormones, cortisol (C), estradiol (E2), prolactin (Prl), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were also measured because of reported effects of hormones on trace mineral distribution. Menstrual status was assessed by questionnaire: 8 women were in the follicular phase, 13 in mid-cycle, 8 in the luteal phase and 9 were amenorrheic (AM). Significant post-race increases were noted for all plasma minerals, associated proteins, and the hormones C and Prl, whereas EZn decreased. No significant changes in ECu, E2, FSH or LH were noted. Menstrual status in terms of cycle phase or amenorrhea did not appear to modify the response. Exercise-induced changes in minerals may reflect release from other tissues and/or changes in the concentration of associated proteins. Whether these changes serve adaptive and/or specific functions during exercise is unknown. PMID:1806733

  2. Role of leukotrienes in exercise-induced bronchoconstriction before and after a pilot rehabilitation training program

    PubMed Central

    El-Akkary, Ibrahim M; Abdel-Fatah, Zeinat El-Khouly; El-Seweify, Mervat El-Sayed; El-Batouti, Gihan A; Aziz, Ekhlas Abdel; Adam, Abdelnasser I

    2013-01-01

    Background Whatever the initial stimulus for the exercise-induced bronchoconstriction (EIB) observed in asthmatic patients after exercise, the final effect is release of bronchoactive mediators, especially cysteinyl leukotrienes. Exercise rehabilitation training programs have been reported to protect against EIB. The exact mechanism(s) involved are not well understood. However, this protective effect may be related to adaptation and better coordination during exercise, depletion of cysteinyl leukotrienes, and/or a sluggish cysteinyl leukotriene response to exercise. The aim of the present work was to test the hypothesis that improvement in the incidence and severity of post-exercise bronchoconstriction after a rehabilitation training program is related to a change in leukotriene levels in response to exercise. Methods Twenty asthmatic children aged 6–12 years and known to develop EIB were enrolled in an exercise training program for 12 weeks. The severity and incidence of EIB before and after training was assessed. Baseline and post-exercise sputum cysteinyl leukotriene levels were assessed before and after the training program. Results The training program offered significant protection against EIB with a concomitant decrease in sputum cysteinyl leukotriene levels in response to exercise. Conclusion A training program can result in depletion and/or a sluggish cysteinyl leukotriene response to exercise and may be responsible for the protective effect of training programs on EIB. It is recommended to use an exercise rehabilitation training program as a complementary tool in the management of bronchial asthma, especially EIB. PMID:23930076

  3. Acute Exercise Induces FGF21 Expression in Mice and in Healthy Humans

    PubMed Central

    Kim, Kook Hwan; Kim, Seong Hun; Min, Young-Ki; Yang, Hun-Mo; Lee, Jeong-Beom; Lee, Myung-Shik

    2013-01-01

    Fibroblast growth factor 21 (FGF21) plays an important role in the regulation of energy homeostasis during starvation and has an excellent therapeutic potential for the treatment of type 2 diabetes in rodents and monkeys. Acute exercise affects glucose and lipid metabolism by increasing glucose uptake and lipolysis. However, it is not known whether acute exercise affects FGF21 expression. Here, we showed that serum FGF21 level is increased in mice after a single bout of acute exercise, and that this is accompanied by increased serum levels of free fatty acid, glycerol and ketone body. FGF21 gene expression was induced in the liver but not in skeletal muscle and white adipose tissue of mice after acute exercise, and further, the gene expression levels of hepatic peroxisome proliferator-activated receptor ? (PPAR?) and activating transcription factor 4 (ATF4) were also increased. In addition, we observed increased FGF21 level in serum of healthy male volunteers performing a treadmill run at 50 or 80% VO2max. These results suggest that FGF21 may also be associated with exercise-induced lipolysis in addition to increased catecholamines and reduced insulin. PMID:23667629

  4. Underweight and overweight men have greater exercise-induced dyspnoea than normal weight men

    PubMed Central

    Ali, Syed a.; Bokhari, Syed S. I.; Khan, Mohammed n.; Ahmad, Hakimuddin r.

    2012-01-01

    Introduction. Persons with high or low body mass index (BMI), involved in clinical or mechanistic trials involving exercise testing, might estimate dyspnoea differently from persons with a normal BMI. Aims. Our objective was to investigate the relationship between BMI and dyspnoea during exercise in normal subjects with varying BMI. Material and methods. A total of 37 subjects undertook progressive exercise testing. Subjects were divided into three groups: underweight (UW), normal weight (NW), and overweight (OW). Dyspnoea was estimated using the visual analogue scale (VAS). Spirometry, maximum voluntary ventilation (MVV), and respiratory muscle strength (RMS) were measured. Results and discussion. The intercept of the VAS/ventilation relationship was significantly higher in NW subjects compared to UW (P = 0.029) and OW subjects (P = 0.040). Relative to the OW group, FVC (P = 0.020), FEV1 (P = 0.024), MVV (P = 0.019), and RMS (P = 0.003) were significantly decreased in the UW group. The greater levels of dyspnoea in UW subjects could possibly be due to decreased RMS. Healthy persons should aim to achieve an optimum BMI range to have the lowest exercise-induced dyspnoea. PMID:22931098

  5. Topical cooling (icing) delays recovery from eccentric exercise-induced muscle damage.

    PubMed

    Tseng, Ching-Yu; Lee, Jo-Ping; Tsai, Yung-Shen; Lee, Shin-Da; Kao, Chung-Lan; Liu, Te-Chih; Lai, Cheng- Hsiu; Harris, M Brennan; Kuo, Chia-Hua

    2013-05-01

    It is generally thought that topical cooling can interfere with blood perfusion and may have positive effects on recovery from a traumatic challenge. This study examined the influence of topical cooling on muscle damage markers and hemodynamic changes during recovery from eccentric exercise. Eleven male subjects (age 20.2 ± 0.3 years) performed 6 sets of elbow extension at 85% maximum voluntary load and randomly assigned to topical cooling or sham groups during recovery in a randomized crossover fashion. Cold packs were applied to exercised muscle for 15 minutes at 0, 3, 24, 48, and 72 hours after exercise. The exercise significantly elevated circulating creatine kinase-MB isoform (CK-MB) and myoglobin levels. Unexpectedly, greater elevations in circulating CK-MB and myoglobin above the control level were noted in the cooling trial during 48-72 hours of the post-exercise recovery period. Subjective fatigue feeling was greater at 72 hours after topical cooling compared with controls. Removal of the cold pack also led to a protracted rebound in muscle hemoglobin concentration compared with controls. Measures of interleukin (IL)-8, IL-10, IL-1?, and muscle strength during recovery were not influenced by cooling. A peak shift in IL-12p70 was noted during recovery with topical cooling. These data suggest that topical cooling, a commonly used clinical intervention, seems to not improve but rather delay recovery from eccentric exercise-induced muscle damage. PMID:22820210

  6. Assessment of eccentric exercise-induced muscle damage of the elbow flexors by tensiomyography.

    PubMed

    Hunter, Angus M; Galloway, Stuart D R; Smith, Iain J; Tallent, Jamie; Ditroilo, Massimiliano; Fairweather, Malcolm M; Howatson, Glyn

    2012-06-01

    Exercise induced muscle damage (EIMD) impairs maximal torque production which can cause a decline in athletic performance and/or mobility. EIMD is commonly assessed by using maximal voluntary contraction (MVC), creatine kinase (CK) and muscle soreness. We propose as an additional technique, tensiomyography (TMG), recently introduced to measure mechanical and muscle contractile characteristics. The purpose of this study was to determine the validity of TMG in detecting changes in maximal torque following EIMD. Nineteen participants performed eccentric elbow flexions to achieve EIMD on the non- dominant arm and used the dominant elbow flexor as a control. TMG parameters, MVC and rate of torque development (RTD) were measured prior to EIMD and repeated for another six consecutive days. Creatine kinase, muscle soreness and limb girth were also measured during this period. Twenty four hours after inducing EIMD, MVC torque, RTD and TMG maximal displacement had significantly (p<0.01) declined by 37%, 44% and 31%, respectively. By day 6 MVC, RTD and TMG recovered to 12%, 24% and 17% of respective pre-EIMD values. In conclusion, as hypothesised TMG maximal displacement significantly followed other standard EIMD responses. This could therefore be useful in detecting muscle damage from impaired muscle function and its recovery following EIMD. PMID:22336641

  7. [Exercised-induced asthma in soccer players ages from 8 to 13 years].

    PubMed

    Sidiropoulou, M; Tsimaras, V; Fotiadou, E; Aggelopoulou-Sakadami, N

    2005-04-01

    The purpose of this study was the detection of exercise induced asthma in soccer players aged 8-13 years. Thirty boys, 8-13 years old participated in the study. They were coming from an athletic team of north of Thessaloniki. The study included clinical examination, administration of a respiratory health questionnaire and the exercise -- free running -- test with spirometric measurements. Spirometric measurements were performed by using a microspirometer, before exercise and 2, 5, 10, 15 and 30 min after a 6 min free running exercise (80 - 90 % max heart rate). The highest forced expiratory volume in one second (FEV (1)) value before exercise was compared with the lowest of post exercise values. The results showed a decline in FEV (1) > 15 % in 12 out of 30 children. Particularly, decline in FEV (1) was present in 1 (11 %) out of 9 children with free personal medical history but positive family history for asthma, in 3 (25 %) out of 12 children with allergies, and in 8 (89 %) out of 9 children with asthma. Symptoms were reported by 9 of 12 children with fall in FEV (1) > 15 %, during the 6 min exercise test, who had no symptoms during the soccer games. Identification of EIA by exercise challenge test in young athletes is a useful component for the diagnosis of bronchial hyperresponsiveness. Similar studies should be performed on older and younger athletes who participate in different sports and games. PMID:15944897

  8. Vascular and central hemodynamic changes following exercise-induced heat stress.

    PubMed

    Lefferts, Wesley K; Heffernan, Kevin S; Hultquist, Eric M; Fehling, Patricia C; Smith, Denise L

    2015-06-01

    This study examined the effects of moderate exercise-induced heat stress (EIHS) on vascular function, central hemodynamic load and indices of coronary perfusion. Vascular-hemodynamic measures were collected in 12 healthy men (aged 22±3 years) pre and post 100 minutes of moderate, intermittent exercise in two randomized conditions: heat stress (HS; wearing firefighter personal protective equipment (PPE)), and no heat stress (NHS; wearing a cooling shirt and equivalent PPE weight). Aortic blood pressure, reflected wave pressure (Pb), systolic (SPTI) and diastolic pressure time-integral (DPTI), and aortic stiffness were assessed before and after each condition. SPTI was significantly greater, and DPTI and Pb were significantly lower for HS-post compared to NHS-post (p<0.05). Pulse wave velocity was not different between conditions. In conclusion, EIHS does not affect aortic stiffness, but increases indices of myocardial work and reduces indices of coronary perfusion which may be related to chronotropic responses to EIHS. The mismatch between oxygen demand and oxygen supply may increase cardiac vulnerability to ischemia during strenuous work in the heat. PMID:25939655

  9. Could a vegetarian diet reduce exercise-induced oxidative stress? A review of the literature.

    PubMed

    Trapp, Denise; Knez, Wade; Sinclair, Wade

    2010-10-01

    Oxidative stress is a natural physiological process that describes an imbalance between free radical production and the ability of the antioxidant defence system of the body to neutralize free radicals. Free radicals can be beneficial as they may promote wound healing and contribute to a healthy immune response. However, free radicals can have a detrimental impact when they interfere with the regulation of apoptosis and thus play a role in the promotion of some cancers and conditions such as cardiovascular disease. Antioxidants are molecules that reduce the damage associated with oxidative stress by counteracting free radicals. Regular exercise is a vital component of a healthy lifestyle, although it can increase oxidative stress. As a typical vegetarian diet comprises a wide range of antioxidant-rich foods, it is plausible that the consumption of these foods will result in an enhanced antioxidant system capable of reducing exercise-induced oxidative stress. In addition, a relationship between a vegetarian diet and lower risks of cardiovascular disease and some cancers has been established. This review explores the current available evidence linking exercise, vegetarians, antioxidants, and oxidative stress. PMID:20845212

  10. Assessment of Eccentric Exercise-Induced Oxidative Stress Using Oxidation-Reduction Potential Markers

    PubMed Central

    Stagos, Dimitrios; Goutzourelas, Nikolaos; Ntontou, Amalia-Maria; Kafantaris, Ioannis; Deli, Chariklia K.; Poulios, Athanasios; Jamurtas, Athanasios Z.; Bar-Or, David; Kouretas, Dimitrios

    2015-01-01

    The aim of the present study was to investigate the use of static (sORP) and capacity ORP (cORP) oxidation-reduction potential markers as measured by the RedoxSYS Diagnostic System in plasma, for assessing eccentric exercise-induced oxidative stress. Nineteen volunteers performed eccentric exercise with the knee extensors. Blood was collected before, immediately after exercise, and 24, 48, and 72?h after exercise. Moreover, common redox biomarkers were measured, which were protein carbonyls, thiobarbituric acid-reactive substances, total antioxidant capacity in plasma, and catalase activity and glutathione levels in erythrocytes. When the participants were examined as one group, there were not significant differences in any marker after exercise. However, in 11 participants there was a high increase in cORP after exercise, while in 8 participants there was a high decrease. Thus, the participants were divided in low cORP group exhibiting significant decrease in cORP after exercise and in high cORP group exhibiting significant increase. Moreover, only in the low cORP group there was a significant increase in lipid peroxidation after exercise suggesting induction of oxidative stress. The results suggested that high decreases in cORP values after exercise may indicate induction of oxidative stress by eccentric exercise, while high increases in cORP values after exercise may indicate no existence of oxidative stress. PMID:25874019

  11. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis.

    PubMed

    Stanford, Kristin I; Middelbeek, Roeland J W; Townsend, Kristy L; Lee, Min-Young; Takahashi, Hirokazu; So, Kawai; Hitchcox, Kristen M; Markan, Kathleen R; Hellbach, Katharina; Hirshman, Michael F; Tseng, Yu-Hua; Goodyear, Laurie J

    2015-06-01

    Exercise training improves whole-body glucose homeostasis through effects largely attributed to adaptations in skeletal muscle; however, training also affects other tissues, including adipose tissue. To determine whether exercise-induced adaptations to adipose tissue contribute to training-induced improvements in glucose homeostasis, subcutaneous white adipose tissue (scWAT) from exercise-trained or sedentary donor mice was transplanted into the visceral cavity of sedentary recipients. Remarkably, 9 days post-transplantation, mice receiving scWAT from exercise-trained mice had improved glucose tolerance and enhanced insulin sensitivity compared with mice transplanted with scWAT from sedentary or sham-treated mice. Mice transplanted with scWAT from exercise-trained mice had increased insulin-stimulated glucose uptake in tibialis anterior and soleus muscles and brown adipose tissue, suggesting that the transplanted scWAT exerted endocrine effects. Furthermore, the deleterious effects of high-fat feeding on glucose tolerance and insulin sensitivity were completely reversed if high-fat-fed recipient mice were transplanted with scWAT from exercise-trained mice. In additional experiments, voluntary exercise training by wheel running for only 11 days resulted in profound changes in scWAT, including the increased expression of ?1,550 genes involved in numerous cellular functions including metabolism. Exercise training causes adaptations to scWAT that elicit metabolic improvements in other tissues, demonstrating a previously unrecognized role for adipose tissue in the beneficial effects of exercise on systemic glucose homeostasis. PMID:25605808

  12. Astragalus membranaceus improves exercise performance and ameliorates exercise-induced fatigue in trained mice.

    PubMed

    Yeh, Tzu-Shao; Chuang, Hsiao-Li; Huang, Wen-Ching; Chen, Yi-Ming; Huang, Chi-Chang; Hsu, Mei-Chich

    2014-01-01

    Astragalus membranaceus (AM) is a popular "Qi-tonifying" herb with a long history of use as a Traditional Chinese Medicine with multiple biological functions. However, evidence for the effects of AM on exercise performance and physical fatigue is limited. We evaluated the potential beneficial effects of AM on ergogenic and anti-fatigue functions following physiological challenge. Male ICR strain mice were randomly assigned to four groups (n = 10 per group) for treatment: (1) sedentary control and vehicle treatment (vehicle control); (2) exercise training with vehicle treatment (exercise control); and (3) exercise training with AM treatment at 0.615 g/kg/day (Ex-AM1) or (4) 3.075 g/kg/day (Ex-AM5). Both the vehicle and AM were orally administered for 6 weeks. Exercise performance and anti-fatigue function were evaluated by forelimb grip strength, exhaustive swimming time, and levels of serum lactate, ammonia, glucose, and creatine kinase after 15-min swimming exercise. Exercise training combined with AM supplementation increased endurance exercise capacity and increased hepatic and muscle glycogen content. AM reduced exercise-induced accumulation of the byproducts blood lactate and ammonia with acute exercise challenge. Moreover, we found no deleterious effects from AM treatment. Therefore, AM supplementation improved exercise performance and had anti-fatigue effects in mice. It may be an effective ergogenic aid in exercise training. PMID:24595275

  13. Hyperpolarized Helium-3 MRI of Exercise-Induced Bronchoconstriction During Challenge and Therapy

    PubMed Central

    Kruger, Stanley J; Niles, David J; Dardzinski, Bernard; Harman, Amy; Jarjour, Nizar N; Ruddy, Marcella; Nagle, Scott K; Francois, Christopher J; Sorkness, Ronald L; Burton, Ryan M; Munoz del Rio, Alejandro; Fain, Sean B

    2013-01-01

    Purpose To investigate the utility of hyperpolarized He-3 MRI for detecting regional lung ventilated volume (VV) changes in response to exercise challenge and leukotriene inhibitor montelukast, human subjects were recruited with Exercise Induced Bronchoconstriction (EIB), a condition described by airway constriction following exercise leading to reduced Forced Expiratory Volume in 1 second (FEV1) coinciding with ventilation defects on hyperpolarized He-3 MRI. Materials and Methods 13 EIB subjects underwent spirometry and He-3 MRI at baseline, post-exercise, and post-recovery at multiple visits. On one visit montelukast was given and on two visits placebo was given. Regional VV was calculated in the apical/basilar dimension, in the anterior/posterior dimension, and for the entire lung volume. The whole lung VV was used as an end-point and compared to spirometry. Results Post-challenge FEV1 dropped with placebo but not with treatment, while post-challenge VV dropped more with placebo than treatment. Sources of variability for VV included region (anterior/posterior), scan, and treatment. VV correlated with FEV1/ Forced Vital Capacity (FVC) and Forced Expiratory Flow between 25%-75% of FVC and showed gravitational dependence after exercise challenge. Conclusion A paradigm testing the response of ventilation to montelukast revealed both a whole-lung and regional response to exercise challenge and therapy in EIB subjects. PMID:24006239

  14. The dynamics of physical exercise-induced increases in thalamic and abdominal temperatures are modified by central cholinergic stimulation.

    PubMed

    Damasceno, William Coutinho; Pires, Washington; Lima, Milene Rodrigues Malheiros; Lima, Nilo Resende Viana; Wanner, Samuel Penna

    2015-03-17

    Evidence has shown that brain and abdominal (T abd) temperatures are regulated by distinct physiological mechanisms. Thus, the present study examined whether central cholinergic stimulation would change the dynamics of exercise-induced increases in T abd and thalamic temperature (T thal), an index of brain temperature. Adult male Wistar rats were used in all of the experiments. Two guide cannulae were implanted in the rats, one in the thalamus and the other in the right lateral cerebral ventricle, to measure T thal and to centrally inject a cholinergic agonist, respectively. Then, a temperature sensor was implanted in the abdominal cavity. On the day of the experiments, the rats received an intracerebroventricular injection of 2 ?L of 10(-2)M physostigmine (Phy) or a vehicle solution (Veh) and were subjected to treadmill running until volitional fatigue occurred. T thal was measured using a thermistor connected to a multimeter, and T abd was recorded by telemetry. Phy injection delayed the exercise-induced increases in T thal (37.6 ± 0.2°C Phy vs 38.7 ± 0.1°C Veh at the 10th min of exercise) and in T abd. Despite the delayed hyperthermia, Phy did not change the rats' physical performance. In addition, the more rapid exercise-induced increase in T thal relative to Tabd in the rats treated with Veh was abolished by Phy. Collectively, our data indicate that central cholinergic stimulation affects the dynamics of exercise-induced increases in T thal and T abd. These results also provide evidence of the involvement of cholinoceptors in the modulation of brain heat loss during physical exercise. PMID:25655022

  15. Exercise-induced lipid mobilization in subcutaneous adipose tissue is mainly related to natriuretic peptides in overweight men.

    PubMed

    Moro, Cedric; Pillard, Fabien; de Glisezinski, Isabelle; Klimcakova, Eva; Crampes, Francois; Thalamas, Claire; Harant, Isabelle; Marques, Marie-Adeline; Lafontan, Max; Berlan, Michel

    2008-08-01

    Involvement of sympathetic nervous system and natriuretic peptides in the control of exercise-induced lipid mobilization was compared in overweight and lean men. Lipid mobilization was determined using local microdialysis during exercise. Subjects performed 35-min exercise bouts at 60% of their maximal oxygen consumption under placebo or after oral tertatolol [a beta-adrenergic receptor (AR) antagonist]. Under placebo, exercise increased dialysate glycerol concentration (DGC) in both groups. Phentolamine (alpha-AR antagonist) potentiated exercise-induced lipolysis in overweight but not in lean subjects; the alpha(2)-antilipolytic effect was only functional in overweight men. After tertatolol administration, the DGC increased similarly during exercise no matter which was used probe in both groups. Compared with the control probe under placebo, lipolysis was reduced in lean but not in overweight men treated with the beta-AR blocker. Tertatolol reduced plasma nonesterified fatty acids and insulin concentration in both groups at rest. Under placebo or tertatolol, the exercise-induced changes in plasma nonesterified fatty acids, glycerol, and insulin concentrations were similar in both groups. Exercise promoted a higher increase in catecholamine and ANP plasma levels after tertatolol administration. In conclusion, the major finding of our study is that in overweight men, in addition to an increased alpha(2)-antilipolytic effect, the lipid mobilization in subcutaneous adipose tissue that persists during exercise under beta-blockade is not dependent on catecholamine action. On the basis of correlation findings, it seems to be related to a concomitant exercise-induced rise in plasma ANP when exercise is performed under tertatolol intake and a decrease in plasma insulin. PMID:18559985

  16. Resistance Training Lowers Exercise-Induced Oxidative Stress and Homocysteine Levels in Overweight and Obese Older Adults

    Microsoft Academic Search

    Heather K. Vincent; Cheryl Bourguignon; Kevin R. Vincent

    2006-01-01

    Objective: To compare exercise-induced oxidative stress and levels of homocysteine and cholesterol in normal-weight and overweight older adults after resistance exercise (RX).Research Methods and Procedures: This interventional study was conducted at a wellness center. Forty-nine older adults (age range, 60 to 72 years) were stratified by BMI (<25 kg\\/m2 normal weight, ?25 kg\\/m2 overweight\\/obese) and then randomly assigned to either

  17. Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain

    Microsoft Academic Search

    Joel P. French; Karyn L. Hamilton; John C. Quindry; Youngil Lee; Patrick A. Upchurch; Scott K. Powers

    2008-01-01

    Exercise provides protection against myo- cardial ischemia-reperfusion (IR) injury. Understanding the mechanisms of this protection may lead to new interventions for the prevention and\\/or treatment of heart disease. Although presently these mechanisms are not well understood, reports suggest that manganese superoxide dismutase (MnSOD) and calpain may be critical mediators of this protection. We hypothesized that an exercise-induced increase in MnSOD

  18. Exercise Induces Isoform-Specific Increase in 5?AMP-Activated Protein Kinase Activity in Human Skeletal Muscle

    Microsoft Academic Search

    Nobuharu Fujii; Tatsuya Hayashi; Michael F. Hirshman; Jeremy T. Smith; Susan A. Habinowski; Lennart Kaijser; James Mu; Olle Ljungqvist; Morris J. Birnbaum; Lee A. Witters; Anders Thorell; Laurie J. Goodyear

    2000-01-01

    The 5?AMP-activated protein kinase (AMPK) is stimulated by contractile activity in rat skeletal muscle. AMPK has emerged as an important signaling intermediary in the regulation of cell metabolism being linked to exercise-induced changes in muscle glucose and fatty acid metabolism. In the present study, we determined the effects of exercise on isoform-specific AMPK activity (?1 and ?2) in human skeletal

  19. Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle.

    PubMed

    Ikeda, Shin-ichi; Tamura, Yoshifumi; Kakehi, Saori; Takeno, Kageumi; Kawaguchi, Minako; Watanabe, Takahiro; Sato, Fumihiko; Ogihara, Takeshi; Kanazawa, Akio; Fujitani, Yoshio; Kawamori, Ryuzo; Watada, Hirotaka

    2013-11-01

    Exercise enhances insulin sensitivity in skeletal muscle, but the underlying mechanism remains obscure. Recent data suggest that alternatively activated M2 macrophages enhance insulin sensitivity in insulin target organs such as adipose tissue and liver. Therefore, the aim of this study was to determine the role of anti-inflammatory M2 macrophages in exercise-induced enhancement of insulin sensitivity in skeletal muscle. C57BL6J mice underwent a single bout of treadmill running (20 m/min, 90 min). Twenty-four hours later, ex vivo insulin-stimulated 2-deoxy glucose uptake was found to be increased in plantaris muscle. This change was associated with increased number of CD163-expressing macrophages (i.e. M2-polarized macrophages) in skeletal muscle. Systemic depletion of macrophages by pretreatment of mice with clodronate-containing liposome abrogated both CD163-positive macrophage accumulation in skeletal muscle as well as the enhancement of insulin sensitivity after exercise, without affecting insulin-induced phosphorylation of Akt and AS160 or exercise-induced GLUT4 expression. These results suggest that accumulation of M2-polarized macrophages is involved in exercise-induced enhancement of insulin sensitivity in mouse skeletal muscle, independently of the phosphorylation of Akt and AS160 and expression of GLUT4. PMID:24120496

  20. Molecular mechanisms of cytochrome c biogenesis: three distinct systems.

    PubMed

    Kranz, R; Lill, R; Goldman, B; Bonnard, G; Merchant, S

    1998-07-01

    The past 10 years have heralded remarkable progress in the understanding of the biogenesis of c-type cytochromes. The hallmark of c-type cytochrome synthesis is the covalent ligation of haem vinyl groups to two cysteinyl residues of the apocytochrome (at a Cys-Xxx-Yyy-Cys-His signature motif). From genetic, genomic and biochemical studies, it is clear that three distinct systems have evolved in nature to assemble this ancient protein. In this review, common principles of assembly for all systems and the molecular mechanisms predicted for each system are summarized. Prokaryotes, plant mitochondria and chloroplasts use either system I or II, which are each predicted to use dedicated mechanisms for haem delivery, apocytochrome ushering and thioreduction. Accessory proteins of systems I and II co-ordinate the positioning of these two substrates at the membrane surface for covalent ligation. The third system has evolved specifically in mitochondria of fungi, invertebrates and vertebrates. For system III, a pivotal role is played by an enzyme called cytochrome c haem lyase (CCHL) in the mitochondrial intermembrane space. PMID:9720859

  1. Cellular and molecular mechanisms of mitochondrial function

    PubMed Central

    Osellame, Laura D.; Blacker, Thomas S.; Duchen, Michael R.

    2012-01-01

    Mitochondria are membrane bound organelles present in almost all eukaryotic cells. Responsible for orchestrating cellular energy production, they are central to the maintenance of life and the gatekeepers of cell death. Thought to have originated from symbiotic ancestors, they carry a residual genome as mtDNA encoding 13 proteins essential for respiratory chain function. Mitochondria comprise an inner and outer membrane that separate and maintain the aqueous regions, the intermembrane space and the matrix. Mitochondria contribute to many processes central to cellular function and dysfunction including calcium signalling, cell growth and differentiation, cell cycle control and cell death. Mitochondrial shape and positioning in cells is crucial and is tightly regulated by processes of fission and fusion, biogenesis and autophagy, ensuring a relatively constant mitochondrial population. Mitochondrial dysfunction is implicated in metabolic and age related disorders, neurodegenerative diseases and ischemic injury in heart and brain. PMID:23168274

  2. Development of pharmacological strategies for mitochondrial disorders

    PubMed Central

    Kanabus, M; Heales, S J; Rahman, S

    2014-01-01

    Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date, a variety of treatments have been evaluated by randomized clinical trials, but unfortunately, none of these has delivered breakthrough results. Increased understanding of mitochondrial pathways and the development of many animal models, some of which are accurate phenocopies of human diseases, are facilitating the discovery and evaluation of novel prospective treatments. Targeting reactive oxygen species has been a treatment of interest for many years; however, only in recent years has it been possible to direct antioxidant delivery specifically into the mitochondria. Increasing mitochondrial biogenesis, whether by pharmacological approaches, dietary manipulation or exercise therapy, is also currently an active area of research. Modulating mitochondrial dynamics and mitophagy and the mitochondrial membrane lipid milieu have also emerged as possible treatment strategies. Recent technological advances in gene therapy, including allotopic and transkingdom gene expression and mitochondrially targeted transcription activator-like nucleases, have led to promising results in cell and animal models of mitochondrial diseases, but most of these techniques are still far from clinical application. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24116962

  3. Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto(mito)phagy markers.

    PubMed

    Marques-Aleixo, I; Santos-Alves, E; Balça, M M; Rizo-Roca, D; Moreira, P I; Oliveira, P J; Magalhães, J; Ascensão, A

    2015-08-20

    We here investigate the effects of two exercise modalities (endurance treadmill training-TM and voluntary free-wheel activity-FW) on the brain cortex and cerebellum mitochondrial bioenergetics, permeability transition pore (mPTP), oxidative stress, as well as on proteins involved in mitochondrial biogenesis, apoptosis, and quality control. Eighteen male rats were assigned to sedentary-SED, TM and FW groups. Behavioral alterations and ex vivo brain mitochondrial function endpoints were assessed. Proteins involved in oxidative phosphorylation (OXPHOS, including the adenine nucleotide translocator), oxidative stress markers and regulatory proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn-SOD), as well as proteins involved in mitochondrial biogenesis (PGC1?, TFAM) were evaluated. Apoptotic signaling was measured through quantifying caspase 3, 8 and 9-like activities, Bax, Bcl2, CypD, and cofilin expression. Mitochondrial dynamics (Mfn1/2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin, p62)-related proteins were also measured by Western blotting. Only the TM exercise group showed increased spontaneous alternation and exploratory activity. Both exercise regimens improved mitochondrial respiratory activity, increased OXPHOS complexes I, III and V subunits in both brain subareas and decreased oxidative stress markers. Increased resistance to mPTP and decreased apoptotic signaling were observed in the brain cortex from TM and in the cerebellum from TM and FW groups. Also, exercise increased the expression of proteins involved in mitochondrial biogenesis, autophagy and fusion, simultaneous with decreased expression of mitochondrial fission-related protein DRP1. In conclusion, physical exercise improves brain cortex and cerebellum mitochondrial function, decreasing oxidative stress and apoptotic related markers. It is also possible that favorable alterations in mitochondrial biogenesis, dynamics and autophagy signaling induced by exercise contributed to increased mitochondrial plasticity leading to a more robust phenotype. PMID:26116519

  4. p21{sup WAF1/CIP1} deficiency induces mitochondrial dysfunction in HCT116 colon cancer cells

    SciTech Connect

    Kim, Ae Jeong; Jee, Hye Jin; Song, Naree; Kim, Minjee [Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of) [Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of); Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan (Korea, Republic of); Jeong, Seon-Young [Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan (Korea, Republic of) [Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan (Korea, Republic of); Department of Medical Genetics, Ajou University School of Medicine (Korea, Republic of); Yun, Jeanho, E-mail: yunj@dau.ac.kr [Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of) [Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of); Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan (Korea, Republic of)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer p21{sup -/-} HCT116 cells exhibited an increase in mitochondrial mass. Black-Right-Pointing-Pointer The expression levels of PGC-1{alpha} and AMPK were upregulated in p21{sup -/-} HCT116 cells. Black-Right-Pointing-Pointer The proliferation of p21{sup -/-} HCT116 cells in galactose medium was significantly impaired. Black-Right-Pointing-Pointer p21 may play a role in maintaining proper mitochondrial mass and respiratory function. -- Abstract: p21{sup WAF1/CIP1} is a critical regulator of cell cycle progression. However, the role of p21 in mitochondrial function remains poorly understood. In this study, we examined the effect of p21 deficiency on mitochondrial function in HCT116 human colon cancer cells. We found that there was a significant increase in the mitochondrial mass of p21{sup -/-} HCT116 cells, as measured by 10-N-nonyl-acridine orange staining, as well as an increase in the mitochondrial DNA content. In contrast, p53{sup -/-} cells had a mitochondrial mass comparable to that of wild-type HCT116 cells. In addition, the expression levels of the mitochondrial biogenesis regulators PGC-1{alpha} and TFAM and AMPK activity were also elevated in p21{sup -/-} cells, indicating that p21 deficiency induces the rate of mitochondrial biogenesis through the AMPK-PGC-1{alpha} axis. However, the increase in mitochondrial biogenesis in p21{sup -/-} cells did not accompany an increase in the cellular steady-state level of ATP. Furthermore, p21{sup -/-} cells exhibited significant proliferation impairment in galactose medium, suggesting that p21 deficiency induces a defect in the mitochondrial respiratory chain in HCT116 cells. Taken together, our results suggest that the loss of p21 results in an aberrant increase in the mitochondrial mass and in mitochondrial dysfunction in HCT116 cells, indicating that p21 is required to maintain proper mitochondrial mass and respiratory function.

  5. Prunus mume extract ameliorates exercise-induced fatigue in trained rats.

    PubMed

    Kim, Soyoung; Park, Sung-Hee; Lee, Hye-Nam; Park, Taesun

    2008-09-01

    This study evaluated the effects of Prunus mume extract on exercise-induced fatigue recovery in a trained rat model. Male Sprague-Dawley rats were raised either on a control diet (EC) or on diets supplemented with 0.15% (0.15EP), 0.3% (0.3EP), or 0.9% (0.9EP) Prunus mume extract for 4 weeks (n = 18). Each dietary group was divided into two subgroups; at the end of the experimental period, one subgroup was sacrificed immediately after a 1-hour exercise, and the other subgroup was sacrificed after a 30-minute rest following the exercise (n = 9). Compared to the values for EC rats, serum ammonia concentration was significantly lower in 0.3EP and 0.9EP rats that were sacrificed immediately after the exercise-loading and in 0.15EP, 0.3EP and 0.9EP rats that were sacrificed after a 30-minute rest following the exercise. Compared to that in EC rats, serum lactate levels were significantly lower in rats fed 0.15% or higher levels of P. mume extract when they were sacrificed after a 30-minute rest following the exercise. Dietary supplementation with the P. mume extract significantly elevated hepatic and muscle glycogen concentrations of the rats sacrificed immediately after the exercise. P. mume extract significantly reduced lactate dehydrogenase activity and increased citrate synthase activity in the skeletal muscles of the rats sacrificed immediately after the exercise-loading. Taken together, these results indicate that the P. mume extract administered during endurance exercise training may enhance the oxidative capacity of exercising skeletal muscle and may induce the muscle to prefer fatty acids for its fuel use rather than amino acids or carbohydrates. PMID:18800892

  6. Tertatolol potentiates exercise-induced atrial natriuretic peptide release by increasing atrial diameter in healthy subjects.

    PubMed

    Berlin, I; Deray, G; Lechat, P; Maistre, G; Landault, C; Chermat, V; Brouard, R; Ressayre, C; Puech, A J

    1993-01-01

    To evaluate the contribution of atrial distension and/or adrenergic mechanisms in the regulation of atrial natriuretic peptide (ANP) secretion, plasma immunoreactive ANP, norepinephrine (NE), epinephrine (E), and left atrial diameter were measured at rest, during, and after graded upright standardised bicycle exercise in 8 healthy male subjects after single-dose administration of placebo, tertatolol (5 mg), prazosin (1 mg), or combination of tertatolol (5 mg) and prazosin (1 mg). Systolic and diastolic left atrial diameters were measured before, during, and just after exercise by bidimensional echocardiography. Exercise raised plasma ANP concentrations. This rise was greater on tertatolol alone and tertatolol and prazosin than on placebo or prazosin alone: mean area under the plasma ANP concentration curve increased by 35% on tertatolol alone, 45% on tertatolol and prazosin when compared with placebo (p < 0.01), and by 82 and 94%, respectively, when compared with prazosin alone (p < 0.01). The rise in plasma ANP was greater during the postexercise period: 80% for tertatolol alone, 67% for tertatolol and prazosin when compared with placebo (p < 0.01) and 133 and 115%, respectively, when compared with prazosin alone (p < 0.01). The rise in plasma ANP was accompanied by an increase in both systolic and diastolic atrial diameters which was significantly greater on tertatolol alone and on the tertatolol and prazosin combination than on placebo or prazosin alone (p < 0.001). Beta-blockade alone did not affect plasma catecholamine concentrations but exercise-induced increase in plasma NE was significantly potentiated by prazosin and the prazosin and tertatolol combination, and that of plasma E by the prazosin and tertatolol combination.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7903211

  7. Is lactic acidosis a cause of exercise induced hyperventilation at the respiratory compensation point?

    PubMed Central

    Meyer, T; Faude, O; Scharhag, J; Urhausen, A; Kindermann, W

    2004-01-01

    Objectives: The respiratory compensation point (RCP) marks the onset of hyperventilation ("respiratory compensation") during incremental exercise. Its physiological meaning has not yet been definitely determined, but the most common explanation is a failure of the body's buffering mechanisms which leads to metabolic (lactic) acidosis. It was intended to test this experimentally. Methods: During a first ramp-like exercise test on a cycle ergometer, RCP (range: 2.51–3.73 l*min–1 oxygen uptake) was determined from gas exchange measurements in five healthy subjects (age 26–42; body mass index (BMI) 20.7–23.9 kg*m–2; VO2peak 51.3–62.1 ml*min–1*kg–1). On the basis of simultaneous determinations of blood pH and base excess, the necessary amount of bicarbonate to completely buffer the metabolic acidosis was calculated. This quantity was administered intravenously in small doses during a second, otherwise identical, exercise test. Results: In each subject sufficient compensation for the acidosis, that is, a pH value constantly above 7.37, was attained during the second test. A delay but no disappearance of the hyperventilation was present in all participants when compared with the first test. RCP occurred on average at a significantly (p = 0.043) higher oxygen uptake (+0.15 l*min–1) compared with the first test. Conclusions: For the first time it was directly demonstrated that exercise induced lactic acidosis is causally involved in the hyperventilation which starts at RCP. However, it does not represent the only additional stimulus of ventilation during intense exercise. Muscle afferents and other sensory inputs from exercising muscles are alternative triggering mechanisms. PMID:15388552

  8. Exercise-Induced Wheeze, Urgent Medical Visits, and Neighborhood Asthma Prevalence

    PubMed Central

    Mainardi, Timothy R.; Mellins, Robert B.; Miller, Rachel L.; Acosta, Luis M.; Cornell, Alexandra; Hoepner, Lori; Quinn, James W.; Yan, Beizhan; Chillrud, Steven N.; Olmedo, Omar E.; Perera, Frederica P.; Goldstein, Inge F.; Rundle, Andrew G.; Jacobson, Judith S.

    2013-01-01

    OBJECTIVE: Exercise-induced wheeze (EIW) may identify a distinct population among asthmatics and give insight into asthma morbidity etiology. The prevalence of pediatric asthma and associated urgent medical visits varies greatly by neighborhood in New York City and is highest in low-income neighborhoods. Although increased asthma severity might contribute to the disparities in urgent medical visits, when controlling for health insurance coverage, we previously observed no differences in clinical measures of severity between asthmatic children living in neighborhoods with lower (3%–9%) versus higher (11%–19%) asthma prevalence. Among these asthmatics, we hypothesized that EIW would be associated with urgent medical visits and a child’s neighborhood asthma prevalence. METHODS: Families of 7- to 8-year-old children were recruited into a case-control study of asthma through an employer-based health insurance provider. Among the asthmatics (n = 195), prevalence ratios (PRs) for EIW were estimated. Final models included children with valid measures of lung function, seroatopy, and waist circumference (n = 140). RESULTS: EIW was associated with urgent medical visits for asthma (PR, 2.29; P = .021), independent of frequent wheeze symptoms. In contrast to frequent wheeze, EIW was not associated with seroatopy or exhaled NO, suggesting a distinct mechanism. EIW prevalence among asthmatics increased with increasing neighborhood asthma prevalence (PR, 1.09; P = .012), after adjustment for race, ethnicity, maternal asthma, environmental tobacco smoke, household income, and neighborhood income. CONCLUSIONS: EIW may contribute to the disparities in urgent medical visits for asthma between high- and low-income neighborhoods. Physicians caring for asthmatics should consider EIW an indicator of risk for urgent medical visits. PMID:23248227

  9. Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators.

    PubMed

    Ortega, E; Forner, M A; Barriga, C

    1997-02-01

    1. Exercise provokes changes in the immune system, including macrophage activity. Chemotaxis is a necessary function of macrophages if they are to reach the focus of infection and strenuous acute exercise may modulate chemotaxis. However, the precise mechanisms remain unknown. 2. Three experiments were performed in the present study. (1) The effect of strenuous acute exercise (swimming until exhaustion) on the chemotactic capacity of macrophages was evaluated. (2) Peritoneal macrophages from control mice were incubated with plasma from exercised mice or control (no exercise) mice. The differences in the resulting chemotactic capacity were measured. (3) Changes in the concentration of plasma corticosterone and prolactin after exercise were also measured, and the effect of incubation with the post-exercise levels of plasma corticosterone and prolactin on the chemotactic capacity of the peritoneal macrophages was then studied in vitro. 3. Exercise induced an increase in the macrophage chemotaxis index (103 +/- 8 vs. 47 +/- 11 in controls). Incubation with plasma from exercised mice led to an increased level of chemotaxis (68 +/- 18 vs. 40 +/- 6 with plasma from controls). Incubation with concentrations of corticosterone and prolactin similar to those observed in plasma immediately after exercise (corticosterone, 0.72 mumol l-1; prolactin, 88 pmol l-1) raised the chemotactic capacity with respect to that following incubation with the basal concentrations of the hormones in control animals (90 +/- 9 vs. 37 +/- 4 for corticosterone; 72 +/- 9 vs. 41 +/- 4 for prolactin). 4. It is concluded that corticosterone and prolactin may mediate the increased chemotaxis of peritoneal macrophages induced by exercise. PMID:9051584

  10. Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion.

    PubMed

    Niijima-Yaoita, Fukie; Tsuchiya, Masahiro; Ohtsu, Hiroshi; Yanai, Kazuhiko; Sugawara, Shunji; Endo, Yasuo; Tadano, Takeshi

    2012-01-01

    Exercise necessitates a large supply of O(2) and nutrients and rapid removal of CO(2) and waste products. Histamine is a regulator of the microcirculation (which performs these exchanges), suggesting a possible involvement of histamine in exercise. Histamine is released from either mast cells or non-mast cells. In the latter, histamine is newly formed via the induction of histidine decarboxylase (HDC) in response to an appropriate stimulus, and it is released without being stored. Here, in mice, we examined the role of histamine or HDC induction in exercise. Prolonged walking (PW) (in a cylindrical cage turned electrically) increased HDC mRNA and HDC activity in quadriceps femoris muscles. Mice given a histamine H1-receptor antagonist [fexofenadine (peripherally acting) or pyrilamine (peripherally and centrally acting)] or an irreversible HDC inhibitor (?-fluoromethylhistidine) displayed less PW endurance than control mice. Ranitidine (H2-receptor antagonist) tended to reduce endurance. Other histamine-receptor (H3 and H4) antagonists had no significant effects on endurance. Mice deficient in HDC or histamine H1-receptors displayed markedly less endurance than control mice, and HDC activity in the quadriceps femoris of H1-deficient mice was rapidly elevated by PW. Fexofenadine significantly reduced the muscle levels of nitric oxide (NO) metabolites and glycogen after PW. The results support the ideas that (i) histamine is involved in protecting against exercise-induced fatigue or exhaustion, (ii) histamine exerts its protective effect via H1 receptors and the ensuing production of NO in skeletal muscle, and (iii) histamine is provided, at least in part, by HDC induction in skeletal muscles during prolonged exercise. PMID:22223343

  11. Microarray analyses reveal novel targets of exercise-induced stress resistance in the dorsal raphe nucleus.

    PubMed

    Loughridge, Alice B; Greenwood, Benjamin N; Day, Heidi E W; McQueen, Matthew B; Fleshner, Monika

    2013-01-01

    Serotonin (5-HT) is implicated in the development of stress-related mood disorders in humans. Physical activity reduces the risk of developing stress-related mood disorders, such as depression and anxiety. In rats, 6 weeks of wheel running protects against stress-induced behaviors thought to resemble symptoms of human anxiety and depression. The mechanisms by which exercise confers protection against stress-induced behaviors, however, remain unknown. One way by which exercise could generate stress resistance is by producing plastic changes in gene expression in the dorsal raphe nucleus (DRN). The DRN has a high concentration of 5-HT neurons and is implicated in stress-related mood disorders. The goal of the current experiment was to identify changes in the expression of genes that could be novel targets of exercise-induced stress resistance in the DRN. Adult, male F344 rats were allowed voluntary access to running wheels for 6 weeks; exposed to inescapable stress or no stress; and sacrificed immediately and 2 h after stressor termination. Laser capture micro dissection selectively sampled the DRN. mRNA expression was measured using the whole genome Affymetrix microarray. Comprehensive data analyses of gene expression included differential gene expression, log fold change (LFC) contrast analyses with False Discovery Rate correction, KEGG and Wiki Web Gestalt pathway enrichment analyses, and Weighted Gene Correlational Network Analysis (WGCNA). Our results suggest that physically active rats exposed to stress modulate expression of twice the number of genes, and display a more rapid and strongly coordinated response, than sedentary rats. Bioinformatics analyses revealed several potential targets of stress resistance including genes that are related to immune processes, tryptophan metabolism, and circadian/diurnal rhythms. PMID:23717271

  12. Prenatally induced changes in muscle structure and metabolic function facilitate exercise-induced obesity prevention.

    PubMed

    Huber, Korinna; Miles, Jennifer L; Norman, Amy M; Thompson, Nichola M; Davison, Michael; Breier, Bernhard H

    2009-09-01

    Effective regulation of energy metabolism is vital for the maintenance of optimal health, and an inability to make these dynamic adjustments is a recognized cause of obesity and metabolic disorders. Epidemiological and experimental studies have highlighted the role of prenatal factors in the disease process, and it is now generally accepted that maternal nutrition during pregnancy significantly influences intrauterine development, shaping postnatal health. Consequences of impaired nutrition during fetal development include intrauterine growth restriction (IUGR) and subsequent obesity development in adult life. We have previously shown that prenatal undernutrition has a lasting effect on behavior, with IUGR offspring expressing a higher preference for voluntary exercise, and moderate daily exercise preventing obesity development. The present study investigated skeletal muscle structure in IUGR offspring and how moderate daily exercise drives changes in metabolic pathways that promote obesity prevention. Pregnant Wistar rats were either fed chow ad libitum or undernourished, generating control or IUGR offspring respectively. Although red muscle structure indicated higher oxidative capacity in IUGR offspring, obesity prevention was not due to increased fatty acid oxidation, indicated by decreased peroxisomal proliferator-activated receptor-gamma coactivator 1 and carnitine-palmitoyltransferase 1 expression. In contrast, increased protein kinase Czeta expression and glycogen content in white muscle of exercised IUGR offspring suggests an enhanced capacity for anaerobic utilization of glucose. Furthermore, exercise-induced lactate accumulation was effectively prevented by stimulation of a lactate shuttle, driven by the increases in monocarboxylate transporters-4 and -1 in white muscle. This enhanced metabolic flexibility in IUGR offspring may facilitate muscle contractile performance and therefore support moderate daily exercise for effective obesity prevention. PMID:19477938

  13. Management of exercise-induced glycemic imbalances in type 1 diabetes.

    PubMed

    Francescato, Maria P; Carrato, Sergio

    2011-07-01

    Regular moderate-intensity exercise is strongly recommended for its beneficial effects in all people. In patients with type 1 diabetes, however, the exercise-associated glycemic imbalances remain an unresolved clinical challenge. Current guidelines require an in-depth understanding of the glycemic responses to exercise and each patient has to discover, by trial-and-error, his/her own strategy, several attempts being usually required to gain sufficient experience. Consequently, fear of hypoglycemia remains the strongest barrier to physical activity. This paper explores the potential strategies that may be employed to minimize the risk of exercise related glycemic imbalances. Moreover, a newly developed algorithm (ECRES, Exercise Carbohydrate Requirement Estimating Software) is described, which estimates on a patient- and situation-specific basis the glucose supplement required by the patient to maintain safe blood glucose levels. The algorithm was tested on 27 patients who performed three 1-hr constant intensity walks (each starting at a different time interval following insulin injection). Results showed that in 70.4% of the trials, independent of the time of day, the algorithm provided a satisfactory estimate of the carbohydrates needed by patients to complete the exercise with a glucose level within safe thresholds (i.e. 3.9 - 10 mmol·L-1). Despite the algorithm requires further experimental testing to be applied by the majority of patients, these results indicate its potential usefulness as a tool for preventing immediate exercise-induced glycemic imbalances (i.e. during exercise) in type 1 diabetic patients, in particular for spontaneous activities not planned in advance, thus allowing all insulin-dependent patients to safely enjoy the benefits of exercise. PMID:21682691

  14. Interrupter technique for evaluation of exercise-induced bronchospasm in children.

    PubMed

    Kannisto, S; Vanninen, E; Remes, K; Korppi, M

    1999-03-01

    The free running test is a useful method for evaluation of exercise-induced bronchospasm in children. In young children this test simulates real-life circumstances and can be done more easily than histamine or methacholine challenges. The interrupter technique is a noninvasive method for measuring airflow resistance during tidal breathing. This approach requires minimal cooperation, and is therefore promising for use in young children. Fifty children aged 5-15 years with asthma symptoms were tested by exercise challenge consisting of free outdoor running for 8 min at 85% of maximal predicted heart rate for age. Pulmonary function was measured by using the interrupter technique (IR), with a Wright's peak flow meter (WPEF), and by flow-volume spirometry (FVS). The measurements were done before and 10 min after exercise. In addition, WPEF was measured at 5, 15, and 20 min after exercise. A fall of 15% or more in WPEF associated with wheezing or cough symptoms was considered a positive test. The exercise challenge was positive in 16 (32%) of the 50 children. Measurements at 10 min by WPEF identified 9 positive cases. At the same time point the IR identified 10 positive cases; a rise in resistance of 15% or more was considered positive, giving it 80% sensitivity and 93% specificity. The repeatability coefficient (CoR) for the interrupter technique was 0.06 kPa x L(-1) x s (13%) before and 0.07 kPa x L(-1) x s (14%) after exercise. The IR provides a useful alternative for estimation of airway obstruction in children following exercise challenge. The results were comparable with the current reference methods of forced expiratory volume in 1 s and peak flow measurements. PMID:10213260

  15. Microarray analyses reveal novel targets of exercise-induced stress resistance in the dorsal raphe nucleus

    PubMed Central

    Loughridge, Alice B.; Greenwood, Benjamin N.; Day, Heidi E. W.; McQueen, Matthew B.; Fleshner, Monika

    2013-01-01

    Serotonin (5-HT) is implicated in the development of stress-related mood disorders in humans. Physical activity reduces the risk of developing stress-related mood disorders, such as depression and anxiety. In rats, 6 weeks of wheel running protects against stress-induced behaviors thought to resemble symptoms of human anxiety and depression. The mechanisms by which exercise confers protection against stress-induced behaviors, however, remain unknown. One way by which exercise could generate stress resistance is by producing plastic changes in gene expression in the dorsal raphe nucleus (DRN). The DRN has a high concentration of 5-HT neurons and is implicated in stress-related mood disorders. The goal of the current experiment was to identify changes in the expression of genes that could be novel targets of exercise-induced stress resistance in the DRN. Adult, male F344 rats were allowed voluntary access to running wheels for 6 weeks; exposed to inescapable stress or no stress; and sacrificed immediately and 2 h after stressor termination. Laser capture micro dissection selectively sampled the DRN. mRNA expression was measured using the whole genome Affymetrix microarray. Comprehensive data analyses of gene expression included differential gene expression, log fold change (LFC) contrast analyses with False Discovery Rate correction, KEGG and Wiki Web Gestalt pathway enrichment analyses, and Weighted Gene Correlational Network Analysis (WGCNA). Our results suggest that physically active rats exposed to stress modulate expression of twice the number of genes, and display a more rapid and strongly coordinated response, than sedentary rats. Bioinformatics analyses revealed several potential targets of stress resistance including genes that are related to immune processes, tryptophan metabolism, and circadian/diurnal rhythms. PMID:23717271

  16. The Circadian Clock Coordinates Ribosome Biogenesis

    PubMed Central

    Symul, Laura; Martin, Eva; Atger, Florian; Naef, Felix; Gachon, Frédéric

    2013-01-01

    Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis. PMID:23300384

  17. Erythropoietin Activates Mitochondrial Biogenesis and Couples Red Cell Mass to Mitochondrial Mass in the Heart

    EPA Science Inventory

    RATIONALE: Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia. O...

  18. Membrane biogenesis in anoxygenic photosynthetic prokaryotes

    Microsoft Academic Search

    Gerhart Drews; Robert A. Niederman

    2002-01-01

    Following the discovery of photosynthetic bacteria in the nineteenth century, technical developments of the 1950s led to their\\u000a use in membrane biogenesis studies. These investigations had their origins in the isolation of subcellular particles designated\\u000a as ‘chromatophores’ by Roger Stanier and colleagues, which were shown to be photosynthetically competent by Albert Frenkel,\\u000a and to originate from the intracytoplasmic membrane (ICM)

  19. Anatomy, biogenesis, and regeneration of salivary glands

    PubMed Central

    Holmberg, Kyle V.; Hoffman, Matthew P.

    2014-01-01

    An overview of the anatomy and biogenesis of salivary glands is important in order to understand the physiology, functions and disorders associated with saliva. A major disorder of salivary glands is salivary hypofunction and resulting xerostomia, or dry mouth, which affects hundreds of thousands of patients per year who suffer from salivary gland diseases or undergo head and neck cancer treatment. There is currently no curative therapy for these patients. To improve these patients’ quality of life, new therapies are being developed based on findings in salivary gland cell and developmental biology. Here we discuss the anatomy and biogenesis of the major human salivary glands and the rodent submandibular gland (SMG), which has been used extensively as a research model. We also include a review of recent research on the identification and function of stem cells in salivary glands, and the emerging field of research suggesting nerves play an instructive role during development and may be essential for adult gland repair and regeneration. Understanding the molecular mechanisms involved in gland biogenesis provides a template for regenerating, repairing or reengineering diseased or damaged adult human salivary glands. We provide an overview of three general approaches currently being developed to regenerate damaged salivary tissue, including gene therapy, stem cell-based therapy, and tissue engineering. In the future, it may be that a combination of all three will be used to repair, regenerate and reengineer functional salivary glands in patients to increase the secretion of their saliva, the focus of this monograph. PMID:24862590

  20. Abnormal Synaptic Vesicle Biogenesis in Drosophila Synaptogyrin Mutants

    E-print Network

    Stevens, Robin Jean

    Sustained neuronal communication relies on the coordinated activity of multiple proteins that regulate synaptic vesicle biogenesis and cycling within the presynaptic terminal. Synaptogyrin and synaptophysin are conserved ...

  1. Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle

    PubMed Central

    Roudier, Emilie; Forn, Paul; Perry, Mary Ellen; Birot, Olivier

    2012-01-01

    Exercise-induced angiogenesis is a key determinant of skeletal muscle function. Here, we investigated whether the E3 ubiquitin ligase murine double minute-2 (Mdm2) exerts a proangiogenic function in exercised skeletal muscle. Mdm2 hypomorphic (Mdm2Puro/?7-9) mice have a 60% reduction in Mdm2 expression compared with that in wild-type animals. Capillary staining on muscle sections from Mdm2Puro/?7-9 sedentary mice with a wild-type or knockout background for p53 revealed that deficiency in Mdm2 resulted in 20% capillary regression independently of p53 status. In response to one bout of exercise, protein expression of the proangiogenic vascular endothelial growth factor-A (VEGF-A) was increased by 64% in muscle from wild-type animals, and endothelial cell outgrowth from exercised muscle biopsy samples cultured in a 3-dimensional collagen gel was enhanced by 37%. These proangiogenic responses to exercise were impaired in exercised Mdm2Puro/?7-9 mice. Prolonged exercise training resulted in increased Mdm2 protein expression (+49%) and capillarization (+24%) in wild-type muscles. However, exercise training-induced angiogenesis was abolished in Mdm2Puro/?7-9 mice. Finally, exercise training restored Mdm2, VEGF-A, and capillarization levels in skeletal muscles from obese Zucker diabetic fatty rats compared with those in healthy animals. Our results define Mdm2 as a crucial regulator of capillary maintenance and exercise-induced angiogenesis in skeletal muscle.—Roudier, E., Forn, P., Perry, M. E., Birot, O. Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle. PMID:22835827

  2. Effect of coenzyme Q10 supplementation on exercise-induced response of inflammatory indicators and blood lactate in male runners

    PubMed Central

    Armanfar, Mostafa; Jafari, Afshar; Dehghan, Gholam Reza; Abdizadeh, Leila

    2015-01-01

    Background: Heavy exercise cause muscle damage associated with production of inflammatory agents. The purpose of present study was to determine the effect of acute and 14-day Coenzyme Q10 supplementation on inflammatory, blood lactate and muscle damage in male middle-distance runners. Methods: Eighteen male middle-distance runners in a randomized and quasi experimental study were allocated into two equal groups: supplement group (n=9, Coenzyme Q10: 5mg/kg/day) and placebo group (n= 9, Dextrose: 5mg/kg/day). After acute (1day) and 14-day supplementation, all subjects were participated in a training like running (competitive 3000 meters). Blood samples were obtained in the four phases: one hour before and 18-24 hours after two running protocols. Lactate, serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP) and creatine kinase (CK) were analyzed. Repeated ANOVA and Bonferuni as a post hoc tests were used to determine the changes in four stages. Differences between groups were determined by t-test. Results: The results showed that acute and short-term Coenzyme Q10 supplementation had not significant effect on basal parameters. The acute coenzyme Q10 supplementation attenuated only the exercise-induced increase in response of the plasma CRP. The short-term (14-day) coenzyme Q10 supplementation attenuated the exercise-induced increase in response of the lactate, serum interleukin- 6, tumor necrosis factor-alpha, and CRP in male middle-distance runners. However, the acute and short-term coenzyme Q10 supplementation had not any significant effect on the exerciseinduced increase response of total serum creatine kinase. Conclusion: Based on the present results, it can be concluded that the 14-day coenzyme Q10 supplementation (5mg.kg-1.day-1) is more effective than the acute supplementation to overcome the exercise-induced adverse responses in some oxidative, inflammatory and biochemical parameters. Therefore, short-term coenzyme Q10 supplementation is recommended to reduce exercise-induced adverse consequences.

  3. Mitochondrial genetics

    Microsoft Academic Search

    B. Dujon; M. Bolotin-Fukuhara; D. Coen; J. Deutsch; P. Netter; P. P. Slonimski; L. Weill

    1976-01-01

    1.A series of CS revertants has been selected from various strains (both ?+ and ?-) carrying a CR mitochondrial mutation at the RIB1 locus. The properties of mitochondrial recombination exhibited by these CS revertants in various crosses, have been examined systematically. The ? allele of the CS revertants has been defined in crosses with ?+ and ?- tester strains using

  4. Mitochondrial diseases.

    PubMed

    Lee, Young-Mock

    2012-03-01

    Mitochondria contain the respiratory chain enzyme complexes that carry out oxidative phosphorylation and produce the main part of cellular energy in the form of ATP. Although several proteins related with signalling, assembling, transporting, and enzymatic function can be impaired in mitochondrial diseases, most frequently the activity of the respiratory chain protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. Mitochondrial diseases usually show a chronic, slowly progressive course and present with multiorgan involvement with varying onset between birth and late adulthood. Neuromuscular system is frequently affected in mitochondrial diseases. Although there is actually no specific therapy and cure for mitochondrial diseases, the understanding of the pathophysiology may further facilitate the diagnostic approach and open perspectives to future in mitochondrial diseases. PMID:24649452

  5. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles

    PubMed Central

    Garnier, A; Fortin, D; Deloménie, C; Momken, I; Veksler, V; Ventura-Clapier, R

    2003-01-01

    Congestive heart failure (CHF) induces alterations in energy metabolism and mitochondrial function that span cardiac as well as skeletal muscles. Whether these defects originate from altered mitochondrial DNA copy number and/or mitochondrial gene transcription is not known at present, nor are the factors that control mitochondrial capacity in different muscle types completely understood. We used an experimental model of CHF induced by aortic banding in the rat and investigated mitochondrial respiration and enzyme activity of biochemical mitochondrial markers in cardiac, slow and fast skeletal muscles. We quantified mitochondrial DNA (mtDNA), expression of nuclear (COX IV) and mitochondrial (COX I) encoded cytochrome c oxidase subunits as well as nuclear factors involved in mitochondrial biogenesis and in the necessary coordinated interplay between nuclear and mitochondrial genomes in health and CHF. CHF induced a decrease in oxidative capacity and mitochondrial enzyme activities with a parallel decrease in the mRNA level of COX I and IV, but no change in mtDNA content. The expression of the peroxisome proliferator activated receptor gamma co-activator 1? (PGC-1?) gene was downregulated in CHF, as well as nuclear respiratory factor 2 and mitochondrial transcription factor A, which act downstream from PGC-1?. Most interestingly, only the level of PGC-1? expression was strongly correlated with muscle oxidative capacity in cardiac and skeletal muscles, both in healthy and CHF rats. Mitochondrial gene transcription is reduced in CHF, and PGC-1? appears as a potential modulator of muscle oxidative capacity under these experimental conditions. PMID:12824444

  6. Topical Review: Molecular and Neurologic Findings of Peroxisome Biogenesis Disorders

    Microsoft Academic Search

    Nobuyuki Shimozawa; Tomoko Nagase; Yasuhiko Takemoto; Michinori Funato; Naomi Kondo; Yasuyuki Suzuki

    2004-01-01

    Peroxisomal disorders, an expanding group of genetic disorders in humans, can be grouped into three categories: peroxisome biogenesis disorders, single peroxisomal enzyme deficiencies, and contiguous gene syndrome. At present, 13 complementation groups of peroxisome biogenesis disorders and their responsible genes have been identified, including our newly identified group with a PEX14 defect. We describe neuronal abnormalities related to deficiencies in

  7. Topical Review: Molecular and Neurologic Findings of Peroxisome Biogenesis Disorders

    Microsoft Academic Search

    Nobuyuki Shimozawa; Tomoko Nagase; Yasuhiko Takemoto; Michinori Funato; Naomi Kondo; Yasuyuki Suzuki

    2005-01-01

    Peroxisomal disorders, an expanding group of genetic disorders in humans, can be grouped into three categories: peroxisome biogenesis disorders, single peroxisomal enzyme deficiencies, and contiguous gene syndrome. At present, 13 complementation groups of peroxisome biogenesis disorders and their responsible genes have been identified, including our newly identified group with a PEX14 defect. We describe neuronal abnormalities related to deficiencies in

  8. Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency.

    PubMed

    Ghosh, Alok; Trivedi, Prachi P; Timbalia, Shrishiv A; Griffin, Aaron T; Rahn, Jennifer J; Chan, Sherine S L; Gohil, Vishal M

    2014-07-01

    Mitochondrial respiratory chain biogenesis is orchestrated by hundreds of assembly factors, many of which are yet to be discovered. Using an integrative approach based on clues from evolutionary history, protein localization and human genetics, we have identified a conserved mitochondrial protein, C1orf31/COA6, and shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells. A recent next-generation sequencing study reported potential pathogenic mutations within the evolutionarily conserved Cx?CxnCx??C motif of COA6, implicating it in mitochondrial disease biology. Using yeast coa6? cells, we show that conserved residues in the motif, including the residue mutated in a patient with mitochondrial disease, are essential for COA6 function, thus confirming the pathogenicity of the patient mutation. Furthermore, we show that zebrafish embryos with zfcoa6 knockdown display reduced heart rate and cardiac developmental defects, recapitulating the observed pathology in the human mitochondrial disease patient who died of neonatal hypertrophic cardiomyopathy. The specific requirement of Coa6 for respiratory complex IV biogenesis, its intramitochondrial localization and the presence of the Cx?CxnCx??C motif suggested a role in mitochondrial copper metabolism. In support of this, we show that exogenous copper supplementation completely rescues respiratory and complex IV assembly defects in yeast coa6? cells. Taken together, our results establish an evolutionarily conserved role of Coa6 in complex IV assembly and support a causal role of the COA6 mutation in the human mitochondrial disease patient. PMID:24549041

  9. Endurance exercise induces REDD1 expression and transiently decreases mTORC1 signaling in rat skeletal muscle

    PubMed Central

    Hayasaka, Miki; Tsunekawa, Haruka; Yoshinaga, Mariko; Murakami, Taro

    2014-01-01

    Abstract Working muscle conserves adenosine triphosphate (ATP) for muscle contraction by attenuating protein synthesis through several different pathways. Regulated in development and DNA damage response 1 (REDD1) is one candidate protein that can itself attenuate muscle protein synthesis during muscle contraction. In this study, we investigated whether endurance exercise induces REDD1 expression in association with decreased mammalian target of rapamycin (mTOR) complex I (mTORC1) signaling and global protein synthesis in rat skeletal muscle. After overnight fasting, rats ran on a treadmill at a speed of 28 m/min for 60 min, and were killed before and immediately, 1, 3, 6, 12, and 24 h after exercise. REDD1 mRNA and corresponding protein levels increased rapidly immediately after exercise, and gradually decreased back to the basal level over a period of 6 h in the gastrocnemius muscle. Phosphorylation of mTOR Ser2448 and S6K1 Thr389 increased with the exercise, but diminished in 1–3 h into the recovery period after cessation of exercise. The rate of protein synthesis, as determined by the surface sensing of translation (SUnSET) method, was not altered by exercise in fasted muscle. These results suggest that REDD1 attenuates exercise?induced mTORC1 signaling. This may be one mechanism responsible for blunting muscle protein synthesis during exercise and in the early postexercise recovery period. PMID:25539833

  10. Exercise-Induced Neuroprotection in the Spastic Han Wistar Rat: The Possible Role of Brain-Derived Neurotrophic Factor

    PubMed Central

    Van Kummer, Brooke H.; Cohen, Randy W.

    2015-01-01

    Moderate aerobic exercise has been shown to enhance motor skills and protect the nervous system from neurodegenerative diseases, like ataxia. Our lab uses the spastic Han Wistar rat as a model of ataxia. Mutant rats develop forelimb tremor and hind limb rigidity and have a decreased lifespan. Our lab has shown that exercise reduced Purkinje cell degeneration and delayed motor dysfunction, significantly increasing lifespan. Our study investigated how moderate exercise may mediate neuroprotection by analyzing brain-derived neurotrophic factor (BDNF) and its receptor TrkB. To link BDNF to exercise-induced neuroprotection, mutant and normal rats were infused with the TrkB antagonist K252a or vehicle into the third ventricle. During infusion, rats were subjected to moderate exercise regimens on a treadmill. Exercised mutants receiving K252a exhibited a 21.4% loss in Purkinje cells compared to their controls. Cerebellar TrkB expression was evaluated using non-drug-treated mutants subjected to various treadmill running regimens. Running animals expressed three times more TrkB than sedentary animals. BDNF was quantified via Sandwich ELISA, and cerebellar expression was found to be 26.6% greater in mutant rats on 7-day treadmill exercise regimen compared to 30 days of treadmill exercise. These results suggest that BDNF is involved in mediating exercise-induced neuroprotection. PMID:25710032

  11. Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle.

    PubMed

    Roudier, Emilie; Forn, Paul; Perry, Mary Ellen; Birot, Olivier

    2012-11-01

    Exercise-induced angiogenesis is a key determinant of skeletal muscle function. Here, we investigated whether the E3 ubiquitin ligase murine double minute-2 (Mdm2) exerts a proangiogenic function in exercised skeletal muscle. Mdm2 hypomorphic (Mdm2(Puro/?7-9)) mice have a 60% reduction in Mdm2 expression compared with that in wild-type animals. Capillary staining on muscle sections from Mdm2(Puro/?7-9) sedentary mice with a wild-type or knockout background for p53 revealed that deficiency in Mdm2 resulted in 20% capillary regression independently of p53 status. In response to one bout of exercise, protein expression of the proangiogenic vascular endothelial growth factor-A (VEGF-A) was increased by 64% in muscle from wild-type animals, and endothelial cell outgrowth from exercised muscle biopsy samples cultured in a 3-dimensional collagen gel was enhanced by 37%. These proangiogenic responses to exercise were impaired in exercised Mdm2(Puro/?7-9) mice. Prolonged exercise training resulted in increased Mdm2 protein expression (+49%) and capillarization (+24%) in wild-type muscles. However, exercise training-induced angiogenesis was abolished in Mdm2(Puro/?7-9) mice. Finally, exercise training restored Mdm2, VEGF-A, and capillarization levels in skeletal muscles from obese Zucker diabetic fatty rats compared with those in healthy animals. Our results define Mdm2 as a crucial regulator of capillary maintenance and exercise-induced angiogenesis in skeletal muscle. PMID:22835827

  12. Poxvirus membrane biogenesis: rupture not disruption

    PubMed Central

    Locker, Jacomine Krijnse; Chlanda, Petr; Sachsenheimer, Timo; Brügger, Britta

    2014-01-01

    Summary Enveloped viruses acquire their membrane from the host by budding at, or wrapping by, cellular membranes. Transmission electron microscopy (TEM) images, however, suggested that the prototype member of the poxviridae, vaccinia virus (VACV), may create its membrane ‘de novo’ with free open ends exposed in the cytosol. Within the frame of the German-wide priority programme we re-addressed the biogenesis and origin of the VACV membrane using electron tomography (ET), cryo-EM and lipid analysis of purified VACV using mass spectrometry (MS). This review discussed how our data led to a model of unconventional membrane biogenesis involving membrane rupture and the generation of a single open membrane from open membrane intermediates. Lipid analyses of purified virus by MS suggest an ER origin with a relatively low cholesterol content compared with whole cells, confirming published data. Unlike previous reports using thin-layer chromatography, no depletion of phosphatidylethanolamine was detected. We did detect, however, an enrichment for phosphatidic acid, diacylglycerol and phosphatidylinositol in the virion. Our data are discussed in the light of other pathogens that may require cellular membrane rupture during their intracellular life cycle. PMID:23168015

  13. PI(5)P Regulates Autophagosome Biogenesis

    PubMed Central

    Vicinanza, Mariella; Korolchuk, Viktor I.; Ashkenazi, Avraham; Puri, Claudia; Menzies, Fiona M.; Clarke, Jonathan H.; Rubinsztein, David C.

    2015-01-01

    Summary Phosphatidylinositol 3-phosphate (PI(3)P), the product of class III PI3K VPS34, recruits specific autophagic effectors, like WIPI2, during the initial steps of autophagosome biogenesis and thereby regulates canonical autophagy. However, mammalian cells can produce autophagosomes through enigmatic noncanonical VPS34-independent pathways. Here we show that PI(5)P can regulate autophagy via PI(3)P effectors and thereby identify a mechanistic explanation for forms of noncanonical autophagy. PI(5)P synthesis by the phosphatidylinositol 5-kinase PIKfyve was required for autophagosome biogenesis, and it increased levels of PI(5)P, stimulated autophagy, and reduced the levels of autophagic substrates. Inactivation of VPS34 impaired recruitment of WIPI2 and DFCP1 to autophagic precursors, reduced ATG5-ATG12 conjugation, and compromised autophagosome formation. However, these phenotypes were rescued by PI(5)P in VPS34-inactivated cells. These findings provide a mechanistic framework for alternative VPS34-independent autophagy-initiating pathways, like glucose starvation, and unravel a cytoplasmic function for PI(5)P, which previously has been linked predominantly to nuclear roles. PMID:25578879

  14. PI(5)P regulates autophagosome biogenesis.

    PubMed

    Vicinanza, Mariella; Korolchuk, Viktor I; Ashkenazi, Avraham; Puri, Claudia; Menzies, Fiona M; Clarke, Jonathan H; Rubinsztein, David C

    2015-01-22

    Phosphatidylinositol 3-phosphate (PI(3)P), the product of class III PI3K VPS34, recruits specific autophagic effectors, like WIPI2, during the initial steps of autophagosome biogenesis and thereby regulates canonical autophagy. However, mammalian cells can produce autophagosomes through enigmatic noncanonical VPS34-independent pathways. Here we show that PI(5)P can regulate autophagy via PI(3)P effectors and thereby identify a mechanistic explanation for forms of noncanonical autophagy. PI(5)P synthesis by the phosphatidylinositol 5-kinase PIKfyve was required for autophagosome biogenesis, and it increased levels of PI(5)P, stimulated autophagy, and reduced the levels of autophagic substrates. Inactivation of VPS34 impaired recruitment of WIPI2 and DFCP1 to autophagic precursors, reduced ATG5-ATG12 conjugation, and compromised autophagosome formation. However, these phenotypes were rescued by PI(5)P in VPS34-inactivated cells. These findings provide a mechanistic framework for alternative VPS34-independent autophagy-initiating pathways, like glucose starvation, and unravel a cytoplasmic function for PI(5)P, which previously has been linked predominantly to nuclear roles. PMID:25578879

  15. Atomic Resolution Insights into Curli Fiber Biogenesis

    PubMed Central

    Taylor, Jonathan D.; Zhou, Yizhou; Salgado, Paula S.; Patwardhan, Ardan; McGuffie, Matt; Pape, Tillmann; Grabe, Grzegorz; Ashman, Elisabeth; Constable, Sean C.; Simpson, Peter J.; Lee, Wei-chao; Cota, Ernesto; Chapman, Matthew R.; Matthews, Steve J.

    2011-01-01

    Summary Bacteria produce functional amyloid fibers called curli in a controlled, noncytotoxic manner. These extracellular fimbriae enable biofilm formation and promote pathogenicity. Understanding curli biogenesis is important for appreciating microbial lifestyles and will offer clues as to how disease-associated human amyloid formation might be ameliorated. Proteins encoded by the curli specific genes (csgA-G) are required for curli production. We have determined the structure of CsgC and derived the first structural model of the outer-membrane subunit translocator CsgG. Unexpectedly, CsgC is related to the N-terminal domain of DsbD, both in structure and oxido-reductase capability. Furthermore, we show that CsgG belongs to the nascent class of helical outer-membrane macromolecular exporters. A cysteine in a CsgG transmembrane helix is a potential target of CsgC, and mutation of this residue influences curli assembly. Our study provides the first high-resolution structural insights into curli biogenesis. PMID:21893289

  16. Protective Effects of Myricetin on Acute Hypoxia-Induced Exercise Intolerance and Mitochondrial Impairments in Rats

    PubMed Central

    Zou, Dan; Liu, Peng; Chen, Ka; Xie, Qi; Liang, Xinyu; Bai, Qian; Zhou, Qicheng; Liu, Kai; Zhang, Ting; Zhu, Jundong; Mi, Mantian

    2015-01-01

    Purpose Exercise tolerance is impaired in hypoxia. The aim of this study was to evaluate the effects of myricetin, a dietary flavonoid compound widely found in fruits and vegetables, on acute hypoxia-induced exercise intolerance in vivo and in vitro. Methods Male rats were administered myricetin or vehicle for 7 days and subsequently spent 24 hours at a barometric pressure equivalent to 5000 m. Exercise capacity was then assessed through the run-to-fatigue procedure, and mitochondrial morphology in skeletal muscle cells was observed by transmission electron microscopy (TEM). The enzymatic activities of electron transfer complexes were analyzed using an enzyme-linked immuno-sorbent assay (ELISA). mtDNA was quantified by real-time-PCR. Mitochondrial membrane potential was measured by JC-1 staining. Protein expression was detected through western blotting, immunohistochemistry, and immunofluorescence. Results Myricetin supplementation significantly prevented the decline of run-to-fatigue time of rats in hypoxia, and attenuated acute hypoxia-induced mitochondrial impairment in skeletal muscle cells in vivo and in vitro by maintaining mitochondrial structure, mtDNA content, mitochondrial membrane potential, and activities of the respiratory chain complexes. Further studies showed that myricetin maintained mitochondrial biogenesis in skeletal muscle cells under hypoxic conditions by up-regulating the expressions of mitochondrial biogenesis-related regluators, in addition, AMP-activated protein kinase(AMPK) plays a crucial role in this process. Conclusions Myricetin may have important applications for improving physical performance under hypoxic environment, which may be attributed to the protective effect against mitochondrial impairment by maintaining mitochondrial biogenesis. PMID:25919288

  17. Disconnecting mitochondrial content from respiratory chain capacity in PGC-1 deficient skeletal muscle

    PubMed Central

    Rowe, Glenn C.; Patten, Ian S.; Zsengeller, Zsuzsanna K.; El-Khoury, Riyad; Okutsu, Mitsuharu; Bampoh, Sophia; Koulisis, Nicole; Farrell, Caitlin; Hirshman, Michael F.; Yan, Zhen; Goodyear, Laurie J.; Rustin, Pierre; Arany, Zolt

    2013-01-01

    Summary The transcriptional coactivators PGC-1? and PGC-1? are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. We show here that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration, but surprisingly have preserved mitochondrial content, isolated muscle contraction capacity, fiber type composition, in-cage ambulation, and voluntary running capacity. Most of these findings are recapitulated in cell culture, and thus cell-autonomous. Functional electron microscopy reveals normal cristae density with decreased cytochrome oxidase activity. These data lead to the following surprising conclusions: that PGC-1s are in fact dispensable for baseline muscle function, mitochondrial content, and fiber typing; that endurance fatigue at low workloads is not limited by muscle mitochondrial capacity; and that mitochondrial content and cristae density can be dissociated from respiratory capacity. PMID:23707060

  18. [2Fe-2S] cluster transfer in iron–sulfur protein biogenesis

    PubMed Central

    Banci, Lucia; Brancaccio, Diego; Ciofi-Baffoni, Simone; Del Conte, Rebecca; Gadepalli, Ravisekhar; Mikolajczyk, Maciej; Neri, Sara; Piccioli, Mario; Winkelmann, Julia

    2014-01-01

    Monothiol glutaredoxins play a crucial role in iron–sulfur (Fe/S) protein biogenesis. Essentially all of them can coordinate a [2Fe-2S] cluster and have been proposed to mediate the transfer of [2Fe-2S] clusters from scaffold proteins to target apo proteins, possibly by acting as cluster transfer proteins. The molecular basis of [2Fe-2S] cluster transfer from monothiol glutaredoxins to target proteins is a fundamental, but still unresolved, aspect to be defined in Fe/S protein biogenesis. In mitochondria monothiol glutaredoxin 5 (GRX5) is involved in the maturation of all cellular Fe/S proteins and participates in cellular iron regulation. Here we show that the structural plasticity of the dimeric state of the [2Fe-2S] bound form of human GRX5 (holo hGRX5) is the crucial factor that allows an efficient cluster transfer to the partner proteins human ISCA1 and ISCA2 by a specific protein–protein recognition mechanism. Holo hGRX5 works as a metallochaperone preventing the [2Fe-2S] cluster to be released in solution in the presence of physiological concentrations of glutathione and forming a transient, cluster-mediated protein–protein intermediate with two physiological protein partners receiving the [2Fe-2S] cluster. The cluster transfer mechanism defined here may extend to other mitochondrial [2Fe-2S] target proteins. PMID:24733926

  19. RECQL4 LOCALIZES TO MITOCHONDRIA AND PRESERVES MITOCHONDRIAL DNA INTEGRITY

    PubMed Central

    Croteau, Deborah L.; Rossi, Marie L.; Canugovi, Chandrika; Tian, Jane; Sykora, Peter; Ramamoorthy, Mahesh; Wang, ZhengMing; Singh, Dharmendra Kumar; Akbari, Mansour; Kasiviswanathan, Rajesh; Copeland, William C.; Bohr, Vilhelm A.

    2012-01-01

    SUMMARY RECQL4 is associated with Rothmund-Thomson Syndrome (RTS), a rare autosomal recessive disorder characterized by premature aging, genomic instability and cancer predisposition. RECQL4 is a member of the RecQ-helicase family, and has many similarities to WRN protein, which is also implicated in premature aging. There is no information about whether any of the RecQ helicases play roles in mitochondrial biogenesis, which is strongly implicated in the aging process. Here, we used microscopy to visualize RECQL4 in mitochondria. Fractionation of human and mouse cells also showed that RECQL4 was present in mitochondria. Q-PCR amplification of mitochondrial DNA demonstrated that mtDNA damage accumulated in RECQL4-deficient cells. Microarray analysis suggested that mitochondrial bioenergetic pathways might be affected in RTS. Measurements of mitochondrial bioenergetics showed a reduction in the mitochondrial reserve capacity after lentiviral knockdown of RECQL4 in two different primary cell lines. Additionally, biochemical assays with RECQL4, mitochondrial transcription factor A and mitochondrial DNA polymerase ? showed that the polymerase inhibited RECQL4’s helicase activity. RECQL4 is the first 3? to 5? RecQ helicase to be found in both human and mouse mitochondria and the loss of RECQL4 alters mitochondrial integrity. PMID:22296597

  20. Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN

    PubMed Central

    2012-01-01

    Background Birt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood. Methods Mice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were crossbred with mice harboring either muscle creatine kinase (CKM) –Cre or myogenin (MYOG) –Cre transgenes to knock out FLCN and/or PPARGC1A in muscle, or cadherin 16 (CDH16)– Cre transgenes to knock out FLCN and/or PPARGC1A in kidney. Real-time polymerase chain reaction, immunoblotting, electron microscopy, and metabolic profiling assay were performed to evaluate mitochondrial biogenesis and function in muscle. Immunoblotting, electron microscopy, and histological analysis were used to investigate expression and the pathological role of PPARGC1A in FLCN-deficient kidney. Real-time polymerase chain reaction, oxygen consumption measurement, and flow cytometry were carried out using a FLCN-null kidney cancer cell line. All statistical analyses were two-sided. Results Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation, including increased mitochondrial biogenesis (FLCN f/f vs FLCN f/f /CKM–Cre: % mitochondrial area mean = 7.8% vs 17.8%; difference = 10.0%; 95% confidence interval = 5.7% to 14.3%; P < .001), and the observed increase in mitochondrial biogenesis was PPARGC1A dependent. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppressed mitochondrial metabolism and PPARGC1A expression. Kidney-targeted PPARGC1A inactivation partially rescued the enlarged kidney phenotype and abrogated the hyperplastic cells observed in the FLCN-deficient kidney. Conclusion FLCN deficiency and subsequent increased PPARGC1A expression result in increased mitochondrial function and oxidative metabolism as the source of cellular energy, which may give FLCN-null kidney cells a growth advantage and drive hyperplastic transformation. PMID:23150719

  1. Molecular basis for an attenuated mitochondrial adaptive plasticity in aged skeletal muscle

    PubMed Central

    Ljubicic, Vladimir; Joseph, Anna-Maria; Adhihetty, Peter J.; Huang, Julianna H.; Saleem, Ayesha; Uguccioni, Giulia; Hood, David A.

    2009-01-01

    Our intent was to investigate the mechanisms driving the adaptive potential of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria in young (6 mo) and senescent (36 mo) animals in response to a potent stimulus for organelle biogenesis. We employed chronic electrical stimulation (10 Hz, 3 h/day, 7 days) to induce contractile activity of skeletal muscle in 6 and 36 mo F344XBN rats. Subsequent to chronic activity, acute stimulation (1 Hz, 5 min) in situ revealed greater fatigue resistance in both age groups. However, the improvement in endurance was significantly greater in the young, compared to the old animals. Chronic muscle use also augmented SS and IMF mitochondrial volume to a greater extent in young muscle. The molecular basis for the diminished organelle expansion in aged muscle was due, in part, to the collective attenuation of the chronic stimulation-evoked increase in regulatory proteins involved in mediating mitochondrial protein import and biogenesis. Furthermore, adaptations in mitochondrial function were also blunted in old animals. However, chronic contractile activity evoked greater reductions in mitochondrially-mediated proapoptotic signaling in aged muscle. Thus, mitochondrial plasticity is retained in aged animals, however the magnitude of the changes are less compared to young animals due to attenuated molecular processes regulating organelle biogenesis. PMID:20157569

  2. [Mitochondrial quality control: the target for exercise to promote health and prevent disease].

    PubMed

    Zhao, Yun-Gang; Li, Can; Ding, Shu-Zhe; Zhang, Yong

    2014-10-01

    Regular exercise has been known to have many benefits, for example, improving physical performance, promoting health and preventing chronic diseases such as metabolic diseases. As a very important organelles in eukaryotic cells, mitochondria exhibit superb plasticity in response to exercise. Exercise may promote mitochondrial biogenesis and eliminate the dysfunctional mitochondria via mitophagy in order to maintain the normal function of the mitochondrial network. These dynamic changes keep mitochondria in health state and ensure the energy supply for cells. This review summarized the studies on the regulation of mitochondrial quality control by exercise, and provided a reasonable explanation for exercise to promote health and prevent diseases. PMID:25764790

  3. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.

    PubMed

    Pfeffer, Gerald; Gorman, Gráinne S; Griffin, Helen; Kurzawa-Akanbi, Marzena; Blakely, Emma L; Wilson, Ian; Sitarz, Kamil; Moore, David; Murphy, Julie L; Alston, Charlotte L; Pyle, Angela; Coxhead, Jon; Payne, Brendan; Gorrie, George H; Longman, Cheryl; Hadjivassiliou, Marios; McConville, John; Dick, David; Imam, Ibrahim; Hilton, David; Norwood, Fiona; Baker, Mark R; Jaiser, Stephan R; Yu-Wai-Man, Patrick; Farrell, Michael; McCarthy, Allan; Lynch, Timothy; McFarland, Robert; Schaefer, Andrew M; Turnbull, Douglass M; Horvath, Rita; Taylor, Robert W; Chinnery, Patrick F

    2014-05-01

    Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis. PMID:24727571

  4. Biogenesis and Function of Multivesicular Bodies

    PubMed Central

    Piper, Robert C.; Katzmann, David J.

    2010-01-01

    The two major cellular sites for membrane protein degradation are the proteasome and the lysosome. Ubiquitin attachment is a sorting signal for both degradation routes. For lysosomal degradation, ubiquitination triggers the sorting of cargo proteins into the lumen of late endosomal multivesicular bodies (MVBs)/endosomes. MVB formation occurs when a portion of the limiting membrane of an endosome invaginates and buds into its own lumen. Intralumenal vesicles are degraded when MVBs fuse to lysosomes. The proper delivery of proteins to the MVB interior relies on specific ubiquitination of cargo, recognition and sorting of ubiquitinated cargo to endosomal subdomains, and the formation and scission of cargo-filled intralumenal vesicles. Over the past five years, a number of proteins that may directly participate in these aspects of MVB function and biogenesis have been identified. However, major questions remain as to exactly what these proteins do at the molecular level and how they may accomplish these tasks. PMID:17506697

  5. The autophagosome: origins unknown, biogenesis complex.

    PubMed

    Lamb, Christopher A; Yoshimori, Tamotsu; Tooze, Sharon A

    2013-12-01

    Healthy cells use autophagy as a general 'housekeeping' mechanism and to survive stress, including stress induced by nutrient deprivation. Autophagy is initiated at the isolation membrane (originally termed the phagophore), and the coordinated action of ATG (autophagy-related) proteins results in the expansion of this membrane to form the autophagosome. Although the biogenesis of the isolation membrane and the autophagosome is complex and incompletely understood, insight has been gained into the molecular processes involved in initiating the isolation membrane, the source from which this originates (for example, it was recently proposed that the isolation membrane forms from the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM)) and the role of ATG proteins and the vesicular trafficking machinery in autophagosome formation. PMID:24201109

  6. Exercise-Induced Pulmonary Artery Hypertension in a Patient with Compensated Cardiac Disease: Hemodynamic and Functional Response to Sildenafil Therapy

    PubMed Central

    Nikolaidis, Lazaros; Memon, Nabeel

    2015-01-01

    We describe the case of a 54-year-old man who presented with exertional dyspnea and fatigue that had worsened over the preceding 2 years, despite a normally functioning bioprosthetic aortic valve and stable, mild left ventricular dysfunction (left ventricular ejection fraction, 0.45). His symptoms could not be explained by physical examination, an extensive biochemical profile, or multiple cardiac and pulmonary investigations. However, abnormal cardiopulmonary exercise test results and a right heart catheterization—combined with the use of a symptom-limited, bedside bicycle ergometer—revealed that the patient's exercise-induced pulmonary artery hypertension was out of proportion to his compensated left heart disease. A trial of sildenafil therapy resulted in objective improvements in hemodynamic values and functional class. PMID:25873799

  7. Compensation for a Defective Interaction of the Hsp70 Ssq1 with the Mitochondrial Fe-S Cluster Scaffold Isu*

    E-print Network

    Craig, Elizabeth A

    , Wisconsin 53706 Ssq1, a specialized yeast mitochondrial Hsp70, plays a critical role in the biogenesis and increased iron lev- els and grew similarly to wild-type cells. Consistent with the reduced affinity for Isu in the maturation of the numerous cellular proteins that contain this prosthetic group. In yeast mitochondria

  8. Saxagliptin Restores Vascular Mitochondrial Exercise Response in the Goto-Kakizaki Rat

    PubMed Central

    Keller, Amy C.; Knaub, Leslie A.; Miller, Matthew W.; Birdsey, Nicholas; Klemm, Dwight J.

    2015-01-01

    Abstract: Cardiovascular disease risk and all-cause mortality are largely predicted by physical fitness. Exercise stimulates vascular mitochondrial biogenesis through endothelial nitric oxide synthase (eNOS), sirtuins, and PPAR? coactivator 1? (PGC-1?), a response absent in diabetes and hypertension. We hypothesized that an agent regulating eNOS in the context of diabetes could reconstitute exercise-mediated signaling to mitochondrial biogenesis. Glucagon-like peptide 1 (GLP-1) stimulates eNOS and blood flow; we used saxagliptin, an inhibitor of GLP-1 degradation, to test whether vascular mitochondrial adaptation to exercise in diabetes could be restored. Goto-Kakizaki (GK) rats, a nonobese, type 2 diabetes model, and Wistar controls were exposed to an 8-day exercise intervention with or without saxagliptin (10 mg·kg?1·d?1). We evaluated the impact of exercise and saxagliptin on mitochondrial proteins and signaling pathways in aorta. Mitochondrial protein expression increased with exercise in the Wistar aorta and decreased or remained unchanged in the GK animals. GK rats treated with saxagliptin plus exercise showed increased expression of mitochondrial complexes, cytochrome c, eNOS, nNOS, PGC-1?, and UCP3 proteins. Notably, a 3-week saxagliptin plus exercise intervention significantly increased running time in the GK rats. These data suggest that saxagliptin restores vascular mitochondrial adaptation to exercise in a diabetic rodent model and may augment the impact of exercise on the vasculature. PMID:25264749

  9. Changes in liver mitochondrial plasticity induced by brain tumor

    PubMed Central

    Pouliquen, Daniel; Olivier, Christophe; Debien, Emilie; Meflah , Khaled; Vallette, François M; Menanteau, Jean

    2006-01-01

    Background Accumulating data suggest that liver is a major target organ of systemic effects observed in the presence of a cancer. In this study, we investigated the consequences of the presence of chemically induced brain tumors in rats on biophysical parameters accounting for the dynamics of water in liver mitochondria. Methods Tumors of the central nervous system were induced by intraveinous administration of ethylnitrosourea (ENU) to pregnant females on the 19th day of gestation. The mitochondrial crude fraction was isolated from the liver of each animal and the dynamic parameters of total water and its macromolecule-associated fraction (structured water, H2Ost) were calculated from Nuclear Magnetic Resonance (NMR) measurements. Results The presence of a malignant brain tumor induced a loss of water structural order that implicated changes in the physical properties of the hydration shells of liver mitochondria macromolecules. This feature was linked to an increase in the membrane cholesterol content, a way to limit water penetration into the bilayer and then to reduce membrane permeability. As expected, these alterations in mitochondrial plasticity affected ionic exchanges and led to abnormal features of mitochondrial biogenesis and caspase activation. Conclusion This study enlightens the sensitivity of the structured water phase in the liver mitochondria machinery to external conditions such as tumor development at a distant site. The profound metabolic and functional changes led to abnormal features of ion transport, mitochondrial biogenesis and caspase activation. PMID:17018136

  10. Role of brain macrophages on IL-1beta and fatigue following eccentric exercise-induced muscle damage.

    PubMed

    Carmichael, Martin D; Davis, J Mark; Murphy, E Angela; Carson, James A; Van Rooijen, N; Mayer, Eugene; Ghaffar, Abdul

    2010-05-01

    Fatigue associated with recovery from muscle damage has recently been linked to increases in brain and muscle proinflammatory cytokines. However, little is known regarding the origin of these cytokines. Since macrophage-like cells in the brain are a primary source of cytokines, we used a brain specific macrophage depletion technique involving liposome encapsulated clodronate (CLD) to examine the role of macrophages on brain IL-1beta and fatigue following eccentric exercise-induced muscle damage. Mice were assigned to six groups: Downhill saline (DWNSAL), downhill clodronate (DWNCLD), uphill saline (UPSAL), uphill clodronate (UPCLD), non-running saline (CONSAL) or non-running clodronate (CONCLD). Mice were given intracerebroventricular (ICV) (10 microL) injections of clodronate-filled liposomes (CLD) to deplete macrophages, or saline-filled liposomes (SAL) and run on a treadmill at 22m/min and -14% (DWN) or 14% (UP) grade for 150 min. A subset of uphill and downhill running mice (n=40) was then run to fatigue on a treadmill at 36m/min, 8% grade at 24h after the uphill and downhill runs. A second subset of uphill, downhill, and control mice (n=30) was sacrificed 24h after the run for analysis of brain IL-1beta concentration. Histological examination confirmed previous reports that CLD administration reduced perivascular and meningeal macrophage subsets in the brain. CLD reduced IL-1beta concentration in the cortex of DWN mice (P<0.05), which was associated with enhanced treadmill performance 24h after both uphill and downhill runs (P<0.05) although the magnitude was greater following the downhill run. These results suggest that brain macrophages can contribute to the increase in brain IL-1beta and fatigue that are associated with recovery from exercise-induced muscle damage. PMID:20051263

  11. Effects of propranolol and nifedipine on exercise-induced attack in patients variant angina: assessment by exercise thallium-201 myocardial scintigraphy with quantitative rotational tomography

    SciTech Connect

    Kugiyama, K.; Yasue, H.; Horio, Y.; Morikami, Y.; Fujii, H.; Koga, Y.; Kojima, A.; Takahashi, M.

    1986-08-01

    To examine the effects of propranolol and nifedipine on exercise-induced attack in patients with variant angina, exercise /sup 201/Tl myocardial scintigraphy with quantitative analysis by emission-computed tomography was performed in 20 patients with variant angina after oral propranolol (80 mg), nifedipine (20 mg), and placebo. Exercise-induced attack occurred in 11 patients on placebo, in 14 on propranolol, and in none on nifedipine. The exercise duration was significantly shorter in those on propranolol (p less than .05), but significantly longer in patients on nifedipine (p less than .05) than in those on placebo. The peak rate-pressure product was significantly lower in patients on propranolol (p less than .01), but did not change in those on nifedipine, as compared with that in patients on placebo. The size of the perfusion defect as measured by /sup 201/Tl tomography was significantly greater in patients on propranolol (p less than .05), but significantly less in those on nifedipine (p less than .01) than in those on placebo. In conclusion, propranolol does not suppress but rather may aggravate exercise-induced attack in patients with variant angina, while nifedipine suppresses it. This unfavorable effect of propranolol on exercise-induced attack in patients with variant angina is likely to be due to a reduction of regional myocardial blood flow.

  12. CHROMIUM PICOLINATE AND CONJUGATED LINOLEIC ACID: EFFECTS ON DIET AND EXERCISE-INDUCED CHANGES IN METABOLIC AND CARDIOVASCULAR HEALTH INDEXES IN OVERWEIGHT WOMEN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study assessed the combined effects of chromium picolinate (CP) and conjugated linoleic acid (CLA) on energy-restriction and exercise-induced changes in body composition, glucose metabolism, lipid-lipoprotein profile, and blood pressure in overweight and obese, pre-menopausal women. For 12 wk,...

  13. Reduction in Obesity and Related Comorbid Conditions after Diet-Induced Weight Loss or Exercise-Induced Weight Loss in Men A Randomized, Controlled Trial

    Microsoft Academic Search

    Robert Ross; Damon Dagnone; Peter J. H. Jones; Heidi Smith; Anne Paddags; Robert Hudson; Ian Janssen

    Background: The independent effects of diet- or exercise-induced weight loss on the reduction of obesity and related comorbid conditions are not known. The effects of exercise without weight loss on fat distribution and other risk factors are also unclear. Objective: To determine the effects of equivalent diet- or exer- cise-induced weight loss and exercise without weight loss on subcutaneous fat,

  14. History of amenorrhoea compromises some of the exercise-induced benefits in cortical and trabecular bone in the peripheral and axial skeleton: A study in retired elite gymnasts

    Microsoft Academic Search

    G. Ducher; P. Eser; B. Hill; S. Bass

    2009-01-01

    BackgroundFemale gymnasts frequently present with overt signs of hypoestrogenism, such as late menarche or menstrual dysfunction. The objective was to investigate the impact of history of amenorrhoea on the exercise-induced skeletal benefits in bone geometry and volumetric density in retired elite gymnasts.

  15. Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees

    Microsoft Academic Search

    M. Davis; R. Brown; A. Dickson; H. Horton; D. James; N. Laing; R. Marston; M. Norgate; D. Perlman; N. Pollock; K. Stowell

    2002-01-01

    Malignant hyperthermia (MH) is rarely associated with specific myopathies or musculoskeletal abnormalities. Three clinical investigations of MH associated with either non-specific myopa- thies or congenital disorders in three separate families are presented. Two of these cases also show evidence of exercise-induced rhabdomyolysis. In each case MH susceptibility was con- firmed by in vitro contracture testing of quadriceps muscle. DNA sequence

  16. Chromium picolinate and conjugated linoleic acid do not synergistically influence diet- and exercise-induced changes in body composition and health indexes in overweight women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: This study assessed the effects of combined chromium picolinate (CP) and conjugated linoleic acid (CLA) supplementation on energy-restriction and exercise-induced changes in body composition, glucose metabolism, lipid-lipoprotein profile, and blood pressure in overweight, pre-menopausal w...

  17. Relation of the hypertonic saline responsiveness of the airways to exercise induced asthma symptom severity and to histamine or methacholine reactivity

    Microsoft Academic Search

    H K Makker; S T Holgate

    1993-01-01

    BACKGROUND: Conflicting views exist over whether responsiveness of the airways to hypertonic saline relates to non-specific bronchial hyperresponsiveness measured by histamine or methacholine challenge. The bronchoconstrictor responses to exercise and hypertonic saline are reported to be closely related, but the relationship between the symptoms of exercise induced asthma and airway responsiveness to hypertonic saline is not known. METHODS: In 29

  18. Evaluación endoscópica de hemorragia pulmonar inducida por el ejercicio en equinos de polo Endoscopic evaluation of Exercise Induced Pulmonary Hemorrhage in Polo Ponies

    Microsoft Academic Search

    G. MORAN; R. CARRILLO; B. CAMPOS; C. GARCIA; Olivares N

    2003-01-01

    SUMMARY The objective of the present study was to determine the presence of Exercise Induced Pulmonary Hemorrhage (EIPH) by endoscopic examination in polo ponie after competition. Thirty nine polo horses in training were used in this study. The animal were classified by the number of polo seasons they had played (two seasons and three or more) and by sex independently

  19. Reloading functionally ameliorates disuse-induced muscle atrophy by reversing mitochondrial dysfunction, and similar benefits are gained by administering a combination of mitochondrial nutrients.

    PubMed

    Liu, Jing; Peng, Yunhua; Feng, Zhihui; Shi, Wen; Qu, Lina; Li, Yinghui; Liu, Jiankang; Long, Jiangang

    2014-04-01

    We previously found that mitochondrial dysfunction occurs in disuse-induced muscle atrophy. However, the mitochondrial remodeling that occurs during reloading, an effective approach for rescuing unloading-induced atrophy, remains to be investigated. In this study, using a rat model of 3-week hindlimb unloading plus 7-day reloading, we found that reloading protected mitochondria against dysfunction, including mitochondrial loss, abnormal mitochondrial morphology, inhibited biogenesis, and activation of mitochondria-associated apoptotic signaling. Interestingly, a combination of nutrients, including ?-lipoic acid, acetyl-L-carnitine, hydroxytyrosol, and CoQ10, which we designed to target mitochondria, was able to efficiently rescue muscle atrophy via a reloading-like action. It is suggested that reloading ameliorates skeletal muscle atrophy through the activation of mitochondrial biogenesis and the amelioration of oxidative stress. Nutrient administration acted similarly in unloaded rats. Here, the study of mitochondrial remodeling in rats during unloading and reloading provides a more detailed picture of the pathology of muscle atrophy. PMID:24418157

  20. Mitochondrial Evolution

    PubMed Central

    Gray, Michael W.

    2012-01-01

    Viewed through the lens of the genome it contains, the mitochondrion is of unquestioned bacterial ancestry, originating from within the bacterial phylum ?-Proteobacteria (Alphaproteobacteria). Accordingly, the endosymbiont hypothesis—the idea that the mitochondrion evolved from a bacterial progenitor via symbiosis within an essentially eukaryotic host cell—has assumed the status of a theory. Yet mitochondrial genome evolution has taken radically different pathways in diverse eukaryotic lineages, and the organelle itself is increasingly viewed as a genetic and functional mosaic, with the bulk of the mitochondrial proteome having an evolutionary origin outside Alphaproteobacteria. New data continue to reshape our views regarding mitochondrial evolution, particularly raising the question of whether the mitochondrion originated after the eukaryotic cell arose, as assumed in the classical endosymbiont hypothesis, or whether this organelle had its beginning at the same time as the cell containing it. PMID:22952398

  1. PGC-1? Regulation of Mitochondrial Degeneration in Experimental Diabetic Neuropathy

    PubMed Central

    Choi, Joungil; Chandrasekaran, Krish; Inoue, Tatsuya; Muragundla, Anjaneyulu; Russell, James W.

    2014-01-01

    Mitochondrial degeneration is considered to play an important role in the development of diabetic peripheral neuropathy in humans. Mitochondrial degeneration and the corresponding protein regulation associated with the degeneration were studied in an animal model of diabetic neuropathy. PGC-1? and its-regulated transcription factors including TFAM and NRF1, which are master regulators of mitochondrial biogenesis, are significantly downregulated in streptozotocin diabetic dorsal root ganglion (DRG) neurons. Diabetic mice develop peripheral neuropathy, loss of mitochondria, decreased mitochondrial DNA content and increased protein oxidation. Importantly, this phenotype is exacerbated in PGC-1? (?/?) diabetic mice, which develop a more severe neuropathy with reduced mitochondrial DNA and a further increase in protein oxidation. PGC-1? (?/?) diabetic mice develop an increase in total cholesterol and triglycerides, and a decrease in TFAM and NRF1 protein levels. Loss of PGC-1? causes severe mitochondrial degeneration with vacuolization in DRG neurons, coupled with reduced state 3 and 4 respiration, reduced expression of oxidative stress response genes and an increase in protein oxidation. In contrast, overexpression of PGC-1? in cultured adult mouse neurons prevents oxidative stress associated with increased glucose levels. The study provides new insights into the role of PGC-1? in mitochondrial regeneration in peripheral neurons and suggests that therapeutic modulation of PGC-1? function may be an attractive approach for treatment of diabetic neuropathy. PMID:24423644

  2. Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production

    PubMed Central

    POWERS, SCOTT K.; JACKSON, MALCOLM J.

    2010-01-01

    The first suggestion that physical exercise results in free radical-mediated damage to tissues appeared in 1978, and the past three decades have resulted in a large growth of knowledge regarding exercise and oxidative stress. Although the sources of oxidant production during exercise continue to be debated, it is now well established that both resting and contracting skeletal muscles produce reactive oxygen species and reactive nitrogen species. Importantly, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Furthermore, oxidants can modulate a number of cell signaling pathways and regulate the expression of multiple genes in eukaryotic cells. This oxidant-mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant-modulated genes have been identified and include antioxidant enzymes, stress proteins, DNA repair proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species promote contractile dysfunction resulting in muscle weakness and fatigue. Ongoing research continues to probe the mechanisms by which oxidants influence skeletal muscle contractile properties and to explore interventions capable of protecting muscle from oxidant-mediated dysfunction. PMID:18923182

  3. Prevalence and prognostic significance of exercise-induced non-sustained ventricular tachycardia in asymptomatic volunteers: The Baltimore Longitudinal Study of Aging

    PubMed Central

    Marine, Joseph E.; Shetty, Veena; Chow, Grant V.; Wright, Jeanette; Gerstenblith, Gary; Najjar, Samer S.; Lakatta, Edward G.; Fleg, Jerome L.

    2013-01-01

    Objectives To determine the clinical predictors and prognostic significance of exercise-induced non-sustained ventricular tachycardia (NSVT) in a large population of asymptomatic volunteers. Background Prior studies report variable risk associated with exercise-induced ventricular arrhythmia. Methods Subjects in the Baltimore Longitudinal Study of Aging free of known cardiovascular (CV) disease who completed at least one symptom-limited exercise treadmill test between 1977 and 2001 were included. NSVT episodes were characterized by QRS morphology, duration, and rate. Subjects underwent follow-up clinical evaluation every two years. Results The 2099 subjects (mean age 52.0 yrs, 52.2% male) underwent a mean of 2.7 exercise tests, on which 79 (3.7%) developed NSVT with exercise on at least 1 test. The NSVT had median duration of 3 beats (?5 beats in 84%), and median rate of 175 bpm. Subjects with (vs. without) NSVT were older (67±12 yr vs. 51±17 yr, p < 0.0001), and more likely to be male (80% vs 51%, p< 0.0001), and to have baseline ECG abnormalities (50% vs. 17%, p<0.0001) or ischemic ST segment changes with exercise (20% vs 10%, p=0.004). Over a mean follow-up of 13.5 ± 7.7 yrs, 518 deaths (24.6%) occurred. After multivariable adjustment for age, sex, and coronary risk factors, exercise-induced NSVT was not significantly associated with total mortality (HR=1.30 [95% CI 0.89–1.90], p=0.17). Conclusions Exercise-induced NSVT occurred in nearly 4% of this asymptomatic adult cohort. This finding increased with age and was more common in men. After adjustment for clinical variables, exercise-induced NSVT did not independently increase risk of total mortality. PMID:23747767

  4. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism.

    PubMed

    Wicks, Shawna E; Vandanmagsar, Bolormaa; Haynie, Kimberly R; Fuller, Scott E; Warfel, Jaycob D; Stephens, Jacqueline M; Wang, Miao; Han, Xianlin; Zhang, Jingying; Noland, Robert C; Mynatt, Randall L

    2015-06-23

    The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1?) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity. PMID:26056297

  5. Exercise-induced activation of the branched-chain 2-oxo acid dehydrogenase in human muscle.

    PubMed

    Wagenmakers, A J; Brookes, J H; Coakley, J H; Reilly, T; Edwards, R H

    1989-01-01

    The present study was conducted to investigate the metabolic regulation of the oxidation of branched-chain amino acids (BCAA) by exercise in human skeletal muscle. Five trained male volunteers were exercised on a cycle ergometer at 70% +/- 10% (mean +/- SD) of their maximal oxygen consumption (VO2max). Percutaneous quadriceps muscle biopsies were obtained under local anaesthesia at rest and after 30 and 120 min of exercise. In the muscle samples the active and total amount of the branched-chain 2-oxo acid dehydrogenase complex (BC-complex), the regulatory enzyme in the oxidative pathway of the BCAA, were measured. Glycogen content and activity of mitochondrial marker enzymes were also measured. Blood samples were obtained every 20 min for the measurement of metabolites. Heart rate and rated perceived exertion on the Borg scale were recorded every 10 min. At rest 4.0% +/- 2.5% of the BC complex was active, after 30 min of exercise 9.9% +/- 9.0% and after 120 min 17.5% +/- 8.5% (mean +/- SD). Exercise did not change the total activity. The largest activation was seen in two of the subjects who developed higher blood lactates early on during exercise and decreased their muscle glycogen more (indications of anaerobic metabolism). These data demonstrate that in trained individuals significant increases in the activity of the BC-complex occur only after prolonged intense exercise. In spite of the 4-fold activation, the data support the classical view that amino acids and protein do not contribute substantially as an energy source during exercise, since VO2 increased more than 20-fold. PMID:2583157

  6. Abnormal Mitochondrial Function and Impaired Granulosa Cell Differentiation in Androgen Receptor Knockout Mice

    PubMed Central

    Wang, Ruey-Sheng; Chang, Heng-Yu; Kao, Shu-Huei; Kao, Cheng-Heng; Wu, Yi-Chen; Yeh, Shuyuan; Tzeng, Chii-Reuy; Chang, Chawnshang

    2015-01-01

    In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR?/?) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR?/? mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR+/+) oocytes had reached metaphase II. Interestingly, we found these AR?/? female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor ? (PPAR?) co-activator 1-? (PGC1-?) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-?-mediated mitochondrial biogenesis in granulosa cells. PMID:25941928

  7. Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans.

    PubMed

    Yang, Fang; Gao, Yanyan; Li, Zhikai; Chen, Luming; Xia, Zhiping; Xu, Tao; Qin, Yan

    2014-10-01

    How animals coordinate cellular bioenergetics in response to stress conditions is an essential question related to aging, obesity and cancer. Elongation factor 4 (EF4/LEPA) is a highly conserved protein that promotes protein synthesis under stress conditions, whereas its function in metazoans remains unknown. Here, we show that, in Caenorhabditis elegans, the mitochondria-localized CeEF4 (referred to as mtEF4) affects mitochondrial functions, especially at low temperature (15°C). At worms' optimum growing temperature (20°C), mtef4 deletion leads to self-brood size reduction, growth delay and mitochondrial dysfunction. Transcriptomic analyses show that mtef4 deletion induces retrograde pathways, including mitochondrial biogenesis and cytoplasmic translation reorganization. At low temperature (15°C), mtef4 deletion reduces mitochondrial translation and disrupts the assembly of respiratory chain supercomplexes containing complex IV. These observations are indicative of the important roles of mtEF4 in mitochondrial functions and adaptation to stressful conditions. PMID:24837196

  8. The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson's Disease

    PubMed Central

    Tufekci, Kemal Ugur; Civi Bayin, Ezgi; Genc, Sermin; Genc, Kursad

    2011-01-01

    Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases as strict regulation of integrated mitochondrial functions is essential for neuronal signaling, plasticity, and transmitter release. Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD). Several PD-associated genes interface with mitochondrial dynamics regulating the structure and function of the mitochondrial network. Mitochondrial dysfunction can induce neuron death through a plethora of mechanisms. Both mitochondrial dysfunction and neuroinflammation, a common denominator of PD, lead to an increased production of reactive oxygen species, which are detrimental to neurons. The transcription factor nuclear factor E2-related factor 2 (Nrf2, NFE2L2) is an emerging target to counteract mitochondrial dysfunction and its consequences in PD. Nrf2 activates the antioxidant response element (ARE) pathway, including a battery of cytoprotective genes such as antioxidants and anti-inflammatory genes and several transcription factors involved in mitochondrial biogenesis. Here, the current knowledge about the role of mitochondrial dysfunction in PD, Nrf2/ARE stress-response mechanisms, and the evidence for specific links between this pathway and PD are summarized. The neuroprotection of nigral dopaminergic neurons by the activation of Nrf2 through several inducers in PD is also emphasized as a promising therapeutic approach. PMID:21403858

  9. Down-regulation of mortalin exacerbates A?-mediated mitochondrial fragmentation and dysfunction.

    PubMed

    Park, So Jung; Shin, Ji Hyun; Jeong, Jae In; Song, Ji Hoon; Jo, Yoon Kyung; Kim, Eun Sung; Lee, Eunjoo H; Hwang, Jung Jin; Lee, Eun Kyung; Chung, Sun Ju; Koh, Jae-Young; Jo, Dong-Gyu; Cho, Dong-Hyung

    2014-01-24

    Mitochondrial dynamics greatly influence the biogenesis and morphology of mitochondria. Mitochondria are particularly important in neurons, which have a high demand for energy. Therefore, mitochondrial dysfunction is strongly associated with neurodegenerative diseases. Until now various post-translational modifications for mitochondrial dynamic proteins and several regulatory proteins have explained complex mitochondrial dynamics. However, the precise mechanism that coordinates these complex processes remains unclear. To further understand the regulatory machinery of mitochondrial dynamics, we screened a mitochondrial siRNA library and identified mortalin as a potential regulatory protein. Both genetic and chemical inhibition of mortalin strongly induced mitochondrial fragmentation and synergistically increased A?-mediated cytotoxicity as well as mitochondrial dysfunction. Importantly we determined that the expression of mortalin in Alzheimer disease (AD) patients and in the triple transgenic-AD mouse model was considerably decreased. In contrast, overexpression of mortalin significantly suppressed A?-mediated mitochondrial fragmentation and cell death. Taken together, our results suggest that down-regulation of mortalin may potentiate A?-mediated mitochondrial fragmentation and dysfunction in AD. PMID:24324263

  10. Biogenesis of pipecolic acid in Rhizoctonia leguminicola

    SciTech Connect

    Wickwire, B.M.

    1989-01-01

    This laboratory has long been interested in the biogenesis and biological properties of two indolizidine alkaloids, slaframine and swainsonine that are produced by the fungal parasite Rhizoctonia Leguminicola. Slaframine, (1S,6S,8aS-1 acetoxy-6-aminooctahydroindolizine) is a parasympathetic secretagogue, and swainsonine (1S,2R,8R,8aR-1,2,8-trihydroxyoctahydroindolizine) is a potent {alpha}-mannosidase inhibitor. This thesis concerns the initial steps of the biosynthesis of these alkaloids from lysine, via the common intermediate pipecolic acid, in whole cells and cell free enzyme systems of R. leguminicola. In confirmation of earlier work performed in this laboratory, L-lysine was used preferentially for pipecolate biosynthesis in R. Leguminicola. This pathway was supported by the finding that cell free extracts of R. leguminicola consistently converted L-(U-{sup 14}C)-lysine to three labelled metabolites: saccharopine, peak II, and pipecolic acid. Peak II was subsequently identified by appropriate proton NMR studies to be {delta}{sup 1}-piperideine-6-carboxylate, and the following pathway of pipecolic acid formation was postulated: L-lysine {yields} saccharopine {yields} {delta}{sup 1}-piperideine-6-carboxylate {yields} pipecolate. This pathway was confirmed by demonstration of each enzymatic step in vitro from purified radiolabeled substrates.

  11. Membrane biogenesis in anoxygenic photosynthetic prokaryotes.

    PubMed

    Drews, Gerhart; Niederman, Robert A

    2002-01-01

    Following the discovery of photosynthetic bacteria in the nineteenth century, technical developments of the 1950s led to their use in membrane biogenesis studies. These investigations had their origins in the isolation of subcellular particles designated as 'chromatophores' by Roger Stanier and colleagues, which were shown to be photosynthetically competent by Albert Frenkel, and to originate from the intracytoplasmic membrane (ICM) continuum observed in electron micrographs. These ultrastrucutral studies by the G. Drews group, Germaine Cohen-Bazire and others also suggested that the ICM originates by invagination of the cytoplasmic membrane, as later established in the biochemical and biophysical work of the R. Niederman and Drews groups. Through a combination of genetic approaches, first introduced in the early 1980s by Barry Marrs, and the atomic resolution structures determined for light-harvesting antennae and reaction centers, a detailed understanding is emerging of mechanisms regulating their levels in the membrane and the roles played by specific protein domains and additional factors in their assembly and supramolecular organization. Prospects for additional progress during the twenty-first century include further elucidation of molecular aspects of the assembly process and the application of newer spectroscopic probes to photosynthetic unit formation. PMID:16245108

  12. Chloroplast RNA polymerases: Role in chloroplast biogenesis.

    PubMed

    Börner, Thomas; Aleynikova, Anastasia Yu; Zubo, Yan O; Kusnetsov, Victor V

    2015-09-01

    Plastid genes are transcribed by two types of RNA polymerase in angiosperms: the bacterial type plastid-encoded RNA polymerase (PEP) and one (RPOTp in monocots) or two (RPOTp and RPOTmp in dicots) nuclear-encoded RNA polymerase(s) (NEP). PEP is a bacterial-type multisubunit enzyme composed of core subunits (coded for by the plastid rpoA, rpoB, rpoC1 and rpoC2 genes) and additional protein factors (sigma factors and polymerase associated protein, PAPs) encoded in the nuclear genome. Sigma factors are required by PEP for promoter recognition. Six different sigma factors are used by PEP in Arabidopsis plastids. NEP activity is represented by phage-type RNA polymerases. Only one NEP subunit has been identified, which bears the catalytic activity. NEP and PEP use different promoters. Many plastid genes have both PEP and NEP promoters. PEP dominates in the transcription of photosynthesis genes. Intriguingly, rpoB belongs to the few genes transcribed exclusively by NEP. Both NEP and PEP are active in non-green plastids and in chloroplasts at all stages of development. The transcriptional activity of NEP and PEP is affected by endogenous and exogenous factors. This article is part of a Special Issue entitled: Chloroplast Biogenesis. PMID:25680513

  13. The fungal vacuole: composition, function, and biogenesis.

    PubMed Central

    Klionsky, D J; Herman, P K; Emr, S D

    1990-01-01

    The fungal vacuole is an extremely complex organelle that is involved in a wide variety of functions. The vacuole not only carries out degradative processes, the role most often ascribed to it, but also is the primary storage site for certain small molecules and biosynthetic precursors such as basic amino acids and polyphosphate, plays a role in osmoregulation, and is involved in the precise homeostatic regulation of cytosolic ion and basic amino acid concentration and intracellular pH. These many functions necessitate an intricate interaction between the vacuole and the rest of the cell; the vacuole is part of both the secretory and endocytic pathways and is also directly accessible from the cytosol. Because of the various roles and properties of the vacuole, it has been possible to isolate mutants which are defective in various vacuolar functions including the storage and uptake of metabolites, regulation of pH, sorting and processing of vacuolar proteins, and vacuole biogenesis. These mutants show a remarkable degree of genetic overlap, suggesting that these functions are not individual, discrete properties of the vacuole but, rather, are closely interrelated. Images PMID:2215422

  14. Biogenesis of the Saccharomyces cerevisiae Mating Pheromone a-Factor

    PubMed Central

    Chen, Peng; Sapperstein, Stephanie K.; Choi, Jonathan D.; Michaelis, Susan

    1997-01-01

    The Saccharomyces cerevisiae mating pheromone a-factor is a prenylated and carboxyl methylated extracellular peptide signaling molecule. Biogenesis of the a-factor precursor proceeds via a distinctive multistep pathway that involves COOH-terminal modification, NH2-terminal proteolysis, and a nonclassical export mechanism. In this study, we examine the formation and fate of a-factor biosynthetic intermediates to more precisely define the events that occur during a-factor biogenesis. We have identified four distinct a-factor biosynthetic intermediates (P0, P1, P2, and M) by metabolic labeling, immunoprecipitation, and SDSPAGE. We determined the biochemical composition of each by defining their NH2-terminal amino acid and COOH-terminal modification status. Unexpectedly, we discovered that not one, but two NH2-terminal cleavage steps occur during the biogenesis of a-factor. In addition, we have shown that COOH-terminal prenylation is required for the NH2-terminal processing of a-factor and that all the prenylated a-factor intermediates (P1, P2, and M) are membrane bound, suggesting that many steps of a-factor biogenesis occur in association with membranes. We also observed that although the biogenesis of a-factor is a rapid process, it is inherently inefficient, perhaps reflecting the potential for regulation. Previous studies have identified gene products that participate in the COOH-terminal modification (Ram1p, Ram2p, Ste14p), NH2-terminal processing (Ste24p, Axl1p), and export (Ste6p) of a-factor. The intermediates defined in the present study are discussed in the context of these biogenesis components to formulate an overall model for the pathway of a-factor biogenesis. PMID:9015298

  15. The use of compression stockings during a marathon competition to reduce exercise-induced muscle damage: are they really useful?

    PubMed

    Areces, Francisco; Salinero, Juan José; Abian-Vicen, Javier; González-Millán, Cristina; Ruiz-Vicente, Diana; Lara, Beatriz; Lledó, María; Del Coso, Juan

    2015-06-01

    Study Design Case-control study; ecological study. Objectives To examine the efficacy of wearing compression stockings to prevent muscle damage and to maintain running performance during a marathon competition. Background Exercise-induced muscle damage has been identified as one of the main causes of the progressive decrease in running and muscular performance found during marathon races. Methods Thirty-four experienced runners were pair-matched for age, anthropometric data, and best race time in the marathon, and randomly assigned to a control group (n = 17) of runners who wore conventional socks or to a group of runners who wore foot-to-knee graduated compression stockings (n = 17). Before and after the race, a sample of venous blood was obtained, and jump height and leg muscle power were measured during a countermovement jump. Serum myoglobin and creatine kinase concentrations were determined as blood markers of muscle fiber damage. Results Total race time was not different between the control group and the compression stockings group (210 ± 23 and 214 ± 22 minutes, respectively; P = .58). Between the control group and the compression stockings group, postrace reductions in leg muscle power (-19.8% ± 17.7% versus -24.8% ± 18.4%, respectively; P = .37) and jump height (-25.3% ± 14.1% versus -32.5% . 20.4%, respectively; P = .27) were similar. At the end of the race, there were no differences between the control group and the compression stockings group in serum myoglobin (568 ± 347 ng·mL(-1) versus 573 ± 270 ng·mL(-1), respectively; P = .97) and creatine kinase concentration (390 ± 166 U·L(-1) versus 487 ± 227 U·L(-1), respectively; P = .16). Conclusion The use of compression stockings did not improve running pace and did not prevent exercise-induced muscle damage during the marathon. Wearing compression stockings during long-distance running events is an ineffective strategy to avoid the deleterious effects of muscle damage on running performance. Level of Evidence Therapy, level 2b. J Orthop Sports Phys Ther 2015;45(6):462-470. Epub 21 Apr 2015. doi:10.2519/jospt.2015.5863. PMID:25899215

  16. Mitochondrial function in vascular endothelial cell in diabetes

    PubMed Central

    Pangare, Meenal; Makino, Ayako

    2013-01-01

    Micro- and macrovascular complications are commonly seen in diabetic patients and endothelial dysfunction contributes to the development and progression of the complications. Abnormal functions in endothelial cells lead to the increase in vascular tension and atherosclerosis, followed by systemic hypertension as well as increased incident of ischemia and stroke in diabetic patients. Mitochondria are organelles serving as a source of energy production and as regulators of cell survival (e.g., apoptosis and cell development) and ion homeostasis (e.g., H+, Ca2+). Endothelial mitochondria are mainly responsible for generation of reactive oxygen species (ROS) and maintaining the Ca2+ concentration in the cytosol. There is increasing evidence that mitochondrial morphological and functional changes are implicated in vascular endothelial dysfunction. Enhanced mitochondrial fission and/or attenuated fusion lead to mitochondrial fragmentation and disrupt the endothelial physiological function. Abnormal mitochondrial biogenesis and disturbance of mitochondrial autophagy increase the accumulation of damaged mitochondria, such as irreversibly depolarized or leaky mitochondria, and facilitate cell death. Augmented mitochondrial ROS production and Ca2+ overload in mitochondria not only cause the maladaptive effect on the endothelial function, but also are potentially detrimental to cell survival. In this article, we review the physiological and pathophysiological role of mitochondria in endothelial function with special focus on diabetes. PMID:22504486

  17. MitoTimer: a novel tool for monitoring mitochondrial turnover.

    PubMed

    Hernandez, Genaro; Thornton, Christine; Stotland, Aleksandr; Lui, Diana; Sin, Jon; Ramil, Jennifer; Magee, Najib; Andres, Allen; Quarato, Giovanni; Carreira, Raquel S; Sayen, M Richard; Wolkowicz, Roland; Gottlieb, Roberta A

    2013-11-01

    Fluorescent Timer, or DsRed1-E5, is a mutant of the red fluorescent protein, dsRed, in which fluorescence shifts over time from green to red as the protein matures. This molecular clock gives temporal and spatial information on protein turnover. To visualize mitochondrial turnover, we targeted Timer to the mitochondrial matrix with a mitochondrial-targeting sequence (coined "MitoTimer") and cloned it into a tetracycline-inducible promoter construct to regulate its expression. Here we report characterization of this novel fluorescent reporter for mitochondrial dynamics. Tet-On HEK 293 cells were transfected with pTRE-tight-MitoTimer and production was induced with doxycycline (Dox). Mitochondrial distribution was demonstrated by fluorescence microscopy and verified by subcellular fractionation and western blot analysis. Dox addition for as little as 1 h was sufficient to induce MitoTimer expression within 4 h, with persistence in the mitochondrial fraction for up to 6 d. The color-specific conformation of MitoTimer was stable after fixation with 4% paraformaldehyde. Ratiometric analysis of MitoTimer revealed a time-dependent transition from green to red over 48 h and was amenable to analysis by fluorescence microscopy and flow cytometry of whole cells or isolated mitochondria. A second Dox administration 48 h after the initial induction resulted in a second round of expression of green MitoTimer. The extent of new protein incorporation during a second pulse was increased by administration of a mitochondrial uncoupler or simvastatin, both of which trigger mitophagy and biogenesis. MitoTimer is a novel fluorescent reporter protein that can reveal new insights into mitochondrial dynamics within cells. Coupled with organelle flow cytometry, it offers new opportunities to investigate mitochondrial subpopulations by biochemical or proteomic methods. PMID:24128932

  18. Exercise-induced muscle damage is not attenuated by beta-hydroxy-beta-methylbutyrate and alpha-ketoisocaproic acid supplementation.

    PubMed

    Nunan, David; Howatson, Glyn; van Someren, Ken A

    2010-02-01

    The purpose of this study was to examine the effects of combined oral beta-hydroxy-beta-methylbutyrate (HMB) and alpha-ketoisocaproic acid (KIC) supplementation on indices of exercise-induced muscle damage (EIMD) after an acute bout of eccentric-biased exercise. Fourteen male subjects were allocated to 2 groups: a placebo group (3 g.d corn flour, N = 7) or an HMB + KIC group (3 g.d HMB and 0.3 g.d KIC, N = 7). Supplementation commenced 11 days before a 40-minute bout of downhill running and continued for 3 days post-exercise. Delayed-onset muscle soreness, mid-thigh girth, knee extensor range of motion, serum creatine kinase (CK) activity, and isometric and concentric torque were assessed pre-exercise and at 24, 48, and 72 hours post-exercise. Delayed-onset muscle soreness, CK activity, and isometric and concentric torque all changed over the 72-hour period (p < 0.05); however, HMB + KIC had no significant effect on any of the indices of muscle damage. Although 14 days HMB and KIC supplementation did not attenuate indices of EIMD after an acute bout of unaccustomed eccentric-biased exercise, there was a trend for a more rapid rate of recovery in isometric and isokinetic muscle function. beta-hydroxy-beta-methylbutyrate and KIC may therefore provide limited benefit in the recovery of muscle function after EIMD in untrained subjects or after unaccustomed exercise. PMID:20072045

  19. [Effect of the diagnosis and prevention of exercise-induced bronchial obstruction on sports participation by asthmatic school children].

    PubMed

    Hussein, A; Forderer, A; Abelitis, M; Koch, I

    1988-12-01

    To assess the sport activities and the previous management of asthmatic children with an exercise-induced bronchial obstruction (EIB), we studied 124 children, aged 8-17 years, with a history of EIB, which was confirmed in a free-running exercise test. Participation in school sports was regular in 38% of the children, irregular in 45% and absent in 17%. Participation in sports outside the school was even lower: In 26% regularly, 18% irregularly and absent in 56%. 17% of all children were not active in any sport. EIB had previously been diagnosed in 38 (31%) children, and 20 (16%) of these had received an appropriate prophylactic medication. Children who received prophylaxis participated significantly more often in school sports (p less than 0.01) and in other sports (p less than 0.05), compared with those who had been diagnosed but had not received prophylaxis. After exercise, peak expiratory flow decreased by a mean of 41% of the preexercise values, but following a prophylactic administration of 0.2 mg Salbutamol-aerosol it decreased only by 2%. A complete protection of EIB was achieved in 94% of the children and the mean %-protection was 95%. The protective effect of 2 mg DNCG-aerosol in 21 children was significantly lower (53%, p less than 0.05) than that of salbutamol and a complete protection was achieved in only 71% (p less than 0.025) of the children. PMID:3148854

  20. Low-frequency fatigue as an indicator of eccentric exercise-induced muscle injury: the role of vitamin E.

    PubMed

    Kyparos, Antonios; Nikolaidis, Michalis G; Dipla, Konstantina; Zafeiridis, Andreas; Paschalis, Vassilis; Grivas, Gerasimos V; Theodorou, Anastasios A; Albani, Maria; Matziari, Chrysoula; Vrabas, Ioannis S

    2012-01-01

    This study investigates whether vitamin E can attenuate eccentric exercise-induced soleus muscle injury as indicated by the amelioration of in situ isometric force decline following a low-frequency fatigue protocol (stimulation at 4?Hz for 5?min) and the ability of the muscle to recover 3?min after the termination of the fatigue protocol. Adult male Wistar rats were divided into vitamin E-supplemented or placebo-supplemented groups studied at rest, immediately post-exercise or 48?h post-exercise. Daily dl-?-tocopheryl acetate intraperitoneal injections of 100?mg/kg body mass for 5 consecutive days prior to exercise doubled its plasma levels. Fatigue index and recovery index expressed as a percentage of the initial tension. FI at 0?h post- and 48?h post-exercise respectively was 88%?±?4.2% and 89%?±?6.8% in the vitamin E groups versus 76%?±?3% and 80%?±?11% in the placebo groups. RI was 99%?±?3.4% and 100%?±?6% in the vitamin E groups versus 82%?±?3.1% and 84%?±?5.9% in the placebo groups. Complementally to the traditionally recorded maximal force, low-frequency fatigue measures may be beneficial for assessing injury-induced decrease in muscle functionality. PMID:22848781

  1. IgE detection to ?/?/?-gliadin and its clinical relevance in wheat-dependent exercise-induced anaphylaxis.

    PubMed

    Hofmann, S C; Fischer, J; Eriksson, C; Bengtsson Gref, O; Biedermann, T; Jakob, T

    2012-11-01

    Wheat-dependent exercise-induced anaphylaxis (WDEIA) is characterized by anaphylactic reactions after wheat ingestion and physical exercise. IgE antibodies to recombinant ?(5) -gliadin are detectable in a majority of WDEIA patients, but other wheat allergens may also play a role in elicitation of WDEIA. Here, we performed a comprehensive analysis of IgE reactivity to different wheat proteins in 17 patients with confirmed WDEIA by ImmunoCAP research prototypes and a semi-quantitative microarray immunoassay with ?/?/?-gliadin, high-molecular-weight (HMW) glutenin, alpha-amylase inhibitor (AAI) dimer, and wheat lipid transfer protein (LTP). By ImmunoCAP, IgE to recombinant ?(5) -gliadin was detectable in 14/17 patients (82%), to ?/?/?-gliadin in 82% including the three patients lacking IgE to ?(5) -gliadin, and to HMW glutenin in 59%. The microarray revealed specifically ?-gliadin as the second most important allergen. These results demonstrate the additional diagnostic value of ?/?- and ?-gliadin in particular in ?(5) -gliadin-negative patients in the diagnosis of WDEIA. PMID:22978369

  2. Exercise-induced oxidative stress influences the motor control during maximal incremental cycling exercise in healthy humans.

    PubMed

    Gravier, Gilles; Steinberg, Jean Guillaume; Lejeune, Pierre Jean; Delliaux, Stephane; Guieu, Regis; Jammes, Yves

    2013-05-01

    We hypothesized that the changes in blood oxidant/antioxidant status during incremental maximal cycling exercise could affect the motor drive to leg muscles. Indeed, the oxygen free radicals activate the metabosensitive muscle afferents which are suspected to elicit an adaptive motor response delaying fatigue. Fifteen healthy subjects performed an incremental cycling exercise reaching the maximal oxygen uptake (VO2) during which venous blood was repeatedly sampled to measure a marker of lipid peroxidation (TBARS), an antioxidant (reduced ascorbic acid, RAA), and the ischaemia-modified albumin (IMA). The surface EMG of rectus femoris was recorded and the median frequency (MF) of power spectrum was computed. Our main results are: 1) TBARS increased in 7/15 subjects, RAA decreased in 7/15 and IMA increased in 13/15 at VO2max; 4) the MF decrease was correlated to maximal end-exercise IMA increase and RAA decrease. During maximal cycling exercise, the adaptive motor response to cycling closely depends on the magnitude of exercise-induced oxidative stress. PMID:23473925

  3. Application of a new oxidation-reduction potential assessment method in strenuous exercise-induced oxidative stress.

    PubMed

    Stagos, Dimitrios; Goutzourelas, Nikolaos; Bar-Or, David; Ntontou, Amalia-Maria; Bella, Evangelia; Becker, Aphrodite Tousia; Statiri, Argyro; Kafantaris, Ioannis; Kouretas, Dimitrios

    2015-07-01

    Objectives The aim of the study was to test a novel method for assessing oxidative stress, the RedoxSYS™ diagnostic system, a holistic, fast, minimally invasive, and requiring small sample volume method, that measures two parameters, the static (sORP) and the capacity (cORP) oxidation-reduction potential. Methods The redox status of 14 athletes participating in a mountain marathon race was assessed. Redox status in blood obtained 1 day before the race and immediately after the race was assessed using the RedoxSYS diagnostic system as well as conventional oxidative stress markers such as glutathione levels (GSH), catalase activity (CAT), thiobarbituric acid reactive substances (TBARS), protein carbonyls (CARB), and total antioxidant activity. Results The results showed that after the race, the sORP was increased significantly by 7% indicating oxidative stress induction, while cORP was decreased by 14.6% but not significantly. Moreover, the conventional oxidative stress markers GSH and CAT were decreased significantly by 13.1 and 23.4%, respectively, while TBARS and CARB were increased significantly by 26.1 and 15.6%, respectively, after the race indicating oxidative stress induction. Discussion The present study demonstrated for the first time that the RedoxSYS diagnostic system can be used for evaluating the exercise-induced oxidative stress in athletes. PMID:25494543

  4. Study of IgE Antigenic Relationships in Hypersensitivity to Hydrolyzed Wheat Proteins and Wheat-Dependent Exercise-Induced Anaphylaxis

    Microsoft Academic Search

    Jacques Snégaroff; Isabelle Bouchez-Mahiout; Catherine Pecquet; Gérard Branlard; Michel Laurière

    2006-01-01

    Background: Wheat is involved in different forms of respiratory, food and contact allergy. The IgE of patients generally reacts with various flour proteins. It is not known if antigenic relationships could explain some of these reactions and if proteins could be involved in different pathologies. Methods: Two sera were selected as representative of patients with either wheat-dependent exercise-induced anaphylaxis (WDEIA)

  5. L-Arginine Supplementation Causes Additional Effects on Exercise-Induced Angiogenesis and VEGF Expression in the Heart and Hind-Leg Muscles of Middle-Aged Rats

    Microsoft Academic Search

    Junichi Suzuki

    2006-01-01

    The effects of dietary L-arginine supplementation on exercise-induced angiogenesis and VEGF expression were ex- amined in male middle-aged (12 months old) Wistar rats. Exer- cise training lasted for six weeks at 20 m\\/min on a 0% gradient for 10-60 min\\/day. Rats in the L-arginine-treated groups drank water containing 2.5% L-arginine. According to histochemical identification of the capillary profile, in the

  6. Non-uniform decay in jumping exercise-induced bone gains following 12 and 24 weeks of cessation of exercise in rats.

    PubMed

    Ooi, Foong-Kiew; Singh, Rabindarjeet; Singh, Harbindar Jeet; Umemura, Yoshohisa; Nagasawa, Seigo

    2011-11-01

    The effects of deconditioning on exercise-induced bone gains in rats were investigated in 12-week-old female WKY rats performing a standard jumping exercise regimen for either 8, 12 or 24 weeks, followed by sedentary periods of either 24, 12 or 0 weeks, respectively. Age-matched controls received no exercise over the same period. At the end of the training/sedentary period, the tibiae were harvested for analyses of bone parameters. Gains in tibial fat-free dry weight decayed within 12 weeks of deconditioning, but gains in tibial ultimate bending force (strength), maximum diameter and cortical area were still present at 12 weeks of deconditioning. With the exception of cortical area, all other exercise-induced bone gains decayed by the 24th week of deconditioning. It appears that the decay in exercise-induced bone gains in strength, physical and morphological properties is not uniform, and that gains in fat-free dry weight seem to decay earlier. PMID:21870136

  7. Complex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses.

    PubMed

    Pulliam, Daniel A; Deepa, Sathyaseelan S; Liu, Yuhong; Hill, Shauna; Lin, Ai-Ling; Bhattacharya, Arunabh; Shi, Yun; Sloane, Lauren; Viscomi, Carlo; Zeviani, Massimo; Van Remmen, Holly

    2014-09-01

    Mutations in SURF1 (surfeit locus protein 1) COX (cytochrome c oxidase) assembly protein are associated with Leigh's syndrome, a human mitochondrial disorder that manifests as severe mitochondrial phenotypes and early lethality. In contrast, mice lacking the SURF1 protein (Surf1-/-) are viable and were previously shown to have enhanced longevity and a greater than 50% reduction in COX activity. We measured mitochondrial function in heart and skeletal muscle, and despite the significant reduction in COX activity, we found little or no difference in ROS (reactive oxygen species) generation, membrane potential, ATP production or respiration in isolated mitochondria from Surf1-/- mice compared with wild-type. However, blood lactate levels were elevated and Surf1-/- mice had reduced running endurance, suggesting compromised mitochondrial energy metabolism in vivo. Decreased COX activity in Surf1-/- mice is associated with increased markers of mitochondrial biogenesis [PGC-1? (peroxisome-proliferator-activated receptor ? co-activator 1?) and VDAC (voltage-dependent anion channel)] in both heart and skeletal muscle. Although mitochondrial biogenesis is a common response in the two tissues, skeletal muscle has an up-regulation of the UPRMT (mitochondrial unfolded protein response) and heart exhibits induction of the Nrf2 (nuclear factor-erythroid 2-related factor 2) antioxidant response pathway. These data are the first to show induction of the UPRMT in a mammalian model of decreased COX activity. In addition, the results of the present study suggest that impaired mitochondrial function can lead to induction of mitochondrial stress pathways to confer protective effects on cellular homoeostasis. PMID:24911525

  8. A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function

    Microsoft Academic Search

    Marco Spinazzi; Silvia Cazzola; Mario Bortolozzi; Alessandra Baracca; Emanuele Loro; Alberto Casarin; Giancarlo Solaini; Gianluca Sgarbi; Gabriella Casalena; Giovanna Cenacchi; Adriana Malena; Christian Frezza; Franco Carrara; Corrado Angelini; Luca Scorrano; Leonardo Salviati; Lodovica Vergani

    2008-01-01

    Autosomal dominant optic atrophy (ADOA), the commonest cause of inherited optic atrophy, is caused by mutations in the ubiquitously expressed gene optic atrophy 1 (OPA1), involved in fusion and biogenesis of the inner membrane of mitochondria. Bioenergetic failure, mitochondrial network abnormalities and increased apoptosis have all been proposed as possible causal factors. However, their relative contribution to pathogenesis as well

  9. Mitochondrial fragmentation in neurodegeneration

    Microsoft Academic Search

    Andrew B. Knott; Guy Perkins; Robert Schwarzenbacher; Ella Bossy-Wetzel

    2008-01-01

    Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in the mitochondrial fusion GTPases mitofusin 2 and optic atrophy 1, neurotoxins and oxidative

  10. Effect of eccentric exercise-induced muscle damage on electromyographyic activity of quadriceps in untrained healthy females

    PubMed Central

    Rezaei, Mandana; Ebrahimi-Takamjani, Ismael; Jamshidi, Ali A.; Vassaghi-Gharamaleki, Behnoush; Hedayatpour, Nosratollah; Havaei, Naser

    2014-01-01

    Background: The aim of this study was to investigate muscle damage indicators and electromyography activities of quadriceps muscles at 25° of hip flexion in untrained healthy females after an eccentric exercise induced muscle fiber damage. Methods: A total of 14 healthy females participated in this pre-experimental study. The subjects performed maximal eccentric quadriceps contractions at 25? of hip flexion. Maximum voluntary extensor isometric and concentric moments, angle of maximum moment for concentric contractions, perceived pain intensity, and pain pressure threshold were examined before, immediately, 48 hours, 120 hours and 14 days after eccentric exercise. Additionally, electromyography of three parts of quadriceps muscle, knee flexion range of motion and thigh circumference were measured before and after eccentric exercise. Results: Significant reductions in maximum isometric moment and maximum concentric moment were observed at angular velocity of 60? per sec immediately after eccentric exercise (p<0.05). Both maximum isometric moment and maximum concentric moment recovered to the baseline 48 hours after eccentric exercise. Increased pain intensity and decreased knee joint range of motion manifested 48 hours after eccentric exercise. Pain pressure threshold for the quadriceps was higher 14 days after exercise as compared to 48 and 120 hours (p<0.05). No significant changes observed in electromyography and thigh circumference (p>0.05). Conclusion: Eccentric exercise performed at 25? of hip flexion resulted in muscle fiber injuries within the quadriceps muscle. However, electromyography of quadriceps muscle was not significantly different than the baseline. The result indicates that hip joint position may modify the effect of eccentric exercise on muscle activation. PMID:25695012

  11. Normal pulmonary gas exchange efficiency and absence of exercise-induced arterial hypoxemia in adults with bronchopulmonary dysplasia.

    PubMed

    Lovering, Andrew T; Laurie, Steven S; Elliott, Jonathan E; Beasley, Kara M; Yang, Ximeng; Gust, Caitlyn E; Mangum, Tyler S; Goodman, Randall D; Hawn, Jerold A; Gladstone, Igor M

    2013-10-01

    Cardiopulmonary function is reduced in adults born very preterm, but it is unknown if this results in reduced pulmonary gas exchange efficiency during exercise and, consequently, leads to reduced aerobic capacity in subjects with and without bronchopulmonary dysplasia (BPD). We hypothesized that an excessively large alveolar to arterial oxygen difference (AaDO2) and resulting exercise-induced arterial hypoxemia (EIAH) would contribute to reduced aerobic fitness in adults born very preterm with and without BPD. Measurements of pulmonary function, lung volumes and diffusion capacity for carbon monoxide (DLco) were made at rest. Measurements of maximal oxygen consumption, peak workload, temperature- and tonometry-corrected arterial blood gases, and direct measure of hemoglobin saturation with oxygen (SaO2) were made preexercise and during cycle ergometer exercise in ex-preterm subjects ?32-wk gestational age, with BPD (n = 12), without BPD (PRE; n = 12), and full term controls (CONT; n = 12) breathing room air. Both BPD and PRE had reduced pulmonary function and reduced DLco compared with CONT. The AaDO2 was not significantly different between groups, and there was no evidence of EIAH (SaO2 < 95% and/or AaDO2 ? 40 Torr) in any subject group preexercise or at any workload. Arterial O2 content was not significantly different between the groups preexercise or during exercise. However, peak power output was decreased in BPD and PRE subjects compared with CONT. We conclude that EIAH in adult subjects born very preterm with and without BPD does not likely contribute to the reduction in aerobic exercise capacity observed in these subjects. PMID:23869070

  12. Exercise-induced AMPK and pyruvate dehydrogenase regulation is maintained during short-term low-grade inflammation.

    PubMed

    Biensø, Rasmus Sjørup; Olesen, Jesper; van Hauen, Line; Meinertz, Simon; Halling, Jens Frey; Gliemann, Lasse; Plomgaard, Peter; Pilegaard, Henriette

    2015-02-01

    The aim of the present study was to examine the effect of lipopolysaccharide (LPS)-induced inflammation on AMP-activated protein kinase (AMPK) and pyruvate dehydrogenase (PDH) regulation in human skeletal muscle at rest and during exercise. Nine young healthy physically inactive male subjects completed two trials. In an LPS trial, the subjects received a single LPS injection (0.3 ng/kg body weight) and blood samples and vastus lateralis muscle biopsies were obtained before and 2 h after the LPS injection and immediately after a 10-min one-legged knee extensor exercise bout performed approximately 2½ h after the LPS injection. The exercise bout with muscle samples obtained before and immediately after was repeated in a control trial without LPS injection. The plasma tumor necrosis factor ? concentration increased 17-fold 2 h after LPS relative to before. Muscle lactate and muscle glycogen were unchanged from before to 2 h after LPS and exercise increased muscle lactate and decreased muscle glycogen in the control (P < 0.05) and the LPS (0.05 ? P < 0.1) trial with no differences between the trials. AMPK, acetyl-CoA carboxylase (ACC) and PDH phosphorylation as well as PDHa activity were unaffected 2 h after LPS relative to before. Exercise decreased (P < 0.05) PDH and increased (P < 0.05) AMPK and ACC phosphorylation as well as increased (P < 0.05) PDHa activity similarly in the LPS and control trial. In conclusion, LPS-induced inflammation does not affect resting or exercise-induced AMPK and PDH regulation in human skeletal muscle. This suggests that metabolic flexibility during exercise is maintained during short-term low-grade inflammation in humans. PMID:24691558

  13. Role of Proinflammatory Cytokines and Redox Homeostasis in Exercise-Induced Delayed Progression of Hypertension in Spontaneously Hypertensive Rats

    PubMed Central

    Agarwal, Deepmala; Haque, Masudul; Sriramula, Srinivas; Mariappan, Nithya; Pariaut, Romain; Francis, Joseph

    2009-01-01

    Hypertension is a well-known risk factor for various cardiovascular diseases. Recently, exercise has been recommended as a part of lifestyle modification for all hypertensive patients. However, the precise mechanisms of exercise training (ExT)-induced effects on the development of hypertension are poorly understood. Therefore, we hypothesized that chronic ExT would delay the progression of hypertension in young spontaneously hypertensive rats (SHR). In addition, we explored whether the beneficial effects of chronic ExT were mediated by reduced pro-inflammatory cytokines (PICs) and improved redox status. We also investigated the involvement of NF-?B in exercise-induced effects. To test our hypotheses, young normotensive (WKY) and spontaneously hypertensive rats (SHR) were given moderate-intensity ExT for 16 weeks. Blood pressure was determined by the tail-cuff method and cardiac function was assessed by echocardiography. Myocardial total reactive oxygen species (ROS) and superoxide (O2•?) production were measured by electron paramagnetic resonance spectroscopy; TNF-?, IL-1?, gp91phox and iNOS by real-time PCR, and NF-?B activity by EMSA. Chronic ExT in hypertensive rats resulted in significantly reduced blood pressure, reduced concentric hypertrophy and improved diastolic function. ExT significantly reduced PICs, iNOS, attenuated total ROS and O2•? production, and increased antioxidants in SHR. ExT also resulted in increased nitric oxide production and decreased NF-?B activity in SHR. In summary, chronic ExT delays the progression of hypertension and improves cardiac function in young SHR; these ExT-induced beneficial effects are mediated by reduced PICs and improved redox homeostasis via downregulation of NF-?B. PMID:19841289

  14. Understanding exercise-induced hyperemia: central and peripheral hemodynamic responses to passive limb movement in heart transplant recipients.

    PubMed

    Hayman, Melissa A; Nativi, Jose N; Stehlik, Josef; McDaniel, John; Fjeldstad, Anette S; Ives, Stephen J; Walter Wray, D; Bader, Feras; Gilbert, Edward M; Richardson, Russell S

    2010-11-01

    To better characterize the contribution of both central and peripheral mechanisms to passive limb movement-induced hyperemia, we studied nine recent (<2 yr) heart transplant (HTx) recipients (56 ± 4 yr) and nine healthy controls (58 ± 5 yr). Measurements of heart rate (HR), stroke volume (SV), cardiac output (CO), and femoral artery blood flow were recorded during passive knee extension. Peripheral vascular function was assessed using brachial artery flow-mediated dilation (FMD). During passive limb movement, the HTx recipients lacked an HR response (0 ± 0 beats/min, ?0%) but displayed a significant increase in CO (0.4 ± 0.1 l/min, ?5%) although attenuated compared with controls (1.0 ± 0.2 l/min, ?18%). Therefore, the rise in CO in the HTx recipients was solely dependent on increased SV (5 ± 1 ml, ?5%) in contrast with the controls who displayed significant increases in both HR (6 ± 2 beats/min, ?11%) and SV (5 ± 2 ml, ?7%). The transient increase in femoral blood volume entering the leg during the first 40 s of passive movement was attenuated in the HTx recipients (24 ± 8 ml) compared with controls (93 ± 7 ml), whereas peripheral vascular function (FMD) appeared similar between HTx recipients (8 ± 2%) and controls (6 ± 1%). These data reveal that the absence of an HR increase in HTx recipients significantly impacts the peripheral vascular response to passive movement in this population and supports the concept that an increase in CO is a major contributor to exercise-induced hyperemia. PMID:20833963

  15. Human alpha-actinin-3 genotype association with exercise-induced muscle damage and the repeated-bout effect.

    PubMed

    Venckunas, Tomas; Skurvydas, Albertas; Brazaitis, Marius; Kamandulis, Sigitas; Snieckus, Audrius; Moran, Colin N

    2012-12-01

    Alpha-actinin-3 (ACTN3) is an integral part of the Z line of the sarcomere. The ACTN3 R577X (rs1815739) polymorphism determines the presence or absence of functional ACTN3, which may influence the extent of exercise-induced muscle damage. This study aimed to compare the impact of, and recovery from, muscle-damaging eccentric exercise on subjects with or without functional ACTN3. Seventeen young men (20-33 years old), homozygous for the R (n = 9) or X (n = 8) alleles, performed two bouts of stretch-shortening exercise (50 drop jumps) two weeks apart. Muscle soreness, plasma creatine kinase (CK) activity, jump height, maximal voluntary isometric torque (MVC), peak concentric isokinetic torque (IT), and electrically stimulated knee extension torques at 20 and 100 Hz were measured at baseline and at a number of time points up to 14 days after each bout. There were no significant baseline differences between the groups. However, significant time point × genotype interactions were observed for MVC (p = 0.021) and IT (p = 0.011) for the immediate effect of eccentric exercise in bout 1. The RR group showed greater voluntary force decrements (RR vs. XX: MVC, -33.3% vs. -24.5%; IT, -35.9% vs. -23.2%) and slower recovery. A repeated-bout effect was clearly observed, but there were no differences by genotype group. The ACTN3 genotype modulates the response of muscle function to plyometric jumping exercise, although the differences are modest. The ACTN3 genotype does not influence the clearly observed repeated-bout effect; however, XX homozygotes recover baseline voluntary torque values faster and thus may be able to undertake more frequent training sessions. PMID:22891846

  16. Diagnosis of mitochondrial myopathies.

    PubMed

    Milone, Margherita; Wong, Lee-Jun

    2013-01-01

    Mitochondria are ubiquitous organelles and play crucial roles in vital functions, most importantly, the oxidative phosphorylation and energy metabolism. Therefore, mitochondrial dysfunction can affect multiple tissues, with muscle and nerve preferentially affected. Mitochondrial myopathy is a common clinical phenotype, which is characterized by early fatigue and/or fixed muscle weakness; rhabdomyolysis can seldom occur. Muscle biopsy often identifies signs of diseased mitochondria by morphological studies, while biochemical analysis may identify respiratory chain deficiencies. The clinical, morphological and biochemical data guide molecular analysis. Being the mitochondrial function under the control of both mitochondrial DNA and nuclear DNA, the search for mitochondrial DNA mutations and mitochondrial DNA quantitation, may not be sufficient for the molecular diagnosis of mitochondrial myopathies. Approximately 1500 nuclear genes can affect mitochondrial structure and function and the targeting of such genes may be necessary to reach the diagnosis. The identification of causative molecular defects in nuclear or mitochondrial genome leads to the definite diagnosis of mitochondrial myopathy. PMID:23911206

  17. Restricted mitochondrial protein acetylation initiates mitochondrial autophagy

    PubMed Central

    Webster, Bradley R.; Scott, Iain; Han, Kim; Li, Jian H.; Lu, Zhongping; Stevens, Mark V.; Malide, Daniela; Chen, Yong; Samsel, Leigh; Connelly, Patricia S.; Daniels, Mathew P.; McCoy, J. Philip; Combs, Christian A.; Gucek, Marjan; Sack, Michael N.

    2013-01-01

    Summary Because nutrient-sensing nuclear and cytosolic acetylation mediates cellular autophagy, we investigated whether mitochondrial acetylation modulates mitochondrial autophagy (mitophagy). Knockdown of GCN5L1, a component of the mitochondrial acetyltransferase machinery, diminished mitochondrial protein acetylation and augmented mitochondrial enrichment of autophagy mediators. This program was disrupted by SIRT3 knockdown. Chronic GCN5L1 depletion increased mitochondrial turnover and reduced mitochondrial protein content and/or mass. In parallel, mitochondria showed blunted respiration and enhanced ‘stress-resilience’. Genetic disruption of autophagy mediators Atg5 and p62 (also known as SQSTM1), as well as GCN5L1 reconstitution, abolished deacetylation-induced mitochondrial autophagy. Interestingly, this program is independent of the mitophagy E3-ligase Parkin (also known as PARK2). Taken together, these data suggest that deacetylation of mitochondrial proteins initiates mitochondrial autophagy in a canonical autophagy-mediator-dependent program and shows that modulation of this regulatory program has ameliorative mitochondrial homeostatic effects. PMID:24006259

  18. Minotaur is critical for primary piRNA biogenesis

    PubMed Central

    Vagin, Vasily V.; Yu, Yang; Jankowska, Anna; Luo, Yicheng; Wasik, Kaja A.; Malone, Colin D.; Harrison, Emily; Rosebrock, Adam; Wakimoto, Barbara T.; Fagegaltier, Delphine; Muerdter, Felix; Hannon, Gregory J.

    2013-01-01

    Piwi proteins and their associated small RNAs are essential for fertility in animals. In part, this is due to their roles in guarding germ cell genomes against the activity of mobile genetic elements. piRNA populations direct Piwi proteins to silence transposon targets and, as such, form a molecular code that discriminates transposons from endogenous genes. Information ultimately carried by piRNAs is encoded within genomic loci, termed piRNA clusters. These give rise to long, single-stranded, primary transcripts that are processed into piRNAs. Despite the biological importance of this pathway, neither the characteristics that define a locus as a source of piRNAs nor the mechanisms that catalyze primary piRNA biogenesis are well understood. We searched an EMS-mutant collection annotated for fertility phenotypes for genes involved in the piRNA pathway. Twenty-seven homozygous sterile strains showed transposon-silencing defects. One of these, which strongly impacted primary piRNA biogenesis, harbored a causal mutation in CG5508, a member of the Drosophila glycerol-3-phosphate O-acetyltransferase (GPAT) family. These enzymes catalyze the first acylation step on the path to the production of phosphatidic acid (PA). Though this pointed strongly to a function for phospholipid signaling in the piRNA pathway, a mutant form of CG5508, which lacks the GPAT active site, still functions in piRNA biogenesis. We have named this new biogenesis factor Minotaur. PMID:23788724

  19. FORUM REVIEW ARTICLE Redox Processes Controlling the Biogenesis

    E-print Network

    Hamel, Patrice

    operate, the rather simple System III in yeast and animals and System I in plants and some protozoans in the different c-type cytochrome biogenesis systems to maintain both heme iron and apocytochrome cys- teines-type cytochromes Cytochromes are redox active hemoproteins. Their activity is based on the change of their heme-iron

  20. Mechanisms of organelle biogenesis govern stochastic fluctuations in organelle abundance

    PubMed Central

    Mukherji, Shankar; O'Shea, Erin K

    2014-01-01

    Fluctuations in organelle abundance can profoundly limit the precision of cell biological processes from secretion to metabolism. We modeled the dynamics of organelle biogenesis and predicted that organelle abundance fluctuations depend strongly on the specific mechanisms that increase or decrease the number of a given organelle. Our model exactly predicts the size of experimentally measured Golgi apparatus and vacuole abundance fluctuations, suggesting that cells tolerate the maximum level of variability generated by the Golgi and vacuole biogenesis pathways. We observe large increases in peroxisome abundance fluctuations when cells are transferred from glucose-rich to fatty acid-rich environments. These increased fluctuations are significantly diminished in mutants lacking peroxisome fission factors, leading us to infer that peroxisome biogenesis switches from de novo synthesis to primarily fission. Our work provides a general framework for exploring stochastic organelle biogenesis and using fluctuations to quantitatively unravel the biophysical pathways that control the abundance of subcellular structures. DOI: http://dx.doi.org/10.7554/eLife.02678.001 PMID:24916159

  1. Lipoprotein biogenesis in Gram-positive bacteria: knowing when to

    E-print Network

    Palmer, Tracy

    Lipoprotein biogenesis in Gram- positive bacteria: knowing when to hold `em, knowing when to fold Tyne, NE1 8ST, UK Gram-positive bacterial lipoproteins are a functionally diverse and important class of these proteins, their role in virulence in Gram-positive bacteria and their potential as vaccine candidates

  2. Platelet biogenesis and functions require correct protein O-glycosylation

    E-print Network

    Gleeson, Joseph G.

    Platelet biogenesis and functions require correct protein O-glycosylation Yingchun Wanga , Shawn M, and approved August 24, 2012 (received for review May 15, 2012) Platelets express a variety of membrane and secreted glycoproteins, but the importance of glycosylation to platelet functions is poorly understood

  3. Centrosome biogenesis and function: centrosomics brings new understanding

    Microsoft Academic Search

    Mónica Bettencourt-Dias; David M. Glover

    2007-01-01

    Centrosomes, which were first described in the late 19th century, are found in most animal cells and undergo duplication once every cell cycle so that their number remains stable, like the genetic material of a cell. However, their function and regulation have remained elusive and controversial. Only recently has some understanding of these fundamental aspects of centrosome function and biogenesis

  4. Defects in mitochondrial DNA replication and oxidative damage in muscle of mtDNA mutator mice.

    PubMed

    Kolesar, Jill E; Safdar, Adeel; Abadi, Arkan; MacNeil, Lauren G; Crane, Justin D; Tarnopolsky, Mark A; Kaufman, Brett A

    2014-10-01

    A causal role for mitochondrial dysfunction in mammalian aging is supported by recent studies of the mtDNA mutator mouse ("PolG" mouse), which harbors a defect in the proofreading-exonuclease activity of mitochondrial DNA polymerase gamma. These mice exhibit accelerated aging phenotypes characteristic of human aging, including systemic mitochondrial dysfunction, exercise intolerance, alopecia and graying of hair, curvature of the spine, and premature mortality. While mitochondrial dysfunction has been shown to cause increased oxidative stress in many systems, several groups have suggested that PolG mutator mice show no markers of oxidative damage. These mice have been presented as proof that mitochondrial dysfunction is sufficient to accelerate aging without oxidative stress. In this study, by normalizing to mitochondrial content in enriched fractions we detected increased oxidative modification of protein and DNA in PolG skeletal muscle mitochondria. We separately developed novel methods that allow simultaneous direct measurement of mtDNA replication defects and oxidative damage. Using this approach, we find evidence that suggests PolG muscle mtDNA is indeed oxidatively damaged. We also observed a significant decrease in antioxidants and expression of mitochondrial biogenesis pathway components and DNA repair enzymes in these mice, indicating an association of maladaptive gene expression with the phenotypes observed in PolG mice. Together, these findings demonstrate the presence of oxidative damage associated with the premature aging-like phenotypes induced by mitochondrial dysfunction. PMID:25106705

  5. The reducible complexity of a mitochondrial molecular machine

    PubMed Central

    Clements, Abigail; Bursac, Dejan; Gatsos, Xenia; Perry, Andrew J.; Civciristov, Srgjan; Celik, Nermin; Likic, Vladimir A.; Poggio, Sebastian; Jacobs-Wagner, Christine; Strugnell, Richard A.; Lithgow, Trevor

    2009-01-01

    Molecular machines drive essential biological processes, with the component parts of these machines each contributing a partial function or structural element. Mitochondria are organelles of eukaryotic cells, and depend for their biogenesis on a set of molecular machines for protein transport. How these molecular machines evolved is a fundamental question. Mitochondria were derived from an ?-proteobacterial endosymbiont, and we identified in ?-proteobacteria the component parts of a mitochondrial protein transport machine. In bacteria, the components are found in the inner membrane, topologically equivalent to the mitochondrial proteins. Although the bacterial proteins function in simple assemblies, relatively little mutation would be required to convert them to function as a protein transport machine. This analysis of protein transport provides a blueprint for the evolution of cellular machinery in general. PMID:19717453

  6. Developmental changes and organelle biogenesis in the reproductive organs of thermogenic skunk cabbage (Symplocarpus renifolius)

    PubMed Central

    Ito-Inaba, Yasuko; Sato, Mayuko; Masuko, Hiromi; Hida, Yamato; Toyooka, Kiminori; Watanabe, Masao; Inaba, Takehito

    2009-01-01

    Sex-dependent thermogenesis during reproductive organ development in the inflorescence is a characteristic feature of some of the protogynous arum species. One such plant, skunk cabbage (Symplocarpus renifolius), can produce massive heat during the female stage but not during the subsequent male stage in which the stamen completes development, the anthers dehisce, and pollen is released. Unlike other thermogenic species, skunk cabbage belongs to the bisexual flower group. Although recent studies have identified the spadix as the thermogenic organ, it remains unclear how individual tissues or intracellular structures are involved in thermogenesis. In this study, reproductive organ development and organelle biogenesis were examined during the transition from the female to the male stage. During the female stage, the stamens exhibit extensive structural changes including changes in organelle structure and density. They accumulate high levels of mitochondrial proteins, including possible thermogenic factors, alternative oxidase, and uncoupling protein. By contrast, the petals and pistils do not undergo extensive changes during the female stage. However, they contain a larger number of mitochondria than during the male stage in which they develop large cytoplasmic vacuoles. Comparison between female and male spadices suggests that mitochondrial number rather than their level of activity correlates with thermogenesis. Their spadices, even in the male, contain a larger amount of mitochondria that had greater oxygen consumption, compared with non-thermogenic plants. Taken together, our data suggest that the extensive maturation process in stamens produces massive heat through increased metabolic activities. The possible mechanisms by which petal and pistil metabolism may affect thermogenesis are also discussed. PMID:19640927

  7. The Core Components of Organelle Biogenesis and Membrane Transport in the Hydrogenosomes of Trichomonas vaginalis

    PubMed Central

    Rada, Petr; Doležal, Pavel; Jedelský, Petr L.; Bursac, Dejan; Perry, Andrew J.; Šedinová, Miroslava; Smíšková, Kate?ina; Novotný, Marian; Beltrán, Neritza Campo; Hrdý, Ivan; Lithgow, Trevor; Tachezy, Jan

    2011-01-01

    Trichomonas vaginalis is a parasitic protist of the Excavata group. It contains an anaerobic form of mitochondria called hydrogenosomes, which produce hydrogen and ATP; the majority of mitochondrial pathways and the organellar genome were lost during the mitochondrion-to-hydrogenosome transition. Consequently, all hydrogenosomal proteins are encoded in the nucleus and imported into the organelles. However, little is known about the membrane machineries required for biogenesis of the organelle and metabolite exchange. Using a combination of mass spectrometry, immunofluorescence microscopy, in vitro import assays and reverse genetics, we characterized the membrane proteins of the hydrogenosome. We identified components of the outer membrane (TOM) and inner membrane (TIM) protein translocases include multiple paralogs of the core Tom40-type porins and Tim17/22/23 channel proteins, respectively, and uniquely modified small Tim chaperones. The inner membrane proteins TvTim17/22/23-1 and Pam18 were shown to possess conserved information for targeting to mitochondrial inner membranes, but too divergent in sequence to support the growth of yeast strains lacking Tim17, Tim22, Tim23 or Pam18. Full complementation was seen only when the J-domain of hydrogenosomal Pam18 was fused with N-terminal region and transmembrane segment of the yeast homolog. Candidates for metabolite exchange across the outer membrane were identified including multiple isoforms of the ?-barrel proteins, Hmp35 and Hmp36; inner membrane MCF-type metabolite carriers were limited to five homologs of the ATP/ADP carrier, Hmp31. Lastly, hydrogenosomes possess a pathway for the assembly of C-tail-anchored proteins into their outer membrane with several new tail-anchored proteins being identified. These results show that hydrogenosomes and mitochondria share common core membrane components required for protein import and metabolite exchange; however, they also reveal remarkable differences that reflect the functional adaptation of hydrogenosomes to anaerobic conditions and the peculiar evolutionary history of the Excavata group. PMID:21935410

  8. Targeting mitochondrial alterations to prevent type 2 diabetes--evidence from studies of dietary redox-active compounds.

    PubMed

    Cheng, Zhiyong; Schmelz, Eva M; Liu, Dongmin; Hulver, Matthew W

    2014-08-01

    As a growing epidemic, type 2 diabetes mellitus (T2DM) has significantly affected the individual's quality of life and economy of the society. Understanding the mechanisms of the disease and discovery of new therapeutic options has become more urgent than ever before. Mitochondrial alterations (e.g. functional alterations, and impaired biogenesis and dynamics) are strongly associated with the development of T2DM. Accumulation of reactive oxygen species or intermediates of incomplete fatty acid oxidation due to mitochondrial deficiency activates stress kinases and dampens insulin signaling. Redox-active compounds such as resveratrol, pyrroloquinoline quinone, and hydroxytyrosol can potently counteract reactive oxygen species, and improve mitochondrial function and biogenesis. Therefore, targeting the mitochondrial alterations with these redox-active compounds may lead to new therapeutic or preventive options for T2DM. In this article, we review the molecular mechanisms of mitochondrial alterations in T2DM, and the action of redox-active compounds to reverse mitochondrial changes and oxidative stress in T2DM. In addition, the current challenges and future directions are discussed and prospected. PMID:24668725

  9. Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis.

    PubMed

    Arancio, Walter; Carina, Valeria; Pizzolanti, Giuseppe; Tomasello, Laura; Pitrone, Maria; Baiamonte, Concetta; Amato, Marco Calogero; Giordano, Carla

    2015-01-01

    It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated. PMID:25705224

  10. Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis

    PubMed Central

    Carina, Valeria; Tomasello, Laura; Pitrone, Maria; Baiamonte, Concetta; Amato, Marco Calogero

    2015-01-01

    It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated. PMID:25705224

  11. Biogenesis of cbb3-type cytochrome c oxidase in Rhodobacter capsulatus

    PubMed Central

    Ekici, Seda; Pawlik, Grzegorz; Lohmeyer, Eva; Koch, Hans-Georg; Daldal, Fevzi

    2011-01-01

    The cbb3-type cytochrome c oxidases (cbb3-Cox) constitute the second most abundant cytochrome c oxidase (Cox) group after the mitochondrial-like aa3-type Cox. They are present in bacteria only, and are considered to represent a primordial innovation in the domain of Eubacteria due to their phylogenetic distribution and their similarity to nitric oxide (NO) reductases. They are crucial for the onset of many anaerobic biological processes, such as anoxygenic photosynthesis or nitrogen fixation. In addition, they are prevalent in many pathogenic bacteria, and important for colonizing low oxygen tissues. Studies related to cbb3-Cox provide a fascinating paradigm for the biogenesis of sophisticated oligomeric membrane proteins. Complex subunit maturation and assembly machineries, producing the c-type cytochromes and the binuclear heme b3-CuB center, have to be coordinated precisely both temporally and spatially to yield a functional cbb3-Cox enzyme. In this review we summarize our current knowledge on the structure, regulation and assembly of cbb3-Cox, and provide a highly tentative model for cbb3-Cox assembly and formation of its heme b3-CuB binuclear center. PMID:22079199

  12. Evolution and significance of the Lon gene family in Arabidopsis organelle biogenesis and energy metabolism

    PubMed Central

    Rigas, Stamatis; Daras, Gerasimos; Tsitsekian, Dikran; Alatzas, Anastasios; Hatzopoulos, Polydefkis

    2014-01-01

    Lon is the first identified ATP-dependent protease highly conserved across all kingdoms. Model plant species Arabidopsis thaliana has a small Lon gene family of four members. Although these genes share common structural features, they have distinct properties in terms of gene expression profile, subcellular targeting and substrate recognition motifs. This supports the notion that their functions under different environmental conditions are not necessarily redundant. This article intends to unravel the biological role of Lon proteases in energy metabolism and plant growth through an evolutionary perspective. Given that plants are sessile organisms exposed to diverse environmental conditions and plant organelles are semi-autonomous, it is tempting to suggest that Lon genes in Arabidopsis are paralogs. Adaptive evolution through repetitive gene duplication events of a single archaic gene led to Lon genes with complementing sets of subfunctions providing to the organism rapid adaptability for canonical development under different environmental conditions. Lon1 function is adequately characterized being involved in mitochondrial biogenesis, modulating carbon metabolism, oxidative phosphorylation and energy supply, all prerequisites for seed germination and seedling establishment. Lon is not a stand-alone proteolytic machine in plant organelles. Lon in association with other nuclear-encoded ATP-dependent proteases builds up an elegant nevertheless, tight interconnected circuit. This circuitry channels properly and accurately, proteostasis and protein quality control among the distinct subcellular compartments namely mitochondria, chloroplasts, and peroxisomes. PMID:24782883

  13. Eccentric exercise-induced delayed-onset muscle soreness and changes in markers of muscle damage and inflammation.

    PubMed

    Kanda, Kazue; Sugama, Kaoru; Hayashida, Harumi; Sakuma, Jun; Kawakami, Yasuo; Miura, Shigeki; Yoshioka, Hiroshi; Mori, Yuichi; Suzuki, Katsuhiko

    2013-01-01

    The purpose of this study was to determine the relationships among delayed-onset muscle soreness (DOMS), muscle damage and inflammatory responses to eccentric exercise and investigate the underlying mechanisms. Nine healthy males performed one-leg calf-raise exercise with their right leg on a force plate. They performed 10 sets of 40 repetitions of exercise at 0.5 Hz by the load corresponding to the half of their body weight, with a rest for 3 min between sets. DOMS was evaluated by a visual analogue scale (VAS). Blood and urine samples were collected before and 2, 4, 24, 48, 72 and 96 h post-exercise. Blood samples were analyzed for leucocyte differential counts and neutrophil functions (migratory activity and oxidative burst activity). We also determined a serum marker of muscle damage, myoglobin (Mb), and plasma and urinary prostaglandin E2 as an algesic substance. As for the inflammatory mediators, plasma and urine were analyzed for cytokines (interleukin (IL)-1beta, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, tumour necrosis factor-alpha, interferon-gamma, monocyte chemotactic protein-1, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and granulocyte macrophage colony-stimulating factor), leucocyte activation markers (calprotectin and myeloperoxidase), and neutrophil chemotactic factor complement 5a. All subjects reported muscle soreness on subsequent days and VAS peaked at 72 h after exercise. Serum Mb concentration significantly increased (p < 0.05) at 72 h after exercise as compared with the pre-exercise values which was correlated with the increases in VAS at 72 h (r = 0.73, p < 0.05). Circulating neutrophil count and migratory activity increased significantly (p < 0.01, and p < 0.05, respectively) at 4 h after exercise, whereas there were no significant changes in the other plasma and urinary inflammatory mediators. These results suggest that neutrophils can be mobilized into the circulation and migrate to the muscle tissue several hours after the eccentric exercise. There were also positive correlations between the exercise-induced increases in neutrophil migratory activity at 4 h and the increases in Mb at 48 h (r = 0.67, p < 0.05). These findings suggest that neutrophil mobilization and migration after exercise may be involved in the muscle damage and inflammatory processes. PMID:23977721

  14. Central blockade of nitric oxide transmission impairs exercise-induced neuronal activation in the PVN and reduces physical performance.

    PubMed

    Lima, Paulo M A; Santiago, Henrique P; Szawka, Raphael E; Coimbra, Cândido C

    2014-09-01

    The blockade of central nitric oxide (NO) signaling modifies the thermoregulatory and metabolic adjustments that occur during exercise, thereby impairing physical performance. However, the brain areas involved in this response remain unknown. Nitrergic neurons are present in the hypothalamic areas that are activated during exercise and participate in autonomic and neuroendocrine responses, such as, the hypothalamic paraventricular nucleus (PVN) and the supraoptic nucleus (SON). To investigate whether brain NO signaling affects thermoregulation during exercise through the activation of hypothalamic neurons, rats underwent acute submaximal treadmill exercise (18 mmin(-1), 5% inclination) until fatigue received an intracerebroventricular injection of 1.43 ?mol N?-nitro-l-arginine metil ester (L-NAME), a nitric oxide synthase inhibitor, or saline (SAL). Skin tail temperature (Tsk) and internal body temperature (Ti) were continuously recorded and c-Fos expression was determined in the PVN and the SON. L-NAME treatment reduced physical performance by 48%, which was positively correlated with tail vasodilation capacity, which was reduced by 28%, and negatively correlated with heat storage rate (HSR), which was increased by 38%. Physical exercise until fatigue increased the number of c-Fos-immunoreactive (ir) neurons in the PVN and the SON. L-NAME-treatment significantly reduced the exercise-induced c-Fos expression in the PVN, whereas it had no effect in the SON. Interestingly, the number of c-Fos-ir neurons in the PVN was closely correlated with physical performance and inversely associated with HSR. Thus, the inhibition of central NO attenuates neuronal activation induced by exercise in the PVN, impairs the autonomic regulation of heat dissipation, and anticipates the fatigue. Brain NO seems to play a role in exercise performance through the regulation of neuronal activation in the PVN, but not in the SON, although the SON neurons are also activated by running exercise. Moreover, this role in performance mediated by neuronal activation in the PVN can be related with the improvement of thermoregulatory adjustments that occur during exercise. PMID:25234442

  15. Mitochondrial neuropathy.

    PubMed

    Finsterer, Josef

    2005-04-01

    Polyneuropathy is a frequent feature of mitochondriopathy (MCP). If and how often polyneuropathy in MCP is primarily due to the underlying disorder (mitochondrial neuropathy, MN) or due to other well-known causes is unknown. Retrospectively investigated were 108 MCP-patients with polyneuropathy. According to established diagnostic criteria 37 patients were classified as definite MCP, 56 as probable MCP and 15 as possible MCP. In 38 of the 108 MCP-patients with polyneuropathy (35%), no plausible cause for polyneuropathy other than MCP could be found. MN was characterized by weakness, muscle cramps, wasting, reduced tendon reflexes, muscle pain, ataxia, restless legs, hypesthesia, paresthesia, dysesthesia, and vegetative impairment. In 21 cases predominantly motor fibers, in 14 cases both motor and sensory fibers and in 3 cases predominantly sensory fibers were affected. Axonal degeneration was found in 19 cases, demyelination in 4 and mixed-type polyneuropathy in 15. On sural nerve biopsy axonal loss was the predominant finding. In a single case tomaculae and abnormally shaped and structured mitochondria were found. MN exists, occurs in one third of the MCP-patients with polyneuropathy, and is characterized by predominant affection of the motor and sensory fibers with diffuse, symmetric and equal distribution between upper and lower limbs and by axonal degeneration. PMID:15823672

  16. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone

    Microsoft Academic Search

    Leanne Wilson-Fritch; Alison Burkart; Gregory Bell; Karen Mendelson; John D. Leszyk; Sarah M. Nicoloro; Michael P. Czech; Silvia Corvera

    2003-01-01

    White adipose tissue is an important endocrine organ involved in the control of whole-body metabolism, insulin sensitivity, and food intake. To better understand these functions, 3T3-L1 cell differentiation was studied by using combined proteomic and genomic strategies. The proteomics approach developed here exploits velocity gradient centrifugation as an alternative to isoelectric focusing for protein separation in the first dimension. A

  17. A mitochondrial ferredoxin is essential for biogenesis of cellular iron-sulfur proteins

    Microsoft Academic Search

    Heike Lange; Anita Kaut; Gyula Kispal; Roland Lill

    2000-01-01

    Institut für Zytobiologie und Zytopathologie der Philipps-Universität Marburg, Robert-Koch-Strasse 5, 35033 Marburg, Germany Edited by Helmut Beinert, University of Wisconsin, Madison, WI, and approved November 24, 1999 (received for review September 28, 1999) Iron-sulfur (Fe\\/S) cluster-containing proteins catalyze a number of electron transfer and metabolic reactions. The components and molecular mechanisms involved in the assembly of the Fe\\/S clusters have

  18. Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the "Warburg Effect." Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerob...

  19. Inadequate mito-biogenesis in primary dermal fibroblasts from old humans is associated with impairment of PGC1A-independent stimulation.

    PubMed

    Kalfalah, Faiza; Sobek, Stefan; Bornholz, Beatrice; Götz-Rösch, Christine; Tigges, Julia; Fritsche, Ellen; Krutmann, Jean; Köhrer, Karl; Deenen, René; Ohse, Sebastian; Boerries, Melanie; Busch, Hauke; Boege, Fritz

    2014-08-01

    Extrinsic skin ageing converges on the dermis, a post-mitotic tissue compartment consisting of extracellular matrix and long-lived fibroblasts prone to damage accumulation and maladaptation. Aged human fibroblasts exhibit mitochondrial and nuclear dysfunctions, which may be a cause or consequence of ageing. We report on a systematic study of human dermal fibroblasts retrieved from female donors aged 20-67 years and analysed ex vivo at low population doubling precluding replicative senescence. According to gene set enrichment analysis of genome wide array data, the most prominent age-associated change of the transcriptome was decreased expression of mitochondrial genes. Consistent with that, mitochondrial content and cell proliferation declined with donor age. This was associated with upregulation of AMP-dependent protein kinase (AMPK), increased mRNA levels of PPAR?-coactivator 1? (PGC1A) and decreased levels of NAD(+)-dependent deacetylase sirtuin 1. In the old cells the PGC1A-mediated mito-biogenetic response to direct AMPK-stimulation by AICAR was undiminished, while the PGC1A-independent mito-biogenetic response to starvation was attenuated and accompanied by increased ROS-production. In summary, these observations suggest an age-associated decline in PGC1A-independent mito-biogenesis, which is insufficiently compensated by upregulation of the AMPK/PGC1A-axis leading under baseline conditions to decreased mitochondrial content and reductive overload of residual respiratory capacity. PMID:24699405

  20. Effect of thyroid hormone on mitochondrial properties and oxidative stress in cells from patients with mtDNA defects.

    PubMed

    Menzies, Keir J; Robinson, Brian H; Hood, David A

    2009-02-01

    Mitochondrial (mt)DNA mutations contribute to various disease states characterized by low ATP production. In contrast, thyroid hormone [3,3',5-triiodothyronine (T(3))] induces mitochondrial biogenesis and enhances ATP generation within cells. To evaluate the role of T(3)-mediated mitochondrial biogenesis in patients with mtDNA mutations, three fibroblast cell lines with mtDNA mutations were evaluated, including two patients with Leigh's syndrome and one with hypertrophic cardiomyopathy. Compared with control cells, patient fibroblasts displayed similar levels of mitochondrial mass, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), mitochondrial transcription factor A (Tfam), and uncoupling protein 2 (UCP2) protein expression. However, patient cells exhibited a 1.6-fold elevation in ROS production, a 1.7-fold elevation in cytoplasmic Ca2+ levels, a 1.2-fold elevation in mitochondrial membrane potential, and 30% less complex V activity compared with control cells. Patient cells also displayed 20-25% reductions in both cytochrome c oxidase (COX) activity and MnSOD protein levels compared with control cells. After T(3) treatment of patient cells, ROS production was decreased by 40%, cytoplasmic Ca2+ was reduced by 20%, COX activity was increased by 1.3-fold, and ATP levels were elevated by 1.6-fold, despite the absence of a change in mitochondrial mass. There were no significant alterations in the protein expression of PGC-1alpha, Tfam, or UCP2 in either T(3)-treated patient or control cells. However, T(3) restored the mitochondrial membrane potential, complex V activity, and levels of MnSOD to normal values in patient cells and elevated MnSOD levels by 21% in control cells. These results suggest that T(3) acts to reduce cellular oxidative stress, which may help attenuate ROS-mediated damage, along with improving mitochondrial function and energy status in cells with mtDNA defects. PMID:19036942

  1. Discovery of a small molecule that inhibits bacterial ribosome biogenesis.

    PubMed

    Stokes, Jonathan M; Davis, Joseph H; Mangat, Chand S; Williamson, James R; Brown, Eric D

    2014-01-01

    While small molecule inhibitors of the bacterial ribosome have been instrumental in understanding protein translation, no such probes exist to study ribosome biogenesis. We screened a diverse chemical collection that included previously approved drugs for compounds that induced cold sensitive growth inhibition in the model bacterium Escherichia coli. Among the most cold sensitive was lamotrigine, an anticonvulsant drug. Lamotrigine treatment resulted in the rapid accumulation of immature 30S and 50S ribosomal subunits at 15 °C. Importantly, this was not the result of translation inhibition, as lamotrigine was incapable of perturbing protein synthesis in vivo or in vitro. Spontaneous suppressor mutations blocking lamotrigine activity mapped solely to the poorly characterized domain II of translation initiation factor IF2 and prevented the binding of lamotrigine to IF2 in vitro. This work establishes lamotrigine as a widely available chemical probe of bacterial ribosome biogenesis and suggests a role for E. coli IF2 in ribosome assembly. PMID:25233066

  2. PPAR?/? activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition

    PubMed Central

    Liu, Jian; Wang, Peiyong; Luo, Jinwen; Huang, Yao; He, Lan; Yang, Huan; Li, Qingbao; Wu, Sijie; Zhelyabovska, Olga; Yang, Qinglin

    2011-01-01

    Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPAR?/? activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPAR?/? in adult mice using a tamoxifen inducible transgenic approach with Cre-LoxP recombination. The expression of PPAR?/? mRNA and protein in cardiomyocytes of adult mice was substantially increased after short-term induction. In these mice, the cardiac expression of key factors involved in mitochondrial biogenesis, such as PPAR? coactivator-1, endogenous anti-oxidants Cu/Zn-Superoxide dismutase and catalase, fatty acid and glucose metabolism such as carnitine palmitoyltransferase Ib, II and glucose transporter 4, were upregulated. Subsequently, myocardial oxidative metabolism was elevated concomitant with an increased mitochondrial DNA copy number and an enhanced cardiac performance. Moreover, activation of PPAR?/? in the adult heart improved cardiac function and resisted to progression pathological development in mechanical stress condition. We conclude that PPAR?/? activation in the adult heart will promote cardiac performance along with transcriptional upregulation of mitochondrial biogenesis and defense, as well as oxidative metabolism at basal and pressure-overload conditions. PMID:21220704

  3. The dynamics of the mitochondrial organelle as a potential therapeutic target

    PubMed Central

    Anne Stetler, R; Leak, Rehana K; Gao, Yanqin; Chen, Jun

    2013-01-01

    Mitochondria play a central role in cell fate after stressors such as ischemic brain injury. The convergence of intracellular signaling pathways on mitochondria and their release of critical factors are now recognized as a default conduit to cell death or survival. Besides the individual processes that converge on or emanate from mitochondria, a mitochondrial organellar response to changes in the cellular environment has recently been described. Whereas mitochondria have previously been perceived as a major center for cellular signaling, one can postulate that the organelle's dynamics themselves affect cell survival. This brief perspective review puts forward the concept that disruptions in mitochondrial dynamics—biogenesis, clearance, and fission/fusion events—may underlie neural diseases and thus could be targeted as neuroprotective strategies in the context of ischemic injury. To do so, we present a general overview of the current understanding of mitochondrial dynamics and regulation. We then review emerging studies that correlate mitochondrial biogenesis, mitophagy, and fission/fusion events with neurologic disease and recovery. An overview of the system as it is currently understood is presented, and current assessment strategies and their limitations are discussed. PMID:23093069

  4. Function and biogenesis of iron-sulphur proteins

    Microsoft Academic Search

    Roland Lill

    2009-01-01

    Iron-sulphur (Fe-S) clusters have long been recognized as essential and versatile cofactors of proteins involved in catalysis, electron transport and sensing of ambient conditions. Despite the relative simplicity of Fe-S clusters in terms of structure and composition, their synthesis and assembly into apoproteins is a highly complex and coordinated process in living cells. Different biogenesis machineries in both bacteria and

  5. Bmi1 promotes erythroid development through regulating ribosome biogenesis.

    PubMed

    Gao, Rui; Chen, Sisi; Kobayashi, Michihiro; Yu, Hao; Zhang, Yingchi; Wan, Yang; Young, Sara K; Soltis, Anthony; Yu, Ming; Vemula, Sasidhar; Fraenkel, Ernest; Cantor, Alan; Antipin, Yevgeniy; Xu, Yang; Yoder, Mervin C; Wek, Ronald C; Ellis, Steven R; Kapur, Reuben; Zhu, Xiaofan; Liu, Yan

    2015-03-01

    While Polycomb group protein Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We have identified Bmi1 as a novel regulator of erythroid development. Bmi1 is highly expressed in mouse erythroid progenitor cells and its deficiency impairs erythroid differentiation. BMI1 is also important for human erythroid development. Furthermore, we discovered that loss of Bmi1 in erythroid progenitor cells results in decreased transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Bmi1 deficiency stabilizes p53 protein, leading to upregulation of p21 expression and subsequent G0/G1 cell cycle arrest. Genetic inhibition of p53 activity rescues the erythroid defects seen in the Bmi1 null mice, demonstrating that a p53-dependent mechanism underlies the pathophysiology of the anemia. Mechanistically, Bmi1 is associated with multiple ribosomal protein genes and may positively regulate their expression in erythroid progenitor cells. Thus, Bmi1 promotes erythroid development, at least in part through regulating ribosome biogenesis. Ribosomopathies are human disorders of ribosome dysfunction, including Diamond-Blackfan anemia (DBA) and 5q- syndrome, in which genetic abnormalities cause impaired ribosome biogenesis, resulting in specific clinical phenotypes. We observed that BMI1 expression in human hematopoietic stem and progenitor cells from patients with DBA is correlated with the expression of some ribosomal protein genes, suggesting that BMI1 deficiency may play a pathological role in DBA and other ribosomopathies. PMID:25385494

  6. Dissecting Escherichia coli Outer Membrane Biogenesis Using Differential Proteomics

    PubMed Central

    Martorana, Alessandra M.; Motta, Sara; Di Silvestre, Dario; Falchi, Federica; Dehò, Gianni; Mauri, Pierluigi; Sperandeo, Paola; Polissi, Alessandra

    2014-01-01

    The cell envelope of Gram-negative bacteria is a complex multi-layered structure comprising an inner cytoplasmic membrane and an additional asymmetric lipid bilayer, the outer membrane, which functions as a selective permeability barrier and is essential for viability. Lipopolysaccharide, an essential glycolipid located in the outer leaflet of the outer membrane, greatly contributes to the peculiar properties exhibited by the outer membrane. This complex molecule is transported to the cell surface by a molecular machine composed of seven essential proteins LptABCDEFG that form a transenvelope complex and function as a single device. While advances in understanding the mechanisms that govern the biogenesis of the cell envelope have been recently made, only few studies are available on how bacterial cells respond to severe envelope biogenesis defects on a global scale. Here we report the use of differential proteomics based on Multidimensional Protein Identification Technology (MudPIT) to investigate how Escherichia coli cells respond to a block of lipopolysaccharide transport to the outer membrane. We analysed the envelope proteome of a lptC conditional mutant grown under permissive and non permissive conditions and identified 123 proteins whose level is modulated upon LptC depletion. Most such proteins belong to pathways implicated in cell envelope biogenesis, peptidoglycan remodelling, cell division and protein folding. Overall these data contribute to our understanding on how E. coli cells respond to LPS transport defects to restore outer membrane functionality. PMID:24967819

  7. Loss of bone strength in response to exercise-induced weight loss in obese postmenopausal women: results from a pilot study

    PubMed Central

    Shea, K.L.; Gozansky, W.S.; Sherk, V.D.; Swibas, T.A.; Wolfe, P.; Scherzinger, A.; Stamm, E.; Kohrt, W.M.

    2015-01-01

    Objective Exercise-induced weight loss (WL) can lead to decreased areal bone mineral density (aBMD). It is unknown whether this translates into decreased volumetric BMD (vBMD) or bone strength. The purpose of this pilot study was to determine whether exercise-induced WL results in decreased vBMD and bone strength in postmenopausal women. Methods Fourteen subjects participated in a 4-month endurance exercise WL intervention. A weight stable (WS) control group (n=10) was followed for 4 months. Proximal femur aBMD was measured by DXA. Femoral neck vBMD and estimates of bone strength (cross-sectional moment of inertia (CSMI) and section modulus (SM)) were measured by quantitative CT. Results Women were 54.6±2.4 years, BMI 32.1±5.9 kg/m2 and 54.4±2.9 years, BMI 27.9±3.6 kg/m2 in the WL and WS groups, respectively. The WL group lost 3.0±2.6 kg which was predominately fat mass. There was a significant decrease in SMmax. Changes in CSMImax and total hip aBMD were not significant. Total hip vBMD did not decrease significantly in response to WL. There were no significant changes in the WS group. Conclusions WL may lead to decreased bone strength before changes in BMD are detected. Further studies are needed to determine whether bone-targeted exercise can preserve bone strength during WL. PMID:24879027

  8. Adiponectin Alleviates Genioglossal Mitochondrial Dysfunction in Rats Exposed to Intermittent Hypoxia

    PubMed Central

    Dong, Yanbin; Zhang, Xiaofeng; Ding, Ning; Liu, Jiannan; Hutchinson, Sean Z.; Lu, Gan; Zhang, Xilong

    2014-01-01

    Background Genioglossal dysfunction is involved in the pathophysiology of obstructive sleep apnea hypoxia syndrome (OSAHS) characterized by nocturnal chronic intermittent hypoxia (CIH). The pathophysiology of genioglossal dysfunction and possible targeted pharmacotherapy for alleviation of genioglossal injury in CIH require further investigation. Methodology/Principal Findings Rats in the control group were exposed to normal air, while rats in the CIH group and CIH+adiponectin (AD) group were exposed to the same CIH condition (CIH 8 hr/day for 5 successive weeks). Furthermore, rats in CIH+AD group were administrated intravenous AD supplementation at the dosage of 10 µg, twice a week for 5 consecutive weeks. We found that CIH-induced genioglossus (GG) injury was correlated with mitochondrial dysfunction, reduction in the numbers of mitochondrias, impaired mitochondrial ultrastructure, and a reduction in type I fibers. Compared with the CIH group, impaired mitochondrial structure and function was significantly improved and a percentage of type I fiber was elevated in the CIH+AD group. Moreover, compared with the control group, the rats’ GG in the CIH group showed a significant decrease in phosphorylation of LKB1, AMPK, and PGC1-?, whereas there was significant rescue of such reduction in phosphorylation within the CIH+AD group. Conclusions CIH exposure reduces mitochondrial biogenesis and impairs mitochondrial function in GG, while AD supplementation increases mitochondrial contents and alleviates CIH-induced mitochondrial dysfunction possibly through the AMPK pathway. PMID:25329318

  9. Animal models of mitochondrial DNA transactions in disease and ageing

    PubMed Central

    Oliveira, Marcos T.; Garesse, Rafael; Kaguni, Laurie S.

    2012-01-01

    Mitochondrial DNA (mtDNA) transactions, processes that include mtDNA replication, repair, recombination and transcription constitute the initial stages of mitochondrial biogenesis, and are at the core of understanding mitochondrial biology and medicine. All of the protein players are encoded in nuclear genes: some are proteins with well-known functions in the nucleus, others are well-known mitochondrial proteins now ascribed new functions, and still others are newly discovered factors. In this article we review recent advances in the field of mtDNA transactions with a special focus on physiological studies. In particular, we consider the expression of variant proteins, or altered expression of factors involved in these processes in powerful model organisms, such as Drosophila melanogaster and the mouse, which have promoted recognition of the broad relevance of oxidative phosphorylation defects resulting from improper maintenance of mtDNA. Furthermore, the animal models recapitulate many phenotypes related to human ageing and a variety of different diseases, a feature that has enhanced our understanding of, and inspired theories about, the molecular mechanisms of such biological processes. PMID:20123011

  10. Mitochondrial protein BmPAPI modulates the length of mature piRNAs.

    PubMed

    Honda, Shozo; Kirino, Yoriko; Maragkakis, Manolis; Alexiou, Panagiotis; Ohtaki, Akashi; Murali, Ramachandran; Mourelatos, Zissimos; Kirino, Yohei

    2013-10-01

    PIWI proteins and their associated PIWI-interacting RNAs (piRNAs) protect genome integrity by silencing transposons in animal germlines. The molecular mechanisms and components responsible for piRNA biogenesis remain elusive. PIWI proteins contain conserved symmetrical dimethylarginines (sDMAs) that are specifically targeted by TUDOR domain-containing proteins. Here we report that the sDMAs of PIWI proteins play crucial roles in PIWI localization and piRNA biogenesis in Bombyx mori-derived BmN4 cells, which harbor fully functional piRNA biogenesis machinery. Moreover, RNAi screenings for Bombyx genes encoding TUDOR domain-containing proteins identified BmPAPI, a Bombyx homolog of Drosophila PAPI, as a factor modulating the length of mature piRNAs. BmPAPI specifically recognized sDMAs and interacted with PIWI proteins at the surface of the mitochondrial outer membrane. BmPAPI depletion resulted in 3'-terminal extensions of mature piRNAs without affecting the piRNA quantity. These results reveal the BmPAPI-involved piRNA precursor processing mechanism on mitochondrial outer membrane scaffolds. PMID:23970546

  11. Unraveling the Intricate Organization of Mammalian Mitochondrial Presequence Translocases: Existence of Multiple Translocases for Maintenance of Mitochondrial Function

    PubMed Central

    Sinha, Devanjan; Srivastava, Shubhi; Krishna, Lekshmi

    2014-01-01

    Mitochondria are indispensable organelles implicated in multiple aspects of cellular processes, including tumorigenesis. Heat shock proteins play a critical regulatory role in accurately delivering the nucleus-encoded proteins through membrane-bound presequence translocase (Tim23 complex) machinery. Although altered expression of mammalian presequence translocase components had been previously associated with malignant phenotypes, the overall organization of Tim23 complexes is still unsolved. In this report, we show the existence of three distinct Tim23 complexes, namely, B1, B2, and A, involved in the maintenance of normal mitochondrial function. Our data highlight the importance of Magmas as a regulator of translocase function and in dynamically recruiting the J-proteins DnaJC19 and DnaJC15 to individual translocases. The basic housekeeping function involves translocases B1 and B2 composed of Tim17b isoforms along with DnaJC19, whereas translocase A is nonessential and has a central role in oncogenesis. Translocase B, having a normal import rate, is essential for constitutive mitochondrial functions such as maintenance of electron transport chain complex activity, organellar morphology, iron-sulfur cluster protein biogenesis, and mitochondrial DNA. In contrast, translocase A, though dispensable for housekeeping functions with a comparatively lower import rate, plays a specific role in translocating oncoproteins lacking presequence, leading to reprogrammed mitochondrial functions and hence establishing a possible link between the TIM23 complex and tumorigenicity. PMID:24636990

  12. The role of aberrant mitochondrial bioenergetics in diabetic neuropathy.

    PubMed

    Chowdhury, Subir K Roy; Smith, Darrell R; Fernyhough, Paul

    2013-03-01

    Diabetic neuropathy is a neurological complication of diabetes that causes significant morbidity and, because of the obesity-driven rise in incidence of type 2 diabetes, is becoming a major international health problem. Mitochondrial phenotype is abnormal in sensory neurons in diabetes and may contribute to the etiology of diabetic neuropathy where a distal dying-back neurodegenerative process is a key component contributing to fiber loss. This review summarizes the major features of mitochondrial dysfunction in neurons and Schwann cells in human diabetic patients and in experimental animal models (primarily exhibiting type 1 diabetes). This article attempts to relate these findings to the development of critical neuropathological hallmarks of the disease. Recent work reveals that hyperglycemia in diabetes triggers nutrient excess in neurons that, in turn, mediates a phenotypic change in mitochondrial biology through alteration of the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) signaling axis. This vital energy sensing metabolic pathway modulates mitochondrial function, biogenesis and regeneration. The bioenergetic phenotype of mitochondria in diabetic neurons is aberrant due to deleterious alterations in expression and activity of respiratory chain components as a direct consequence of abnormal AMPK/PGC-1? signaling. Utilization of innovative respirometry equipment to analyze mitochondrial function of cultured adult sensory neurons from diabetic rodents shows that the outcome for cellular bioenergetics is a reduced adaptability to fluctuations in ATP demand. The diabetes-induced maladaptive process is hypothesized to result in exhaustion of the ATP supply in the distal nerve compartment and induction of nerve fiber dissolution. The role of mitochondrial dysfunction in the etiology of diabetic neuropathy is compared with other types of neuropathy with a distal dying-back pathology such as Friedreich ataxia, Charcot-Marie-Tooth disease type 2 and human immunodeficiency virus-associated distal-symmetric neuropathy. PMID:22446165

  13. INHIBITION OF MITOCHONDRIAL TRANSLATION AS A THERAPEUTIC STRATEGY FOR HUMAN ACUTE MYELOID LEUKEMIA

    PubMed Central

    Škrti?, Marko; Sriskanthadevan, Shrivani; Jhas, Bozhena; Gebbia, Marinella; Wang, Xiaoming; Wang, Zezhou; Hurren, Rose; Jitkova, Yulia; Gronda, Marcela; Maclean, Neil; Lai, Courteney K.; Eberhard, Yanina; Bartoszko, Justyna; Spagnuolo, Paul; Rutledge, Angela C.; Datti, Alessandro; Ketela, Troy; Moffat, Jason; Robinson, Brian H.; Cameron, Jessie H.; Wrana, Jeffery; Eaves, Connie J.; Minden, Mark D.; Wang, Jean C.Y.; Dick, John E.; Humphries, Keith; Nislow, Corey; Giaever, Guri; Schimmer, Aaron D.

    2011-01-01

    SUMMARY To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed anti-leukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the anti-leukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis which, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity. PMID:22094260

  14. The roles of exercise-induced immune system disturbances in the pathology of heat stroke : the dual pathway model of heat stroke.

    PubMed

    Lim, Chin Leong; Mackinnon, Laurel T

    2006-01-01

    Heat stroke is a life-threatening condition that can be fatal if not appropriately managed. Although heat stroke has been recognised as a medical condition for centuries, a universally accepted definition of heat stroke is lacking and the pathology of heat stroke is not fully understood. Information derived from autopsy reports and the clinical presentation of patients with heat stroke indicates that hyperthermia, septicaemia, central nervous system impairment and cardiovascular failure play important roles in the pathology of heat stroke. The current models of heat stroke advocate that heat stroke is triggered by hyperthermia but is driven by endotoxaemia. Endotoxaemia triggers the systemic inflammatory response, which can lead to systemic coagulation and haemorrhage, necrosis, cell death and multi-organ failure. However, the current heat stroke models cannot fully explain the discrepancies in high core temperature (Tc) as a trigger of heat stroke within and between individuals. Research on the concept of critical Tc as a limitation to endurance exercise implies that a high Tc may function as a signal to trigger the protective mechanisms against heat stroke. Athletes undergoing a period of intense training are subjected to a variety of immune and gastrointestinal (GI) disturbances. The immune disturbances include the suppression of immune cells and their functions, suppression of cell-mediated immunity, translocation of lipopolysaccharide (LPS), suppression of anti-LPS antibodies, increased macrophage activity due to muscle tissue damage, and increased concentration of circulating inflammatory and pyrogenic cytokines. Common symptoms of exercise-induced GI disturbances include diarrhoea, vomiting, gastrointestinal bleeding, and cramps, which may increase gut-related LPS translocation. This article discusses the current evidence that supports the argument that these exercise-induced immune and GI disturbances may contribute to the development of endotoxaemia and heat stroke. When endotoxaemia can be tolerated or prevented, continuing exercise and heat exposure will elevate Tc to a higher level (>42 degrees C), where heat stroke may occur through the direct thermal effects of heat on organ tissues and cells. We also discuss the evidence suggesting that heat stroke may occur through endotoxaemia (heat sepsis), the primary pathway of heat stroke, or hyperthermia, the secondary pathway of heat stroke. The existence of these two pathways of heat stroke and the contribution of exercise-induced immune and GI disturbances in the primary pathway of heat stroke are illustrated in the dual pathway model of heat stroke. This model of heat stroke suggests that prolonged intense exercise suppresses anti-LPS mechanisms, and promotes inflammatory and pyrogenic activities in the pathway of heat stroke. PMID:16445310

  15. Late onset of exercise induced focal ventricular tachycardia originating from the ventricular end of an A-V accessory pathway after elimination of conduction.

    PubMed

    Sriram, Chenni S; Gonzalez, Mario D; Naccarelli, Gerald V; Luck, Jerry C

    2015-01-01

    The authors report the unique case of remote onset of exercise induced focal ventricular tachycardia in a 40-year old male patient that originated from the ventricular end of an accessory atrioventricular pathway 18 months after a successful ablation. There was no residual conduction across the pathway after the first ablation. The ventricular tachycardia (VT) was mapped to and successfully ablated at the same site where the ventricular end of the pathway was previously ablated. The VT morphology was similar to that of the pre-excited QRS beats noted before. Thus far, in all reported cases of accessory pathway related automaticity there was intact conduction over the pathway or acute injury to it. To the best of our knowledge a case similar to our patient is not yet reported. PMID:25454008

  16. A novel N440K sodium channel mutation causes myotonia with exercise-induced weakness--exclusion of CLCN1 exon deletion/duplication by MLPA.

    PubMed

    Lehmann-Horn, F; Orth, M; Kuhn, M; Jurkat-Rott, K

    2011-10-01

    We report a 4-generation Turkish family with 10 affected members presenting with myotonia and potassium- and exercise-induced paralytic attacks. The clinical presentation was neither typical for the chloride channel myotonias Thomsen and Becker nor for the separate sodium channel myotonia entities potassium-aggravated myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis. It is best described by a combination of potassium-aggravated myotonia and hyperkalemic periodic paralysis. We excluded exonic chloride channel mutations including CLCN1 exon deletion/duplication by MLPA. Instead we identified a novel p.N440K sodium channel mutation that is located at the inner end of segment S6 of repeat I. We discuss the genotype phenotype relation. PMID:22106717

  17. Paroxysmal exercise-induced dyskinesia, writer's cramp, migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense mutation.

    PubMed

    Urbizu, Aintzane; Cuenca-León, Ester; Raspall-Chaure, Miquel; Gratacòs, Margarida; Conill, Joan; Redecillas, Susana; Roig-Quilis, Manuel; Macaya, Alfons

    2010-08-15

    We report two monochorionic twins that progressively developed, between ages 5 and 10, a combination of episodic neurological disorders including paroxysmal exercise-induced dyskinesia, migraine without or with aura, absence seizures and writer's cramp. CSF/serum glucose ratio was moderately decreased in both patients. Mutational analysis of SLC2A1 gene identified a de novo heterozygous missense mutation in exon 4. This novel mutation has been previously showed to disrupt glucose transport in vitro. Both patients showed immediate and near-complete response to ketogenic diet. This clinical observation suggests that a high index of suspicion for GLUT1 deficiency syndrome is warranted in evaluating patients with multiple neurological paroxysmal events. PMID:20621801

  18. The biogenesis of lysosomes and lysosome-related organelles.

    PubMed

    Luzio, J Paul; Hackmann, Yvonne; Dieckmann, Nele M G; Griffiths, Gillian M

    2014-09-01

    Lysosomes were once considered the end point of endocytosis, simply used for macromolecule degradation. They are now recognized to be dynamic organelles, able to fuse with a variety of targets and to be re-formed after fusion events. They are also now known to be the site of nutrient sensing and signaling to the cell nucleus. In addition, lysosomes are secretory organelles, with specialized machinery for regulated secretion of proteins in some cell types. The biogenesis of lysosomes and lysosome-related organelles is discussed, taking into account their dynamic nature and multiple roles. PMID:25183830

  19. Peroxisome biogenesis and molecular defects in peroxisome assembly disorders

    Microsoft Academic Search

    Yukio Fujiki; Kanji Okumoto; Hidenori Otera; Shigehiko Tamura

    2000-01-01

    Peroxisome assembly in mammals requires more than 14 genes. So far, we have isolated seven complementation groups (CGs) of\\u000a peroxisome biogenesis-defective Chinese hamster ovary (CHO) cell mutants, Z65, Z24\\/ZP107, ZP92, ZP105\\/ZP139, ZP109, ZP110,\\u000a ZP114. Two peroxin cDNAs, PEX2 and PEX6, were first cloned by genetic phenotype-complementation assay using Z65 and ZP92, respectively, and were shown to be responsible\\u000a for peroxisome

  20. ?1-Pyrroline-5-Carboxylate/Glutamate Biogenesis Is Required for Fungal Virulence and Sporulation

    PubMed Central

    Yao, Ziting; Zou, Chengwu; Zhou, Hui; Wang, Jinzi; Lu, Lidan; Li, Yang; Chen, Baoshan

    2013-01-01

    Proline dehydrogenase (Prodh) and ?1-pyrroline-5-carboxylate dehydrogenase (P5Cdh) are two key enzymes in the cellular biogenesis of glutamate. Recombinant Prodh and P5Cdh proteins of the chestnut blight fungus Cryphonectria parasitica were investigated and showed activity in in vitro assays. Additionally, the C. parasitica Prodh and P5Cdh genes were able to complement the Saccharomyces cerevisiae put1 and put2 null mutants, respectively, to allow these proline auxotrophic yeast mutants to grow on media with proline as the sole source of nitrogen. Deletion of the Prodh gene in C. parasitica resulted in hypovirulence and a lower level of sporulation, whereas deletion of P5Cdh resulted in hypovirulence though no effect on sporulation; both ?prodh and ?p5cdh mutants were unable to grow on minimal medium with proline as the sole nitrogen source. In a wild-type strain, the intracellular level of proline and the activity of Prodh and P5Cdh increased after supplementation of exogenous proline, though the intracellular ?1-pyrroline-5-carboxylate (P5C) content remained unchanged. Prodh and P5Cdh were both transcriptionally down-regulated in cells infected with hypovirus. The disruption of other genes with products involved in the conversion of arginine to ornithine, ornithine and glutamate to P5C, and P5C to proline in the cytosol did not appear to affect virulence; however, asexual sporulation was reduced in the ?pro1 and ?pro2 mutants. Taken together, our results showed that Prodh, P5Cdh and related mitochondrial functions are essential for virulence and that proline/glutamate pathway components may represent down-stream targets of hypovirus regulation in C. parasitica. PMID:24039956

  1. Suprathreshold Heat Pain Response Predicts Activity-Related Pain, but Not Rest-Related Pain, in an Exercise-Induced Injury Model

    PubMed Central

    Coronado, Rogelio A.; Simon, Corey B.; Valencia, Carolina; Parr, Jeffrey J.; Borsa, Paul A.; George, Steven Z.

    2014-01-01

    Exercise-induced injury models are advantageous for studying pain since the onset of pain is controlled and both pre-injury and post-injury factors can be utilized as explanatory variables or predictors. In these studies, rest-related pain is often considered the primary dependent variable or outcome, as opposed to a measure of activity-related pain. Additionally, few studies include pain sensitivity measures as predictors. In this study, we examined the influence of pre-injury and post-injury factors, including pain sensitivity, for induced rest and activity-related pain following exercise induced muscle injury. The overall goal of this investigation was to determine if there were convergent or divergent predictors of rest and activity-related pain. One hundred forty-three participants provided demographic, psychological, and pain sensitivity information and underwent a standard fatigue trial of resistance exercise to induce injury of the dominant shoulder. Pain at rest and during active and resisted shoulder motion were measured at 48- and 96-hours post-injury. Separate hierarchical models were generated for assessing the influence of pre-injury and post-injury factors on 48- and 96-hour rest-related and activity-related pain. Overall, we did not find a universal predictor of pain across all models. However, pre-injury and post-injury suprathreshold heat pain response (SHPR), a pain sensitivity measure, was a consistent predictor of activity-related pain, even after controlling for known psychological factors. These results suggest there is differential prediction of pain. A measure of pain sensitivity such as SHPR appears more influential for activity-related pain, but not rest-related pain, and may reflect different underlying processes involved during pain appraisal. PMID:25265560

  2. Cross-cultural Adaptation and Validation of the Exercise-Induced Leg Pain Questionnaire for English- and Greek-Speaking Individuals.

    PubMed

    Korakakis, Vasileios; Malliaropoulos, Nikos; Baliotis, Konstantinos; Papadopoulou, Sofia; Padhiar, Nat; Nauck, Tanja; Lohrer, Heinz

    2015-06-01

    Study Design Clinical measurement. Objectives To translate the German version of the Exercise-Induced Leg Pain Questionnaire (EILP-G) to Greek and English and evaluate the psychometric properties of the Greek version. Background The EILP-G was developed to evaluate the severity of symptoms and sports ability in individuals with exercise-induced leg pain (EILP). Translation of the questionnaire to other languages will provide a standard outcome measure across populations. Methods The EILP-G questionnaire was cross-culturally adapted to Greek and English, according to established guidelines. The validity and reliability of the Greek version were assessed in 40 patients with EILP, 40 patients with other lower extremity injuries, 40 track-and-field athletes with no history of EILP, and 40 young adults without pathology. Participants completed the questionnaire at baseline and again after 7 to 10 days. Results The expert committee and the participants considered the questionnaire to have good face and content validity. Concurrent validity as assessed using the Schepsis score was almost perfect (rho = 0.947, P<.001). Dimensionality analysis revealed a 1-factor solution, explaining 83.8% of the total variance. Known group validity was demonstrated by significant differences between patients compared with the asymptomatic groups (P<.001). The Greek version exhibited excellent test-retest reliability (intraclass correlation coefficient = 0.995 for the EILP group) and internal consistency (Cronbach ? = .942 for the EILP group). Finally, no ceiling or floor effects were found, as none of the individuals with EILP scored the maximum or minimum possible values on the questionnaire. Conclusion The Greek version, adapted from the original EILP-G, is a valid and reliable questionnaire, and its psychometric properties are comparable with the original version. J Orthop Sports Phys Ther 2015;45(6):485-496. Epub 30 Apr 2015. doi:10.2519/jospt.2015.5428. PMID:25927499

  3. The interrelationship between mitochondrial dysfunction and transcriptional dysregulation in Huntington disease

    PubMed Central

    Jin, Youngnam N.

    2010-01-01

    Huntington disease (HD) is an inherited neuro-degenerative disease caused by an abnormal expansion of the CAG repeat region in the huntingtin (Htt) gene. Although the pathogenic mechanisms by which mutant Htt (mHtt) causes HD have not been fully elucidated, it is becoming increasingly apparent that mHtt can impair mitochondrial function directly, as well as indirectly by dysregulation of transcriptional processes. mHtt causes increased sensitivity to Ca2+-induced decreases in state 3 respiration and mitochondrial permeability transition pore (mPTP) opening concurrent with a reduction in mitochondrial Ca2+ uptake capacity. Treatment of striatal cells expressing mHtt with thapsigargin results in a decrease in mitochondrial Ca2+ uptake and membrane potential and an increase in reactive oxygen species (ROS) production. Transcriptional processes regulated by peroxisome proliferator-activated receptor ? (PPAR?) coactivator-1? (PGC-1?), which are critical for mitochondrial biogenesis, have been shown to be impaired in HD. In addition, the PPAR? signaling pathway is impaired by mHtt and the activation of this pathway ameliorates many of the mitochondrial deficits, suggesting that PPAR? agonists may represent an important treatment strategy for HD. PMID:20556492

  4. Deficiency in repair of the mitochondrial genome sensitizes proliferating myoblasts to oxidative damage.

    PubMed

    Szczesny, Bartosz; Olah, Gabor; Walker, Dillon K; Volpi, Elena; Rasmussen, Blake B; Szabo, Csaba; Mitra, Sankar

    2013-01-01

    Reactive oxygen species (ROS), generated as a by-product of mitochondrial oxidative phosphorylation, are particularly damaging to the genome of skeletal muscle because of their high oxygen consumption. Proliferating myoblasts play a key role during muscle regeneration by undergoing myogenic differentiation to fuse and restore damaged muscle. This process is severely impaired during aging and in muscular dystrophies. In this study, we investigated the role of oxidatively damaged DNA and its repair in the mitochondrial genome of proliferating skeletal muscle progenitor myoblasts cells and their terminally differentiated product, myotubes. Using the C2C12 cell line as a well-established model for skeletal muscle differentiation, we show that myoblasts are highly sensitive to ROS-mediated DNA damage, particularly in the mitochondrial genome, due to deficiency in 5' end processing at the DNA strand breaks. Ectopic expression of the mitochondrial-specific 5' exonuclease, EXOG, a key DNA base excision/single strand break repair (BER/SSBR) enzyme, in myoblasts but not in myotubes, improves the cell's resistance to oxidative challenge. We linked loss of myoblast viability by activation of apoptosis with deficiency in the repair of the mitochondrial genome. Moreover, the process of myoblast differentiation increases mitochondrial biogenesis and the level of total glutathione. We speculate that our data may provide a mechanistic explanation for depletion of proliferating muscle precursor cells during the development of sarcopenia, and skeletal muscle dystrophies. PMID:24066171

  5. Deficiency in Repair of the Mitochondrial Genome Sensitizes Proliferating Myoblasts to Oxidative Damage

    PubMed Central

    Szczesny, Bartosz; Olah, Gabor; Walker, Dillon K.; Volpi, Elena; Rasmussen, Blake B.; Szabo, Csaba; Mitra, Sankar

    2013-01-01

    Reactive oxygen species (ROS), generated as a by-product of mitochondrial oxidative phosphorylation, are particularly damaging to the genome of skeletal muscle because of their high oxygen consumption. Proliferating myoblasts play a key role during muscle regeneration by undergoing myogenic differentiation to fuse and restore damaged muscle. This process is severely impaired during aging and in muscular dystrophies. In this study, we investigated the role of oxidatively damaged DNA and its repair in the mitochondrial genome of proliferating skeletal muscle progenitor myoblasts cells and their terminally differentiated product, myotubes. Using the C2C12 cell line as a well-established model for skeletal muscle differentiation, we show that myoblasts are highly sensitive to ROS-mediated DNA damage, particularly in the mitochondrial genome, due to deficiency in 5’ end processing at the DNA strand breaks. Ectopic expression of the mitochondrial-specific 5’ exonuclease, EXOG, a key DNA base excision/single strand break repair (BER/SSBR) enzyme, in myoblasts but not in myotubes, improves the cell’s resistance to oxidative challenge. We linked loss of myoblast viability by activation of apoptosis with deficiency in the repair of the mitochondrial genome. Moreover, the process of myoblast differentiation increases mitochondrial biogenesis and the level of total glutathione. We speculate that our data may provide a mechanistic explanation for depletion of proliferating muscle precursor cells during the development of sarcopenia, and skeletal muscle dystrophies. PMID:24066171

  6. Reduced hepatic mitochondrial respiration following acute high-fat diet is prevented by PGC-1? overexpression

    PubMed Central

    Morris, E. Matthew; Jackman, Matthew R.; Meers, Grace M. E.; Johnson, Ginger C.; Lopez, Jordan L.; MacLean, Paul S.

    2013-01-01

    Changes in substrate utilization and reduced mitochondrial respiratory capacity following exposure to energy-dense, high-fat diets (HFD) are putatively key components in the development of obesity-related metabolic disease. We examined the effect of a 3-day HFD on isolated liver mitochondrial respiration and whole body energy utilization in obesity-prone (OP) rats. We also examined if hepatic overexpression of peroxisomal proliferator-activated receptor-? coactivator-1? (PGC-1?), a master regulator of mitochondrial respiratory capacity and biogenesis, would modify liver and whole body responses to the HFD. Acute, 3-day HFD (45% kcal) in OP rats resulted in increased daily energy intake, energy balance, weight gain, and adiposity, without an increase in liver triglyceride (triacylglycerol) accumulation. HFD-fed OP rats also displayed decreased whole body substrate switching from the dark to the light cycle, which was paired with reductions in hepatic mitochondrial respiration of multiple substrates in multiple respiratory states. Hepatic PGC-1? overexpression was observed to protect whole body substrate switching, as well as maintain mitochondrial respiration, following the acute HFD. Additionally, liver PGC-1? overexpression did not alter whole body dietary fatty acid oxidation but resulted in greater storage of dietary free fatty acids in liver lipid, primarily as triacylglycerol. Together, these data demonstrate that a short-term HFD can result in a decrease in metabolic flexibility and hepatic mitochondrial respiratory capacity in OP rats that is completely prevented by hepatic overexpression of PGC-1?. PMID:24091599

  7. Mitochondrial genomes: anything goes

    Microsoft Academic Search

    Gertraud Burger; Michael W. Gray; B. Franz Lang

    2003-01-01

    Mitochondria have their own genetic system – a vestigial genome originating from an endosymbiotic ?-proteobacterial ancestor. The genetic function of mitochondrial DNA (mtDNA) is well-conserved, being involved in a maximum of five mitochondrial processes: invariantly in respiration and\\/or oxidative phosphorylation and translation, and also in transcription, RNA maturation and protein import. Recent data from mitochondrial genomics research demonstrate that this

  8. Nar1p, a conserved eukaryotic protein with similarity to Fe-only hydrogenases, functions in cytosolic iron-sulphur protein biogenesis.

    PubMed

    Balk, J; Pierik, A J; Aguilar Netz, D J; Mühlenhoff, U; Lill, R

    2005-02-01

    The genome of the yeast Saccharomyces cerevisiae encodes the essential protein Nar1p that is conserved in virtually all eukaryotes and exhibits striking sequence similarity to bacterial iron-only hydrogenases. Previously, we have shown that Nar1p is an Fe-S protein and that assembly of its co-factors depends on the mitochondrial Fe-S cluster biosynthesis apparatus. Using functional studies in vivo, we demonstrated that Nar1p has an essential role in the maturation of cytosolic and nuclear, but not of mitochondrial, Fe-S proteins. Here we provide further spectroscopic evidence that Nar1p possesses two Fe-S clusters. We also show that Nar1p is required for Fe-S cluster assembly on the P-loop NTPase Nbp35p, another newly identified component of the cytosolic Fe-S protein assembly machinery. These data suggest a complex biochemical pathway of extra-mitochondrial Fe-S protein biogenesis involving unique eukaryotic proteins. PMID:15667273

  9. Mitochondrial Eve, The

    NSDL National Science Digital Library

    Henry Schaffer

    Analysis of mitochondrial DNA indicates that all humankind traces back to common female ancestor referred to as the "mitochondrial eve." This simulation shows the process prospectively, starting with 10 female parental mitochondrial genotypes, and with random mating tracing the number of mitochondrial types in each succeeding generation. A record is kept of outcomes, and different "runs" can be compared to show the randomness of the process. Thought questions and reading references are included. A short discussion of the construction of this learning object is at http://www.cals.ncsu.edu/gn/ex/mit-eve-disc.html

  10. [Mitochondrial and oocyte development].

    PubMed

    Deng, Wei-Ping; Ren, Zhao-Rui

    2007-12-01

    Oocyte development and maturation is a complicated process. The nuclear maturation and cytoplasmic maturation must synchronize which can ensure normal oocyte fertilization and following development. Mitochondrial is the most important cellular organell in cytoplasm, and the variation of its distribution during oocyte maturation, the capacity of OXPHOS generating ATP as well as the content or copy number or transcription level of mitochondrial DNA play an important role in oocyte development and maturation. Therefore, the studies on the variation of mitochondrial distribution, function and mitochondrial DNA could enhance our understanding of the physiology of reproduction and provide new insight to solve the difficulties of assisted reproduction as well as cloning embryo technology. PMID:18065375

  11. Energizing Genetics and Epi-genetics: Role in the Regulation of Mitochondrial Function

    PubMed Central

    Audano, Matteo; Ferrari, Alessandra; Fiorino, Erika; Kuenzl, Martin; Caruso, Donatella; Mitro, Nico; Crestani, Maurizio; Fabiani, Emma De

    2014-01-01

    Energy metabolism and mitochondrial function hold a core position in cellular homeostasis. Oxidative metabolism is regulated at multiple levels, ranging from gene transcription to allosteric modulation. To accomplish the fine tuning of these multiple regulatory circuits, the nuclear and mitochondrial compartments are tightly and reciprocally controlled. The fact that nuclear encoded factors, PPAR? coactivator 1? and mitochondrial transcription factor A, play pivotal roles in the regulation of oxidative metabolism and mitochondrial biogenesis is paradigmatic of this crosstalk. Here we provide an updated survey of the genetic and epigenetic mechanisms involved in the control of energy metabolism and mitochondrial function. Chromatin dynamics highly depends on post-translational modifications occurring at specific amino acids in histone proteins and other factors associated to nuclear DNA. In addition to the well characterized enzymes responsible for histone methylation/demethylation and acetylation/deacetylation, other factors have gone on the “metabolic stage”. This is the case of the new class of ?-ketoglutarate-regulated demethylases (Jumonji C domain containing demethylases) and of the NAD+-dependent deacetylases, also known as sirtuins. Moreover, unexpected features of the machineries involved in mitochondrial DNA (mtDNA) replication and transcription, mitochondrial RNA processing and maturation have recently emerged. Mutations or defects of any component of these machineries profoundly affect mitochondrial activity and oxidative metabolism. Finally, recent evidences support the importance of mtDNA packaging in replication and transcription. These observations, along with the discovery that non-classical CpG islands present in mtDNA undergo methylation, indicate that epigenetics also plays a role in the regulation of the mitochondrial genome function. PMID:25646072

  12. Mitochondrial uncoupling reduces exercise capacity despite several skeletal muscle metabolic adaptations.

    PubMed

    Schlagowski, A I; Singh, F; Charles, A L; Gali Ramamoorthy, T; Favret, F; Piquard, F; Geny, B; Zoll, J

    2014-02-15

    The effects of mitochondrial uncoupling on skeletal muscle mitochondrial adaptation and maximal exercise capacity are unknown. In this study, rats were divided into a control group (CTL, n = 8) and a group treated with 2,4-dinitrophenol, a mitochondrial uncoupler, for 28 days (DNP, 30 mg·kg(-1)·day(-1) in drinking water, n = 8). The DNP group had a significantly lower body mass (P < 0.05) and a higher resting oxygen uptake (Vo2, P < 0.005). The incremental treadmill test showed that maximal running speed and running economy (P < 0.01) were impaired but that maximal Vo2 (Vo2max) was higher in the DNP-treated rats (P < 0.05). In skinned gastrocnemius fibers, basal respiration (V0) was higher (P < 0.01) in the DNP-treated animals, whereas the acceptor control ratio (ACR, Vmax/V0) was significantly lower (P < 0.05), indicating a reduction in OXPHOS efficiency. In skeletal muscle, DNP activated the mitochondrial biogenesis pathway, as indicated by changes in the mRNA expression of PGC1-? and -?, NRF-1 and -2, and TFAM, and increased the mRNA expression of cytochrome oxidase 1 (P < 0.01). The expression of two mitochondrial proteins (prohibitin and Ndufs 3) was higher after DNP treatment. Mitochondrial fission 1 protein (Fis-1) was increased in the DNP group (P < 0.01), but mitofusin-1 and -2 were unchanged. Histochemical staining for NADH dehydrogenase and succinate dehydrogenase activity in the gastrocnemius muscle revealed an increase in the proportion of oxidative fibers after DNP treatment. Our study shows that mitochondrial uncoupling induces several skeletal muscle adaptations, highlighting the role of mitochondrial coupling as a critical factor for maximal exercise capacities. These results emphasize the importance of investigating the qualitative aspects of mitochondrial function in addition to the amount of mitochondria. PMID:24336883

  13. Dissecting the complete lipoprotein biogenesis pathway in Streptomyces scabies.

    PubMed

    Widdick, David A; Hicks, Matthew G; Thompson, Benjamin J; Tschumi, Andreas; Chandra, Govind; Sutcliffe, Iain C; Brülle, Juliane K; Sander, Peter; Palmer, Tracy; Hutchings, Matthew I

    2011-06-01

    Following translocation, bacterial lipoproteins are lipidated by lipoprotein diacylglycerol transferase (Lgt) and cleaved of their signal peptides by lipoprotein signal peptidase (Lsp). In Gram-negative bacteria and mycobacteria, lipoproteins are further lipidated by lipoprotein N-acyl transferase (Lnt), to give triacylated lipoproteins. Streptomyces are unusual amongst Gram-positive bacteria because they export large numbers of lipoproteins via the twin arginine protein transport (Tat) pathway. Furthermore, some Streptomyces species encode two Lgt homologues and all Streptomyces species encode two homologues of Lnt. Here we characterize lipoprotein biogenesis in the plant pathogen Streptomyces scabies and report that lgt and lsp mutants are defective in growth and development while only moderately affected in virulence. Lipoproteins are lost from the membrane in an S. scabies lgt mutant but restored by expression of Streptomyces coelicolor lgt1 or lgt2 confirming that both encode functional Lgt enzymes. Furthermore, lipoproteins are N-acylated in Streptomyces with efficient N-acylation dependent on Lnt1 and Lnt2. However, deletion of lnt1 and lnt2 has no effect on growth, development or virulence. We thus present a detailed study of lipoprotein biogenesis in Streptomyces, the first study of Lnt function in a monoderm bacterium and the first study of bacterial lipoproteins as virulence factors in a plant pathogen. PMID:21477129

  14. Phosphatidylinositol 3-Monophosphate Is Involved in Toxoplasma Apicoplast Biogenesis

    PubMed Central

    Tawk, Lina; Dubremetz, Jean-François; Montcourrier, Philippe; Chicanne, Gaëtan; Merezegue, Fabrice; Richard, Véronique; Payrastre, Bernard; Meissner, Markus; Vial, Henri J.; Roy, Christian

    2011-01-01

    Apicomplexan parasites cause devastating diseases including malaria and toxoplasmosis. They harbour a plastid-like, non-photosynthetic organelle of algal origin, the apicoplast, which fulfils critical functions for parasite survival. Because of its essential and original metabolic pathways, the apicoplast has become a target for the development of new anti-apicomplexan drugs. Here we show that the lipid phosphatidylinositol 3-monophosphate (PI3P) is involved in apicoplast biogenesis in Toxoplasma gondii. In yeast and mammalian cells, PI3P is concentrated on early endosomes and regulates trafficking of endosomal compartments. Imaging of PI3P in T. gondii showed that the lipid was associated with the apicoplast and apicoplast protein-shuttling vesicles. Interference with regular PI3P function by over-expression of a PI3P specific binding module in the parasite led to the accumulation of vesicles containing apicoplast peripheral membrane proteins around the apicoplast and, ultimately, to the loss of the organelle. Accordingly, inhibition of the PI3P-synthesising kinase interfered with apicoplast biogenesis. These findings point to an unexpected implication for this ubiquitous lipid and open new perspectives on how nuclear encoded proteins traffic to the apicoplast. This study also highlights the possibility of developing specific pharmacological inhibitors of the parasite PI3-kinase as novel anti-apicomplexan drugs. PMID:21379336

  15. Multicilin drives centriole biogenesis via E2f proteins.

    PubMed

    Ma, Lina; Quigley, Ian; Omran, Heymut; Kintner, Chris

    2014-07-01

    Multiciliate cells employ hundreds of motile cilia to produce fluid flow, which they nucleate and extend by first assembling hundreds of centrioles. In most cells, entry into the cell cycle allows centrioles to undergo a single round of duplication, but in differentiating multiciliate cells, massive centriole assembly occurs in G0 by a process initiated by a small coiled-coil protein, Multicilin. Here we show that Multicilin acts by forming a ternary complex with E2f4 or E2f5 and Dp1 that binds and activates most of the genes required for centriole biogenesis, while other cell cycle genes remain off. This complex also promotes the deuterosome pathway of centriole biogenesis by activating the expression of deup1 but not its paralog, cep63. Finally, we show that this complex is disabled by mutations in human Multicilin that cause a severe congenital mucociliary clearance disorder due to reduced generation of multiple cilia. By coopting the E2f regulation of cell cycle genes, Multicilin drives massive centriole assembly in epithelial progenitors in a manner required for multiciliate cell differentiation. PMID:24934224

  16. Multicilin drives centriole biogenesis via E2f proteins

    PubMed Central

    Ma, Lina; Quigley, Ian; Omran, Heymut; Kintner, Chris

    2014-01-01

    Multiciliate cells employ hundreds of motile cilia to produce fluid flow, which they nucleate and extend by first assembling hundreds of centrioles. In most cells, entry into the cell cycle allows centrioles to undergo a single round of duplication, but in differentiating multiciliate cells, massive centriole assembly occurs in G0 by a process initiated by a small coiled-coil protein, Multicilin. Here we show that Multicilin acts by forming a ternary complex with E2f4 or E2f5 and Dp1 that binds and activates most of the genes required for centriole biogenesis, while other cell cycle genes remain off. This complex also promotes the deuterosome pathway of centriole biogenesis by activating the expression of deup1 but not its paralog, cep63. Finally, we show that this complex is disabled by mutations in human Multicilin that cause a severe congenital mucociliary clearance disorder due to reduced generation of multiple cilia. By coopting the E2f regulation of cell cycle genes, Multicilin drives massive centriole assembly in epithelial progenitors in a manner required for multiciliate cell differentiation. PMID:24934224

  17. Investigating CRISPR RNA Biogenesis and Function Using RNA-seq.

    PubMed

    Heidrich, Nadja; Dugar, Gaurav; Vogel, Jörg; Sharma, Cynthia M

    2015-01-01

    The development of deep sequencing technology has greatly facilitated transcriptome analyses of both prokaryotes and eukaryotes. RNA-sequencing (RNA-seq), which is based on massively parallel sequencing of cDNAs, has been used to annotate transcript boundaries and revealed widespread antisense transcription as well as a wealth of novel noncoding transcripts in many bacteria. Moreover, RNA-seq is nowadays widely used for gene expression profiling and about to replace hybridization-based approaches such as microarrays. RNA-seq has also informed about the biogenesis and function of CRISPR RNAs (crRNAs) of different types of bacterial RNA-based CRISPR-Cas immune systems. Here we describe several studies that employed RNA-seq for crRNA analyses, with a particular focus on a differential RNA-seq (dRNA-seq) approach, which can distinguish between primary and processed transcripts and allows for a genome-wide annotation of transcriptional start sites. This approach helped to identify a new crRNA biogenesis pathway of Type II CRISPR-Cas systems that involves a trans-encoded small RNA, tracrRNA, and the host factor RNase III. PMID:25981463

  18. Early steps of slaframine and swainsonine biogenesis in Rhizoctonia leguminicola

    SciTech Connect

    Wickwire, B.M.; Broquist, H.P.

    1986-05-01

    Pipecolic acid (PIP), a precursor of slaframine (SF) and swainsonine (SW) in the fungus R. leguminicola, is thought to arise from L-lysine (LYS). The epsilon-N atom of LYS constitutes the N atom of PIP. Interest in these reactions arises in relation to mechanisms of regulation of SF and SW, and perhaps to piperidine alkaloid biogenesis in general. The authors have not been able to demonstrate an L-LYS oxidase, reaction A, in R. leguminicola. Rather when (U-/sup 14/C)-L-LYS was incubated with cell-free R. leguminicola extracts together with ..cap alpha..-ketoglutarate and NADH,H/sup +/ and subsequently deproteinized and chromatographed (HPLC), large amounts of saccharopine (SAC) together with small amounts of two other radioactive metabolites (II, III) were formed. Compound III is PIP. Metabolite II appears to be an intermediate between SAC and PIP. Growing cultures of R. leguminicola also accumulate SAC. Thus, SAC formed via the aminoadipate pathway of LYS biosynthesis may be at a branch point in the pathways for LYS and PIP biogenesis and be subject to enzymic regulation with subsequent accumulation following formation of LYS, SF, and SW.

  19. New insights into the biogenesis of nuclear RNA polymerases?1

    PubMed Central

    Cloutier, Philippe; Coulombe, Benoit

    2015-01-01

    More than 30 years of research on nuclear RNA polymerases (RNAP I, II, and III) has uncovered numerous factors that regulate the activity of these enzymes during the transcription reaction. However, very little is known about the machinery that regulates the fate of RNAPs before or after transcription. In particular, the mechanisms of biogenesis of the 3 nuclear RNAPs, which comprise both common and specific subunits, remains mostly uncharacterized and the proteins involved are yet to be discovered. Using protein affinity purification coupled to mass spectrometry (AP–MS), we recently unraveled a high-density interaction network formed by nuclear RNAP subunits from the soluble fraction of human cell extracts. Validation of the dataset using a machine learning approach trained to minimize the rate of false positives and false negatives yielded a high-confidence dataset and uncovered novel interactors that regulate the RNAP II transcription machinery, including a set of proteins we named the RNAP II-associated proteins (RPAPs). One of the RPAPs, RPAP3, is part of an 11-subunit complex we termed the RPAP3/R2TP/prefoldin-like complex. Here, we review the literature on the subunits of this complex, which points to a role in nuclear RNAP biogenesis. PMID:20453924

  20. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo

    PubMed Central

    Brunham, Liam R.; Kruit, Janine K.; Iqbal, Jahangir; Fievet, Catherine; Timmins, Jenelle M.; Pape, Terry D.; Coburn, Bryan A.; Bissada, Nagat; Staels, Bart; Groen, Albert K.; Hussain, M. Mahmood; Parks, John S.; Kuipers, Folkert; Hayden, Michael R.

    2006-01-01

    Plasma HDL cholesterol levels are inversely related to risk for atherosclerosis. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation, the assembly of free cholesterol and phospholipids with apoA-I. ABCA1 is expressed in many tissues; however, the physiological functions of ABCA1 in specific tissues and organs are still elusive. The liver is known to be the major source of plasma HDL, but it is likely that there are other important sites of HDL biogenesis. To assess the contribution of intestinal ABCA1 to plasma HDL levels in vivo, we generated mice that specifically lack ABCA1 in the intestine. Our results indicate that approximately 30% of the steady-state plasma HDL pool is contributed by intestinal ABCA1 in mice. In addition, our data suggest that HDL derived from intestinal ABCA1 is secreted directly into the circulation and that HDL in lymph is predominantly derived from the plasma compartment. These data establish a critical role for intestinal ABCA1 in plasma HDL biogenesis in vivo. PMID:16543947

  1. Chemotherapeutic Drugs Inhibit Ribosome Biogenesis at Various Levels*

    PubMed Central

    Burger, Kaspar; Mühl, Bastian; Harasim, Thomas; Rohrmoser, Michaela; Malamoussi, Anastassia; Orban, Mathias; Kellner, Markus; Gruber-Eber, Anita; Kremmer, Elisabeth; Hölzel, Michael; Eick, Dirk

    2010-01-01

    Drugs for cancer therapy belong to different categories of chemical substances. The cellular targets for the therapeutic efficacy are often not unambiguously identified. Here, we describe the process of ribosome biogenesis as a target of a large variety of chemotherapeutic drugs. We determined the inhibitory concentration of 36 chemotherapeutic drugs for transcription and processing of ribosomal RNA by in vivo labeling experiments. Inhibitory drug concentrations were correlated to the loss of nucleolar integrity. The synergism of drugs inhibiting ribosomal RNA synthesis at different levels was studied. Drugs inhibited ribosomal RNA synthesis either at the level of (i) rRNA transcription (e.g. oxaliplatin, doxorubicin, mitoxantrone, methotrexate), (ii) early rRNA processing (e.g. camptothecin, flavopiridol, roscovitine), or (iii) late rRNA processing (e.g. 5-fluorouracil, MG-132, homoharringtonine). Blockage of rRNA transcription or early rRNA processing steps caused nucleolar disintegration, whereas blockage of late rRNA processing steps left the nucleolus intact. Flavopiridol and 5-fluorouracil showed a strong synergism for inhibition of rRNA processing. We conclude that inhibition of ribosome biogenesis by chemotherapeutic drugs potentially may contribute to the efficacy of therapeutic regimens. PMID:20159984

  2. The Retrograde Response: When Mitochondrial Quality Control Is Not Enough

    PubMed Central

    Jazwinski, S. Michal

    2012-01-01

    Mitochondria are responsible for generating ATP and metabolic intermediates for biosynthesis. These dual functions require the activity of the electron transport chain in the mitochondrial inner membrane. The performance of these electron carriers is imperfect, resulting in release of damaging reactive oxygen species. Thus, continued mitochondrial activity requires maintenance. There are numerous means by which this quality control is ensured. Autophagy and selective mitophagy are among them. However, the cell inevitably must compensate for declining quality control by activating a variety of adaptations that entail the signaling of the presence of mitochondrial dysfunction to the nucleus. The best known of these is the retrograde response. This signaling pathway is triggered by the loss of mitochondrial membrane potential, which engages a series of signal transduction proteins, and it culminates in the induction of a broad array of nuclear target genes. One of the hallmarks of the retrograde response is its capacity to extend the replicative life span of the cell. The retrograde signaling pathway interacts with several other signaling pathways, such as TOR and ceramide signaling. All of these pathways respond to stress, including metabolic stress. The retrograde response is also linked to both autophagy and mitophagy at the gene and protein activation levels. Another quality control mechanism involves age-asymmetry in the segregation of dysfunctional mitochondria. One of the processes that impinge on this age-asymmetry is related to biogenesis of the organelle. Altogether, it is apparent that mitochondrial quality control constitutes a complex network of processes, whose full understanding will require a systems approach. PMID:22374136

  3. Blood cell mitochondrial DNA content and premature ovarian aging.

    PubMed

    Bonomi, Marco; Somigliana, Edgardo; Cacciatore, Chiara; Busnelli, Marta; Rossetti, Raffaella; Bonetti, Silvia; Paffoni, Alessio; Mari, Daniela; Ragni, Guido; Persani, Luca

    2012-01-01

    Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase ? (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction. PMID:22879975

  4. Blood Cell Mitochondrial DNA Content and Premature Ovarian Aging

    PubMed Central

    Cacciatore, Chiara; Busnelli, Marta; Rossetti, Raffaella; Bonetti, Silvia; Paffoni, Alessio; Mari, Daniela; Ragni, Guido; Persani, Luca; Arosio, M.; Beck-Peccoz, P.; Biondi, M.; Bione, S.; Bruni, V.; Brigante, C.; Cannavo`, S.; Cavallo, L.; Cisternino, M.; Colombo, I.; Corbetta, S.; Crosignani, P.G.; D'Avanzo, M.G.; Dalpra, L.; Danesino, C.; Di Battista, E.; Di Prospero, F.; Donti, E.; Einaudi, S.; Falorni, A.; Foresta, C.; Fusi, F.; Garofalo, N.; Giotti, I.; Lanzi, R.; Larizza, D.; Locatelli, N.; Loli, P.; Madaschi, S.; Maghnie, M.; Maiore, S.; Mantero, F.; Marozzi, A.; Marzotti, S.; Migone, N.; Nappi, R.; Palli, D.; Patricelli, M.G.; Pisani, C.; Prontera, P.; Petraglia, F.; Radetti, G.; Renieri, A.; Ricca, I.; Ripamonti, A.; Rossetti, R.; Russo, G.; Russo, S.; Tonacchera, M.; Toniolo, D.; Torricelli, F.; Vegetti, W.; Villa, N.; Vineis, P.; Wasniewsk, M.; Zuffardi, O.

    2012-01-01

    Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase ? (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction. PMID:22879975

  5. Genome-wide Responses to Mitochondrial DysfunctionV?

    PubMed Central

    Epstein, Charles B.; Waddle, James A.; Hale, Walker; Davé, Varshal; Thornton, Janet; Macatee, Timothy L.; Garner, Harold R.; Butow, Ronald A.

    2001-01-01

    Mitochondrial dysfunction can lead to diverse cellular and organismal responses. We used DNA microarrays to characterize the transcriptional responses to different mitochondrial perturbations in Saccharomyces cerevisiae. We examined respiratory-deficient petite cells and respiratory-competent wild-type cells treated with the inhibitors of oxidative phosphorylation antimycin, carbonyl cyanide m-chlorophenylhydrazone, or oligomycin. We show that respiratory deficiency, but not inhibition of mitochondrial ATP synthesis per se, induces a suite of genes associated with both peroxisomal activities and metabolite-restoration (anaplerotic) pathways that would mitigate the loss of a complete tricarboxylic acid cycle. The array data suggested, and direct microscopic observation of cells expressing a derivative of green fluorescent protein with a peroxisomal matrix-targeting signal confirmed, that respiratory deficiency dramatically induces peroxisome biogenesis. Transcript profiling of cells harboring null alleles of RTG1, RTG2, or RTG3, genes known to control signaling from mitochondria to the nucleus, suggests that there are multiple pathways of cross-talk between these organelles in yeast. PMID:11179416

  6. Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination

    PubMed Central

    West, A. Phillip; Joshi, Samit R.; Ueda, Ikuyo; Wilson, Jean; Meng, Hailong; Blevins, Tamara P.; Tsang, Sui; Trentalange, Mark; Siconolfi, Barbara; Park, Koonam; Gill, Thomas M.; Belshe, Robert B.; Kaech, Susan M.; Shadel, Gerald S.; Kleinstein, Steven H.; Shaw, Albert C.

    2015-01-01

    To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age ?65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders. The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders). We also identified a mitochondrial signature in young vaccine responders containing genes mediating mitochondrial biogenesis and oxidative phosphorylation that was consistent in two different vaccine seasons and verified by analyses of mitochondrial content and protein expression. These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness. PMID:25596819

  7. An essential function of the mitochondrial sulfhydryl oxidase Erv1p\\/ALR in the maturation of cytosolic Fe\\/S proteins

    Microsoft Academic Search

    Heike Lange; Thomas Lisowsky; Jana Gerber; Ulrich Mühlenhoff; Gyula Kispal; Roland Lill

    2001-01-01

    Biogenesis of Fe\\/S clusters involves a number of essential mitochondrial proteins. Here, we identify the essential Erv1p of Saccharomyces cerevisia mitochondria as a novel component that is specifically required for the maturation of Fe\\/S proteins in the cytosol, but not in mitochondria. Furthermore, Erv1p was found to be important for cellular iron homeostasis. The homologous mammalian protein ALR ('augmenter of

  8. Defects of mitochondrial DNA replication.

    PubMed

    Copeland, William C

    2014-09-01

    Mitochondrial DNA is replicated by DNA polymerase ? in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. Defects in mitochondrial DNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mitochondrial DNA deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mitochondrial DNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mitochondrial DNA deletion disorders, such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mitochondrial DNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mitochondrial DNA and mitochondrial disease. PMID:24985751

  9. Effects of Fcj1-Mos1 and mitochondrial division on aggregation of mitochondrial DNA nucleoids and organelle morphology.

    PubMed

    Itoh, Kie; Tamura, Yasushi; Iijima, Miho; Sesaki, Hiromi

    2013-06-01

    Mitochondrial DNA (mtDNA) is packaged into DNA-protein complexes called nucleoids, which are distributed as many small foci in mitochondria. Nucleoids are crucial for the biogenesis and function of mtDNA. Here, using a yeast genetic screen for components that control nucleoid distribution and size, we identify Fcj1 and Mos1, two evolutionarily conserved mitochondrial proteins that maintain the connection between the cristae and boundary membranes. These two proteins are also important for establishing tubular morphology of mitochondria, as mitochondria lacking Fcj1 and Mos1 form lamellar sheets. We find that nucleoids aggregate, increase in size, and decrease in number in fcj1 and mos1 cells. In addition, Fcj1 form punctate structures and localized adjacent to nucleoids. Moreover, connecting mitochondria by deleting the DNM1 gene required for organelle division enhances aggregation of mtDNA nucleoids in fcj1 and mos1 cells, whereas single deletion of DNM1 does not affect nucleoids. Conversely, deleting F1Fo-ATP synthase dimerization factors generates concentric ring-like cristae, restores tubular mitochondrial morphology, and suppresses nucleoid aggregation in these mutants. Our findings suggest an unexpected role of Fcj1-Mos1 and organelle division in maintaining the distribution and size of mtDNA nucleoids. PMID:23615445

  10. Myoclonus in mitochondrial disorders.

    PubMed

    Mancuso, Michelangelo; Orsucci, Daniele; Angelini, Corrado; Bertini, Enrico; Catteruccia, Michela; Pegoraro, Elena; Carelli, Valerio; Valentino, Maria L; Comi, Giacomo P; Minetti, Carlo; Bruno, Claudio; Moggio, Maurizio; Ienco, Elena Caldarazzo; Mongini, Tiziana; Vercelli, Liliana; Primiano, Guido; Servidei, Serenella; Tonin, Paola; Scarpelli, Mauro; Toscano, Antonio; Musumeci, Olimpia; Moroni, Isabella; Uziel, Graziella; Santorelli, Filippo M; Nesti, Claudia; Filosto, Massimiliano; Lamperti, Costanza; Zeviani, Massimo; Siciliano, Gabriele

    2014-05-01

    Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases," we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as "the MERRF mutation"). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term "myoclonic epilepsy" seems inadequate and potentially misleading. PMID:24510442

  11. Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease.

    PubMed

    Tufi, Roberta; Gandhi, Sonia; de Castro, Inês P; Lehmann, Susann; Angelova, Plamena R; Dinsdale, David; Deas, Emma; Plun-Favreau, Hélène; Nicotera, Pierluigi; Abramov, Andrey Y; Willis, Anne E; Mallucci, Giovanna R; Loh, Samantha H Y; Martins, L Miguel

    2014-02-01

    Mutations in PINK1 cause early-onset Parkinson's disease (PD). Studies in Drosophila melanogaster have highlighted mitochondrial dysfunction on loss of Pink1 as a central mechanism of PD pathogenesis. Here we show that global analysis of transcriptional changes in Drosophila pink1 mutants reveals an upregulation of genes involved in nucleotide metabolism, critical for neuronal mitochondrial DNA synthesis. These key transcriptional changes were also detected in brains of PD patients harbouring PINK1 mutations. We demonstrate that genetic enhancement of the nucleotide salvage pathway in neurons of pink1 mutant flies rescues mitochondrial impairment. In addition, pharmacological approaches enhancing nucleotide pools reduce mitochondrial dysfunction caused by Pink1 deficiency. We conclude that loss of Pink1 evokes the activation of a previously unidentified metabolic reprogramming pathway to increase nucleotide pools and promote mitochondrial biogenesis. We propose that targeting strategies enhancing nucleotide synthesis pathways may reverse mitochondrial dysfunction and rescue neurodegeneration in PD and, potentially, other diseases linked to mitochondrial impairment. PMID:24441527

  12. Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I.

    PubMed

    Sobek, Stefan; Dalla Rosa, Ilaria; Pommier, Yves; Bornholz, Beatrice; Kalfalah, Faiza; Zhang, Hongliang; Wiesner, Rudolf J; von Kleist-Retzow, Jürgen-Christoph; Hillebrand, Frank; Schaal, Heiner; Mielke, Christian; Christensen, Morten O; Boege, Fritz

    2013-11-01

    Mitochondrial topoisomerase I is a genetically distinct mitochondria-dedicated enzyme with a crucial but so far unknown role in the homeostasis of mitochondrial DNA metabolism. Here, we present data suggesting a negative regulatory function in mitochondrial transcription or transcript stability. Deficiency or depletion of mitochondrial topoisomerase I increased mitochondrial transcripts, whereas overexpression lowered mitochondrial transcripts, depleted respiratory complexes I, III and IV, decreased cell respiration and raised superoxide levels. Acute depletion of mitochondrial topoisomerase I triggered neither a nuclear mito-biogenic stress response nor compensatory topoisomerase II? upregulation, suggesting the concomitant increase in mitochondrial transcripts was due to release of a local inhibitory effect. Mitochondrial topoisomerase I was co-immunoprecipitated with mitochondrial RNA polymerase. It selectively accumulated and rapidly exchanged at a subset of nucleoids distinguished by the presence of newly synthesized RNA and/or mitochondrial RNA polymerase. The inactive Y559F-mutant behaved similarly without affecting mitochondrial transcripts. In conclusion, mitochondrial topoiso