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Sample records for exercise-induced mitochondrial biogenesis

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

    PubMed Central

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

    2015-01-01

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

  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. 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

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

    SciTech Connect

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

    2007-12-01

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

  5. Mitochondrial biogenesis and dynamics in the developing and diseased heart.

    PubMed

    Dorn, Gerald W; Vega, Rick B; Kelly, Daniel P

    2015-10-01

    The mitochondrion is a complex organelle that serves essential roles in energy transduction, ATP production, and a myriad of cellular signaling events. A finely tuned regulatory network orchestrates the biogenesis, maintenance, and turnover of mitochondria. The high-capacity mitochondrial system in the heart is regulated in a dynamic way to generate and consume enormous amounts of ATP in order to support the constant pumping function in the context of changing energy demands. This review describes the regulatory circuitry and downstream events involved in mitochondrial biogenesis and its coordination with mitochondrial dynamics in developing and diseased hearts. PMID:26443844

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

    PubMed

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

    2015-04-01

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

  7. 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...

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

    PubMed

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

    2016-01-01

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

  9. 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

  10. Markers of human skeletal muscle mitochondrial biogenesis and quality control: effects of age and aerobic exercise training.

    PubMed

    Konopka, Adam R; Suer, Miranda K; Wolff, Christopher A; Harber, Matthew P

    2014-04-01

    Perturbations in mitochondrial health may foster age-related losses of aerobic capacity (VO2peak) and skeletal muscle size. However, limited data exist regarding mitochondrial dynamics in aging human skeletal muscle and the influence of exercise. The purpose of this study was to examine proteins regulating mitochondrial biogenesis and dynamics, VO2peak, and skeletal muscle size before and after aerobic exercise training in young men (20 ± 1 y) and older men (74 ± 3 y). Exercise-induced skeletal muscle hypertrophy occurred independent of age, whereas the improvement in VO2peak was more pronounced in young men. Aerobic exercise training increased proteins involved with mitochondrial biogenesis, fusion, and fission, independent of age. This is the first study to examine pathways of mitochondrial quality control in aging human skeletal muscle with aerobic exercise training. These data indicate normal aging does not influence proteins associated with mitochondrial health or the ability to respond to aerobic exercise training at the mitochondrial and skeletal muscle levels. PMID:23873965

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

    PubMed

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

    2015-10-01

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

  12. Mitochondrial 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

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

    PubMed

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

    2015-09-01

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

  14. Biogenesis of mitochondrial outer membrane proteins, problems and diseases.

    PubMed

    Ellenrieder, Lars; Mårtensson, Christoph U; Becker, Thomas

    2015-10-01

    Proteins of the mitochondrial outer membrane are synthesized as precursors on cytosolic ribosomes and sorted via internal targeting sequences to mitochondria. Two different types of integral outer membrane proteins exist: proteins with a transmembrane ?-barrel and proteins embedded by a single or multiple ?-helices. The import pathways of these two types of membrane proteins differ fundamentally. Precursors of ?-barrel proteins are first imported across the outer membrane via the translocase of the outer membrane (TOM complex). The TOM complex is coupled to the sorting and assembly machinery (SAM complex), which catalyzes folding and membrane insertion of these precursors. The mitochondrial import machinery (MIM complex) promotes import of proteins with multiple ?-helical membrane spans. Depending on the topology precursors of proteins with a single ?-helical membrane anchor are imported via several distinct routes. We summarize current models and open questions of biogenesis of mitochondrial outer membrane proteins and discuss the impact of malfunctions of protein sorting on the development of diseases. PMID:25980382

  15. Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise.

    PubMed

    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

    2011-09-01

    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

  16. 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

  17. Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial dysfunction through mitochondrial biogenesis improvement.

    PubMed

    Bullón, Pedro; Román-Malo, Lourdes; Marín-Aguilar, Fabiola; Alvarez-Suarez, José Miguel; Giampieri, Francesca; Battino, Maurizio; Cordero, Mario D

    2015-01-01

    Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1? and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications. PMID:25447593

  18. 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...

  19. 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

  20. 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

  1. MTERF3 Regulates Mitochondrial Ribosome Biogenesis in Invertebrates and Mammals

    PubMed Central

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

    2013-01-01

    Regulation of mitochondrial DNA (mtDNA) expression is critical for the control of oxidative phosphorylation in response to physiological demand, and this regulation is often impaired in disease and aging. We have previously shown that mitochondrial transcription termination factor 3 (MTERF3) is a key regulator that represses mtDNA transcription in the mouse, but its molecular mode of action has remained elusive. Based on the hypothesis that key regulatory mechanisms for mtDNA expression are conserved in metazoans, we analyzed Mterf3 knockout and knockdown flies. We demonstrate here that decreased expression of MTERF3 not only leads to activation of mtDNA transcription, but also impairs assembly of the large mitochondrial ribosomal subunit. This novel function of MTERF3 in mitochondrial ribosomal biogenesis is conserved in the mouse, thus we identify a novel and unexpected role for MTERF3 in coordinating the crosstalk between transcription and translation for the regulation of mammalian mtDNA gene expression. PMID:23300484

  2. 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

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

    PubMed

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

    2015-12-01

    Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase in mitochondrial oxidative capacity following physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1(+/-)) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1(+/-) mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1(+/-) mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1(+/-) mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2±0.2 vs. 7.1±0.2, P=0.001), but not in cPDPK1(+/-) (6.2±0.3 vs. 6.5±0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7±0.1 vs. 4.0±0.1mm, P=0.01) but not in cPDPK1(+/-) (3.8±0.1 vs. 3.7±0.1mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6±0.6 vs.16.1±0.9, P=0.04; cPDPK1(+/-): 12.4±0.6 vs.15.9±1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function. PMID:26476238

  4. Endurance training accelerates exhaustive exercise-induced mitochondrial DNA deletion and apoptosis of left ventricle myocardium in rats.

    PubMed

    Huang, Chi-Chang; Lin, Tien-Jen; Chen, Chun-Chieh; Lin, Wan-Teng

    2009-12-01

    Even though exhaustive exercise-induced oxidative stress increases the risk of tissue damage, regular endurance training is widely assumed to improve cardiac function and protects against heart disease. We tested the hypothesis that an endurance training program prevents exhaustive exercise-induced increases in cardiac dysfunction and apoptosis in left ventricle (LV). Thirty-two male Sprague-Dawley rats were randomly divided into four groups: sedentary control (C), trained (T), exhaustively exercised (E), and trained plus exhaustively exercised (TE). Rats in T and TE groups ran on a motorized treadmill for 12 weeks. Rats in groups E and TE performed an exhaustive running test on a treadmill. The main effects of training were indicated by increased running time to exhaustion (80 +/- 5 and 151 +/- 13 min for groups E and TE, respectively, P = 0.0001), myocardial hypertrophy (0.38% and 0.47% for untrained and trained rats, respectively, P = 0.0002), decreased LV ejection fraction (88% and 71% for untrained and trained rats, respectively, P < 0.0001), accelerated mitochondrial DNA 4834-bp large deletion (mtDNA4834 deletion), and up-regulated protein levels of heat shock protein-70, cytochrome C, cleaved capsase-3, and cleaved PARP in LV following a bout of exhaustive exercise. Contrary to our hypothesis, these results suggest that endurance training induced significant impairment of regional systolic and diastolic LV myocardial function and ejection fraction in rats. Our findings show that endurance training accelerates exhaustive exercise-induced mtDNA4834 deletion and apoptosis in the LV. PMID:19730878

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

    SciTech Connect

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

    2012-05-15

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

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

    PubMed Central

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

    2011-01-01

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

  7. GPER mediates the effects of 17?-estradiol in cardiac mitochondrial biogenesis and function.

    PubMed

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

    2016-01-15

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

  8. Pharmacological induction of mitochondrial biogenesis as a therapeutic strategy for the treatment of type 2 diabetes.

    PubMed

    Zamora, Mònica; Pardo, Rosario; Villena, Josep A

    2015-11-01

    Defects in mitochondrial oxidative function have been associated with the onset of type 2 diabetes. Although the causal relationship between mitochondrial dysfunction and diabetes has not been fully established, numerous studies indicate that improved glucose homeostasis achieved via lifestyle interventions, such as exercise or calorie restriction, is tightly associated with increased mitochondrial biogenesis and oxidative function. Therefore, it is conceivable that potentiating mitochondrial biogenesis by pharmacological means could constitute an efficacious therapeutic strategy that would particularly benefit those diabetic patients who cannot adhere to comprehensive programs based on changes in lifestyle or that require a relatively rapid improvement in their diabetic status. In this review, we discuss several pharmacological targets and drugs that modulate mitochondrial biogenesis as well as their potential use as treatments for insulin resistance and diabetes. PMID:26212547

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    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

  11. 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

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

    PubMed Central

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

    2015-01-01

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

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

    SciTech Connect

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

    2005-12-16

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

  14. 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

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

    SciTech Connect

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2012-11-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  18. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis.

    PubMed

    Reznick, Richard M; Zong, Haihong; Li, Ji; Morino, Katsutaro; Moore, Irene K; Yu, Hannah J; Liu, Zhen-Xiang; Dong, Jianying; Mustard, Kirsty J; Hawley, Simon A; Befroy, Douglas; Pypaert, Marc; Hardie, D Grahame; Young, Lawrence H; Shulman, Gerald I

    2007-02-01

    Recent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-alpha(2) activity by 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats. Furthermore, mitochondrial biogenesis in response to chronic activation of AMPK with beta-guanidinopropionic acid (beta-GPA) feeding was also diminished in old rats. These results suggest that aging-associated reductions in AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging. PMID:17276357

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

    PubMed Central

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

    2007-01-01

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

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

    SciTech Connect

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

    2013-08-16

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

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

    SciTech Connect

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

    2013-03-29

    Highlights: ? First time to show that cilostazol promotes the expressions of PGC-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.

  2. 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

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

    PubMed Central

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

    2014-01-01

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

  4. Interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity.

    PubMed

    Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios

    2015-01-01

    Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis and calcium homeostasis, among others. Alterations in mitochondrial activity not only influence individual cell function but also, through non-cell autonomous mechanisms, whole body metabolism, healthspan and lifespan. Energy homeostasis is orchestrated by the complex interplay between mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy). However, the cellular and molecular pathways that coordinate these 2 opposing processes remained obscure. In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of the mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy, and functions in the same genetic pathway with PINK-1 and PDR-1 (the nematode homologs of PINK1 and Parkin respectively) to promote longevity and prevent cell damage under stress conditions. Interestingly, accumulation of damaged mitochondria activates SKN-1 (SKiNhead-1), the nematode homolog of NRF2, which in turn initiates a compensatory retrograde signaling response that impinges on both mitochondrial biogenesis and removal. In this commentary, we discuss the implications of these new findings in the context of innate immunity and aging. Unraveling the regulatory network that governs the crosstalk between mitochondrial biogenesis and mitophagy will enhance our understanding of the molecular mechanisms that link aberrant energy metabolism to aging and disease. PMID:26430570

  5. 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

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

    PubMed

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

    2016-01-01

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

  7. Dietary isoflavone daidzein promotes Tfam expression that increases mitochondrial biogenesis in C2C12 muscle cells.

    PubMed

    Yoshino, Makiko; Naka, Ayano; Sakamoto, Yuri; Shibasaki, Ayako; Toh, Mariko; Tsukamoto, Sakuka; Kondo, Kazuo; Iida, Kaoruko

    2015-11-01

    Mitochondrial dysfunction in muscles leads to a wide range of metabolic and age-related disorders. Recently, it has been reported that a natural polyphenol, resveratrol, affects mitochondrial biogenesis. This study aimed to identify other natural polyphenolic compounds that regulate mitochondrial biogenesis in muscles. For this purpose, we used the C2C12 murine muscle cell line. Screening involved a reporter assay based on the promoter of mitochondrial transcription factor A (Tfam). We found that several polyphenols exhibited the ability to increase Tfam promoter activity and that the soy isoflavone daidzein was a most potent candidate that regulated mitochondrial biogenesis. When C2C12 myotubes were treated with 25-50?M daidzein for 24h, there were significant increases in the expression of Tfam and mitochondrial genes such as COX1 and Cytb as well as the mitochondrial content. Using several mutant Tfam promoter fragments, we found that the transcription factor, nuclear respiratory factor (NRF) and its coactivator, PGC1?, were necessary for the effect of daidzein on Tfam expression. Finally, silencing of sirtuin-1 (SIRT1) by shRNA resulted in inhibition of the daidzein effects on mitochondrial gene expression. In conclusion, daidzein regulates mitochondrial biogenesis in muscle cells by regulating transcriptional networks through a SIRT1-associated pathway. These results suggest that daidzein would be beneficial to protect against a wide range of diseases caused by muscle mitochondrial dysfunction. PMID:26166229

  8. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

    SciTech Connect

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

    2014-07-18

    Highlights: • 14,15-EET inhibits OGD-induced apoptosis in cortical neurons. • Mitochondrial biogenesis of cortical neurons is promoted by 14,15-EET. • 14,15-EET preserves mitochondrial function of cortical neurons under OGD. • CREB mediates effect of 14,15-EET on mitochondrial biogenesis and function. - Abstract: 14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and function in cortical neurons under the condition of oxygen–glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-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.

  9. 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

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

    PubMed Central

    Komen, J C; Thorburn, D R

    2014-01-01

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

  11. 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

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

    PubMed

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

    2015-08-01

    The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise, which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in prehypertensive individuals and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31(+)/CD42a(-)) and activated (CD62E(+)) microparticles released by endothelial cells were significantly decreased (?40% for both) after a 6-mo supervised aerobic exercise training program in individuals with prehypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a sirtuin 1 (SIRT1)-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using small-interfering RNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or peroxisome proliferator-activated receptor-? coactivator-1? small-interfering RNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial biogenesis. PMID:26024684

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

    PubMed

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

    2015-03-01

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

  14. 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...

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

    piRNA (PIWI-interacting RNA) is a germ cell–specific small RNA in which biogenesis PIWI (P-element wimpy testis) family proteins play crucial roles. MILI (mouse Piwi-like), one of the three mouse PIWI family members, is indispensable for piRNA production, DNA methylation of retrotransposons presumably through the piRNA, and spermatogenesis. The biogenesis of piRNA has been divided into primary and secondary processing pathways; in both of these MILI is involved in mice. To analyze the molecular function of MILI in piRNA biogenesis, we utilized germline stem (GS) cells, which are derived from testicular stem cells and possess a spermatogonial phenotype. We established MILI-null GS cell lines and their revertant, MILI-rescued GS cells, by introducing the Mili gene with Sendai virus vector. Comparison of wild-type, MILI-null, and MILI-rescued GS cells revealed that GS cells were quite useful for analyzing the molecular mechanisms of piRNA production, especially the primary processing pathway. We found that glycerol-3-phosphate acyltransferase 2 (GPAT2), a mitochondrial outer membrane protein for lysophosphatidic acid, bound to MILI using the cells and that gene knockdown of GPAT2 brought about impaired piRNA production in GS cells. GPAT2 is not only one of the MILI bound proteins but also a protein essential for primary piRNA biogenesis. PMID:23611983

  17. MicroRNA-761 regulates mitochondrial biogenesis in mouse skeletal muscle in response to exercise.

    PubMed

    Xu, Yanli; Zhao, Chaoxian; Sun, Xuewen; Liu, Zhijun; Zhang, Jianzhong

    2015-11-01

    MicroRNAs (miRNAs) have been suggested to play critical roles in skeletal muscle in response to exercise. Previous study has shown that miR-761 was involved in a novel model regulating the mitochondrial network. However, its role in mitochondrial biogenesis remains poorly understood. Therefore, the current study was aimed to examine the effect of miR-761 on mitochondrial biogenesis in skeletal muscle. Real-time quantitative PCR analysis demonstrated that aberrantly expressed miR-761 is involved in exercise activity and miR-761 is decreased by exercise training compared with the sedentary control mice. miR-761 suppresses mitochondrial biogenesis of C2C12 myocytes by targeting the 3'-UTR of peroxisome proliferator-activated receptor gamma (PPAR?) coactivator-1 (PGC-1?). Overexpression of miR-761 was capable of inhibiting the protein expression levels of PGC-1?. Moreover, miR-761 overexpression suppressed the p38 MAPK signaling pathway and down-regulated the expression of phosphorylated MAPK-activated protein kinase-2 (P-MK2), a downstream kinase of p38 MAPK. The phosphorylation of activating transcription factors 2 (ATF2) that plays a functional role in linking the activation of the p38 MAPK pathway to enhanced transcription of the PGC-1? was also inhibited by the overexpression of miR-761. These findings revealed a novel regulation mechanism for miR-761 in skeletal myocytes, and contributed to a better understanding of the modulation of skeletal muscle in response to exercise. PMID:26408907

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

    PubMed

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

    2015-11-01

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

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

    PubMed

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

    2014-01-01

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

  20. 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.; Bal, Amanjit; Gill, Kiran Dip

    2013-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 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.

  1. 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

  2. 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

  3. 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

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

    PubMed Central

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

    2015-01-01

    Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the 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

  5. 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

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

    PubMed

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

    2008-03-28

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

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

    PubMed Central

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

    2015-01-01

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

  8. Metastasis suppressor KISS1 appears to reverse the Warburg effect by enhancing mitochondrial biogenesis

    PubMed Central

    Liu, Wen; Beck, Benjamin H.; Vaidya, Kedar S.; Nash, Kevin T.; Feeley, Kyle P.; Ballinger, Scott W.; Pounds, Keke M.; Denning, Warren L.; Diers, Anne R.; Landar, Aimee; Dhar, Animesh; Iwakuma, Tomoo; Welch, Danny R.

    2014-01-01

    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, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (?SS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30–50% more mitochondrial mass than ?SS-expressing cells, which is accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1?, a master co-activator that regulates mitochondrial mass and metabolism. PGC1?-mediated downstream pathways (i.e. fatty acid synthesis and ?-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using shRNA to KISS1 or PGC1?, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism and metastasis. PMID:24351292

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

    PubMed

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

    2014-01-01

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

  11. Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms.

    PubMed

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

    2014-08-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    2014-01-01

    Background Mitochondrial dysfunction has been linked to neuronal death and a wide array of neurodegenerative diseases. Previously, we have shown sex differences in mitochondria-mediated cell death pathways following hypoxia-ischemia. However, the role of mitochondrial biogenesis in hypoxic-ischemic brain injury between male vs. female has not been studied yet. Results Primary cerebellar granule neurons (CGNs), isolated from P7 male and female mice (CD-1) segregated based on visual inspection of sex, were exposed to 2 h of oxygen glucose deprivation (OGD) followed by 6–24 h of reoxygenation (Reox). Mitochondrial membrane potential (??m) and cellular ATP levels were reduced significantly in XX CGNs as compared to XY CGNs. Mitochondrial DNA (mtDNA) content was increased (>2-fold) at 2 h OGD in XY CGNs and remained increased up to 24 h of Reox compared to XX neurons and normoxia controls. The expression of mitochondrial transcription factor A (Tfam), the nuclear respiratory factor-1 (NRF-1) and the peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), a master regulator of mitochondrial biogenesis, were up-regulated (2-fold, ***p?mitochondrial proteins HSP60 and COXIV were increased in XY neurons only. Supportively, a balanced stimulation of fusion (Mfn 1and Mfn 2) and fission (Fis 1 and Drp 1) genes and enhanced formation of donut-shaped mitochondria were observed in XY CGNs vs. XX neurons (**p?mitochondrial biogenesis and morphological changes in a sex-specific way, influencing neuronal injury/survival differently in both sexes. PMID:24410996

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

    PubMed

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

    2015-09-01

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

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

    PubMed

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

    2015-12-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    Mordas, Amelia; Tokatlidis, Kostas

    2015-08-18

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

  18. The MIA Pathway: A Key Regulator of Mitochondrial Oxidative Protein Folding and Biogenesis

    PubMed Central

    2015-01-01

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

  19. Phosphatidylcholine Affects the Role of the Sorting and Assembly Machinery in the Biogenesis of Mitochondrial ?-Barrel Proteins.

    PubMed

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

    2015-10-30

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Pijuan, Jordi; María, Carlos; Herrero, Enrique; Bellí, Gemma

    2015-12-15

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

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

    PubMed Central

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

    2013-01-01

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

  3. Human ISCA1 Interacts with IOP1/NARFL and Functions in Both Cytosolic and Mitochondrial Iron-Sulfur Protein Biogenesis*

    PubMed Central

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

    2009-01-01

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

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

    SciTech Connect

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

    2007-05-01

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

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

    PubMed

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

    2014-11-01

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

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

    PubMed Central

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

    2015-01-01

    Background Mitochondrial dysfunction in adipose tissue has been implicated as a pathogenic step in the development of type 2 diabetes mellitus (T2DM). In adipose tissue, chronic nutrient overload results in mitochondria driven increased reactive oxygen species (ROS) leading to carbonylation of proteins that impair mitochondrial function and downregulation of key genes linked to mitochondrial biogenesis. In patients with T2DM, Roux-en-Y gastric bypass (RYGB) surgery leads to improvements in glycemic profile prior to significant weight loss. Consequently, we hypothesized that improved glycemia early after RYGB would be paralleled by decreased protein carbonylation and increased expression of genes related to mitochondrial biogenesis in adipose tissue. Methods To evaluate this hypothesis, 16 obese individuals were studied before and 7–8 days following RYGB and adjustable gastric banding (AGB). Subcutaneous adipose tissue was obtained pre- and post-bariatric surgery as well as from eight healthy, non-obese individual controls. Results Prior to surgery, adipose tissue expression of PGC1?, NRF1, Cyt C, and eNOS (but not Tfam) showed significantly lower expression in the obese bariatric surgery group when compared to lean controls (p<0.05). Following RYGB, but not after AGB, patients showed significant decrease in HOMA-IR, reduction in adipose protein carbonylation, and increased expression of genes linked to mitochondrial biogenesis. Conclusions These results suggest that rapid reduction in protein carbonylation and increased mitochondrial biogenesis may explain postoperative metabolic improvements following RYGB. PMID:25975200

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

    SciTech Connect

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

    2012-10-15

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

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

    SciTech Connect

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

    2013-01-11

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  11. 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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed Central

    Ber?sewicz, Ma?gorzata; Dymkowska, Dorota; Zab?ocki, Krzysztof; Zab?ocka, Barbara

    2015-01-01

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

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

    SciTech Connect

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

    1995-01-20

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

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

    PubMed Central

    Delaveau, Thierry; Jourdren, Laurent; Le Crom, Stephane; Lemoine, Sophie; Tanty, Veronique; Devaux, Frederic; Jacq, Claude

    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 allowed the characterization of two classes of genes whose mRNAs are translated to the vicinity of mitochondria. Class I mRNAs (256 genes) have a Puf3p binding motif in their 3'UTR region and many of them have their MLR properties deeply affected by PUF3 deletion. Conversely, mutations in the Puf3p binding motif alter the mitochondrial localization of BCS1 mRNA. Class II mRNAs (224 genes) have no Puf3p binding site and their asymmetric localization is not affected by the absence of PUF3. In agreement with a co-translational import process, we observed that the presence of puromycin loosens the interactions between most of the MLR-mRNAs and mitochondria. Unexpectedly, cycloheximide, supposed to solidify translational complexes, turned out to destabilize a class of mRNA-mitochondria interactions. Classes I and II mRNAs, which are therefore transported to the mitochondria through different pathways, correlated with different functional modules. Indeed, Class I genes code principally for the assembly factors of respiratory chain complexes and the mitochondrial translation machinery (ribosomes and translation regulators). Class II genes encode proteins of the respiratory chain or proteins involved in metabolic pathways. Thus, MLR, which is intimately linked to translation control, and the activity of mRNA-binding proteins like Puf3p, may provide the conditions for a fine spatiotemporal control of mitochondrial protein import and mitochondrial protein complex assembly. This work therefore provides new openings for the global study of mitochondria biogenesis. PMID:18523582

  20. 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

  1. Exercise-induced asthma.

    PubMed

    Tan, R A; Spector, S L

    1998-01-01

    Exercise-induced asthma (EIA) is characterised by transient airway obstruction occurring after strenuous exertion. A fall of 10% or more in the FEV1 after exercise is diagnostic. Inhalation of large volumes of dry, cold air during exercise leads to loss of heat and water from the bronchial mucosa and airway cooling and drying. Proposed mechanisms for bronchoconstriction include: (i) mucosal drying and increased osmolarity stimulating mast cell degranulation; and (ii) rapid airway rewarming after exercise causing vascular congestion, increased permeability and oedema leading to obstruction. EIA symptoms start after exercise, peak 8 to 15 minutes after exercise and spontaneously resolve in about 60 minutes. A refractory period of up to 3 hours after recovery, during which repeat exercise causes less bronchospasm, has been observed. The amount of ventilation and the temperature of inspired air are important factors in determining the severity of EIA. Greater ventilation and cold, dry air increase the risk for EIA. Education regarding the nature and management of EIA is important not only for asthmatics but also for their families and coaches. With the proper precautions and workout techniques, there is no limit to what individuals with asthma can achieve in sports. Prevention is the main objective in managing EIA. Nonpharmacological measures include warming up before vigorous exertion, covering the mouth and nose in cold weather, exercising in warm, humidified environments if possible and warming down after exercise. Aerobic fitness and good control of baseline bronchial reactivity also help to diminish the effects of EIA. Inhaled beta-agonists are the medications of choice in EIA prophylaxis. Inhaled sodium cromoglycate (cromolyn sodium) or nedocromil may also be used. Agents that may be added if inhaled beta-agonists or sodium cromoglycate are not adequate include anticholinergic agents (such as ipratropium bromide), theophylline, calcium channel blockers, alpha-agonists, antihistamines and oral beta-agonists. Newer agents include antileukotriene agents, inhaled heparin and inhaled furosemide (frusemide). PMID:9458523

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

    PubMed Central

    Nie, Yaohui; Wong, Chiwai

    2009-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-01-01

    Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O2 alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-? coactivator 1-? (PGC-1?) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O2 was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of FiO2 , partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN-PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O2 amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen. PMID:26519208

  5. 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

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

    PubMed

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

    2015-09-01

    During transition from rest to exercise, metabolic reaction rates increase substantially to sustain intracellular ATP use. These metabolic demands activate several kinases that initiate signal transduction pathways which modulate transcriptional regulation of mitochondrial biogenesis. The purpose of this study was to determine whether metabolic fluctuations per se affect the signaling cascades known to regulate peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?). On two separate occasions, nine men performed a continuous (30-min) and an intermittent exercise (30 × 1-min intervals separated by 1-min of recovery) at 70% of V?O2peak. Skeletal muscle biopsies from the vastus lateralis were taken at rest and at +0 h and +3 h after each exercise. Metabolic fluctuations that correspond to exercise-induced variation in metabolic rates were determined by analysis of VO2 responses. During intermittent exercise metabolic fluctuations were 2.8-fold higher despite identical total work done to continuous exercise (317 ± 41 vs. 312 ± 56 kJ after intermittent and continuous exercise, respectively). Increased phosphorylation of AMP-activated protein kinase (AMPK) (~2.9-fold, P < 0.01), calcium/calmodulin-dependent protein kinase II (CaMKII) (~2.7-fold, P < 0.01) and p38-mitogen-activated protein kinase (MAPK) (~4.2-fold, P < 0.01) occurred immediately in both exercises and to a greater extent after the intermittent exercise (condition x time interaction, P < 0.05). A single bout of intermittent exercise induces a greater activation of these signaling pathways regulating PGC-1? when compared to a single bout of continuous exercise of matched work and intensity. Chronic adaptations to exercise on mitochondria biogenesis are yet to be investigated. PMID:26359238

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

    PubMed Central

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

    2015-01-01

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

  8. 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.)

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

    PubMed

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

    2014-02-01

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

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

    PubMed Central

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

    2014-01-01

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

  11. Mitochondrial and sarcoplasmic protein changes in hearts from copper-deficient rats: up-regulation of PGC-1alpha transcript and protein as a cause for mitochondrial biogenesis in copper deficiency.

    PubMed

    Medeiros, Denis M; Jiang, Yu; Klaahsen, Darcey; Lin, Dingbo

    2009-10-01

    Changes in mitochondrial and sarcoplasmic proteins using proteinomics and Western blotting in hearts from copper-deficient rats were explored in this study. Also, key enzymes that are involved in cardiac energy metabolism via glycolysis and fatty acid oxidation and related transcription factors were determined. Rats were fed one of two diets: a copper-adequate diet containing 6 mg Cu/kg diet or a diet with less than 1 mg Cu/kg diet for 5 weeks. Copper deficiency was confirmed by low liver copper levels, decreased hematocrit levels and cardiac hypertrophy. Proteinomic data revealed that of the more than 50 proteins identified from the mitochondrial fraction of heart tissue, six were significantly down-regulated and nine were up-regulated. The proteins that were decreased were beta enolase 3, carbonic anhydrase 2, aldose reductase 1, glutathione peroxidase, muscle creatine kinase and mitochondrial aconitase 2. The proteins that were up-regulated were isocitrate dehydrogenase, dihydrolipoamide dehydrogenase, transferrin, subunit d of ATP synthase, transthyretin, preproapolipoprotein A-1, GRP 75, alpha-B crystalline and heat shock protein alpha. Follow-up Western blots on rate-limiting enzymes in glycolysis (phosphofructose kinase), fatty acid oxidation (medium chain acyl dehydrogenase, peroxisome proliferator-actvator receptor-alpha or PPARalpha) and gluconeogenesis (phosphoenolpyruvate carboxykinase) did not reveal changes in metabolic enzymes. However, a significant increase in peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha protein, as well as the transcript, which increased 2.5-fold, was observed. It would appear that increased mitochondrial biogenesis known to occur in copper deficiency hearts is caused by an increased expression in the master regulator of mitochondrial biogenesis, PGC-1alpha. PMID:18993053

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

    PubMed

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

    2005-03-18

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

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

    PubMed

    G?ombik, Katarzyna; Stachowicz, Aneta; ?lusarczyk, Joanna; Trojan, Ewa; Budziszewska, Bogus?awa; Suski, Maciej; Kubera, Marta; Laso?, W?adys?aw; W?dzony, Krzysztof; Olszanecki, Rafa?; Basta-Kaim, Agnieszka

    2015-10-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

    The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1-/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1-/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1-/- mice expressed increased amounts of PGC1?, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1? promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1?. Since STAT1-/- mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1-/- mice did not lose lipid from WAT. ?-adrenergic stimulation of glycerol release from isolated STAT1-/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1-/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1-/- mice. PMID:26689548

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

    PubMed

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

    2015-09-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. Can nutrition limit exercise-induced immunodepression?

    PubMed

    Gleeson, Michael

    2006-03-01

    Prolonged exercise and heavy training are associated with depressed immune cell function. To maintain immune function, athletes should eat a well-balanced diet sufficient to meet their energy, carbohydrate, protein, and micronutrient requirements. Consuming carbohydrate during prolonged strenuous exercise attenuates rises in stress hormones and appears to limit the degree of exercise-induced immune depression. Recent evidence suggests that antioxidant vitamin supplementation may also reduce exercise stress and impairment of leukocyte functions. Further research is needed to evaluate the effects of other antioxidants and dietary immunostimulants such as probiotics and echinacea on exercise-induced immune impairment. PMID:16572599

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

    PubMed

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

    2013-01-15

    Based on the rapid hydrolysis of acetyl salicylic acid (ASA, Aspirin) to salicylic acid (SA), the ability of SA to form dihydroxy benzoic acid (DBA), and the latter's redox reactions to yield hydrogen peroxide (H(2)O(2)), we predicted that ASA may have the potential to induce Sirtuin1 (Sirt1) and its downstream effects. We observed that treatment of cultured liver cells with ASA resulted in the induction of Sirt1, peroxisome proliferator-activated receptor-gamma co-activator-1? (PGC-1?), and NAD(P)H quinone oxidoreductase 1 (Nqo1) genes. Paraoxonase 1 (PON1) and Aryl hydrocarbon receptor (AhR) siRNA transfections inhibited the induction of gene expressions by ASA suggesting the need for the acetyl ester hydrolysis and hydroxylation to DHBA. The latter also induced Sirt1, confirming the proposed pathway. As predicted, ASA and SA treatment resulted in the production of H(2)O(2), a known inducer of Sirt1 and confirmed in the current studies. More importantly, ASA treatment resulted in an increase in mitochondria as seen by tracking dyes. We suggest that DHBA, generated from ASA, via its oxidation/reduction reactions mediated by Nqo1 might be involved in the production of O(2)(-.) and H(2)O(2). As Sirt1 and PGC-1? profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases. PMID:23228932

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-09-01

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

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

    PubMed Central

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

    2011-01-01

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

  6. Mechanisms of Exercise-Induced Cardioprotection

    PubMed Central

    Smuder, Ashley J.; Kavazis, Andreas N.; Quindry, John C.

    2014-01-01

    Myocardial ischemia-reperfusion (IR) injury can cause ventricular cell death and is a major pathological event leading to morbidity and mortality in those with coronary artery disease. Interestingly, as few as five bouts of exercise on consecutive days can rapidly produce a cardiac phenotype that resists IR-induced myocardial injury. This review summarizes the development of exercise-induced cardioprotection and the mechanisms responsible for this important adaptive response. PMID:24382869

  7. 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

  8. Exercise-induced analgesia: fact or artifact?

    PubMed

    Padawer, W J; Levine, F M

    1992-02-01

    This study critically examines the reported exercise-induced analgesia effect in view of the potential stress-induced analgesia of pain testing itself. Two designs were used to test whether previous findings of analgesia were induced by the exercise procedures or by the stress of the pain testing procedures themselves used in such experiments. In the first design, post-test cold pressor pain ratings were obtained from college students following exercise (bicycle ergometry) and two control tasks (minimal exercise and non-exercise). No significant differences between these groups were found. In the second design, exercise and non-exercise groups pre-exposed to cold pressor pain testing were compared to groups that were not pre-exposed to pain testing. There were no significant effects for exercise; however, significant analgesia effects for pain test pre-exposure were demonstrated. Therefore previous research claiming exercise-induced analgesia may have confounded the effects of exercise with the effects of pre-exposure to pain testing itself. PMID:1589230

  9. Exercise-induced anaphylaxis and antileukotriene montelukast

    PubMed Central

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

    2015-01-01

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

  10. Nutritional Support for Exercise-Induced Injuries.

    PubMed

    Tipton, Kevin D

    2015-11-01

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

  11. Central oxytocin modulates exercise-induced tachycardia.

    PubMed

    Braga, D C; Mori, E; Higa, K T; Morris, M; Michelini, L C

    2000-06-01

    We have shown that vasopressinergic projections to dorsal brain stem are activated during exercise and facilitate exercise tachycardia in both trained (T) and sedentary (S) rats (Dufloth DL, Morris M, and Michelini LC. Am J Physiol Regulatory Integrative Comp Physiol 273: R1271-R1282, 1997). In the present study, we investigated whether oxytocinergic projections to the nucleus of the solitary tract (NTS)-dorsal motor nucleus of the vagus (DMV) complex (NTS/DMV) are involved in the differential heart rate (HR) response to exercise in T and S rats. Arterial pressure (AP) and HR responses to dynamic exercise (0.4-1.4 km/h) were compared in S and T pretreated with vehicle (saline), oxytocin (OT; 20 pmol/200 nl) or OT-receptor antagonist (OT(ant); 20 pmol/200 nl) into the NTS/DMV. OT content in specific brain regions and plasma were measured in separate S and T groups at rest and immediately after exercise. Exercise increased OT content in dorsal (4.5-fold) and ventral brain stem (2.7-fold) and spinal cord (3.4-fold) only in T rats. No significant changes were observed in neurosecretory regions or medial eminence and posterior pituitary, but plasma levels of T rats were reduced immediately after exercise. Blockade of NTS/DMV OT receptors did not change basal mean AP (MAP) and HR or the MAP response to exercise. However, OT(ant) potentiated exercise-induced tachycardia (average increase of 26%) only in the T group. Pretreatment with exogenous OT in the NTS/DMV blunted the tachycardic response both in S and T rats without changing the MAP response. Administration of OT-receptor antagonist or OT into the fourth cerebral ventricle had no effect on the cardiovascular response to dynamic exercise. Taken together, the results suggest that oxytocinergic projections to the NTS/DMV are stimulated when T rats exercise and that OT released at this level acts on OT receptors to restrain exercise-induced tachycardia. PMID:10848513

  12. Mechanisms of Exercise-Induced Hypoalgesia

    PubMed Central

    Koltyn, Kelli F.; Brellenthin, Angelique G.; Cook, Dane B.; Sehgal, Nalini; Hillard, Cecilia

    2014-01-01

    The purpose of this study was to examine opioid and endocannabinoid mechanisms of exercise-induced hypoalgesia (EIH). Fifty-eight men and women (mean age = 21 yrs) completed three sessions. During the first session, participants were familiarized with the temporal summation of heat pain and pressure pain protocols. In the exercise sessions, following double-blind administration of either an opioid antagonist (50 mg naltrexone) or placebo, participants rated the intensity of heat pulses and indicated their pressure pain thresholds (PPT) and ratings (PPR) before and after 3 minutes of submaximal isometric exercise. Blood was drawn before and after exercise. Results indicated circulating concentrations of two endocannabinoids, N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) as well as related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), N-docsahexaenoylethanolamine (DHEA), and 2-oleoylglycerol (2-OG) increased significantly (p < 0.05) following exercise. PPT increased significantly (p < 0.05) while PPR decreased significantly (p < 0.05) following exercise. Also, temporal summation ratings were significantly lower (p < 0.05) following exercise. These changes in pain responses did not differ between placebo or naltrexone conditions (p > 0.05). A significant association was found between EIH and DHEA. These results suggest involvement of a non-opioid mechanism in EIH following isometric exercise. PMID:25261342

  13. Exercise-induced bronchospasm - pathophysiology and treatment.

    PubMed

    Shephard, R J

    1981-09-01

    The practical importance, prevalence, typical features, physiopathology and therapy of exercise-induced bronchospasm (E.I.B.) are briefly reviewed. The condition is common, especially in children. Prevalence is influenced by the mode, intensity and duration of exercise, the age and possibly the sex of the subjects, the number of test repetitions, and the criterion for presence of spasm. The main site of obstruction is in the large airways. Symptoms appear a few minutes post-effort, peaking 10-15 minutes after exercise. At different times, spasm may arise in the vagal reflex arc, from alterations of sympathetic balance, prostaglandin release, and sensitization of the mast cell. Until recently, the main basis of prophylaxis has been inhalation of sodium cromoglycate (20 mg, 60 minutes prior to competition). Beta agonists have until recently been prohibited in international competitions. However, the use of selective beta agonists such as salbutamol and terbutaline was allowed in the 1978 World Swimming Championship and the 1980 World Cross-Country Championship with a supporting medical letter. The Medical Commission of the International Olympic Committee has also moved recently to sanction the use of salbutamol and terbutaline. Future prophylaxis will thus be based on combinations of selective beta agonists and sodium cromoglycate. PMID:6794921

  14. 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.

  15. Dietary supplementation with the microalga Galdieria sulphuraria (Rhodophyta) reduces prolonged exercise-induced oxidative stress in rat tissues.

    PubMed

    Carfagna, Simona; Napolitano, Gaetana; Barone, Daniela; Pinto, Gabriele; Pollio, Antonino; Venditti, Paola

    2015-01-01

    We studied the effects of ten-day 1% Galdieria sulphuraria dietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming) determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle) homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2 mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria. G. sulphuraria supplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2 release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion, G. sulphuraria ability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion. PMID:25874021

  16. Dietary Supplementation with the Microalga Galdieria sulphuraria (Rhodophyta) Reduces Prolonged Exercise-Induced Oxidative Stress in Rat Tissues

    PubMed Central

    Carfagna, Simona; Napolitano, Gaetana; Barone, Daniela; Pinto, Gabriele; Venditti, Paola

    2015-01-01

    We studied the effects of ten-day 1% Galdieria sulphuraria dietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming) determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle) homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2 mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria. G. sulphuraria supplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2 release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion, G. sulphuraria ability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion. PMID:25874021

  17. Chronic Mesenteric Ischemia Presenting as Exercise-induced Abdominal Pain.

    PubMed

    Famularo, Marissa; Lombardi, Joseph

    2015-11-01

    Patients with a stenosis of the superior mesenteric artery and a widely patent celiac axis are often asymptomatic because of a rich network of collaterals between the two. Compression of the celiac axis by the diaphragm is, in patients without additional vascular disease, also frequently asymptomatic. Here, we describe an unusual case of exercise-induced abdominal pain caused by a combination of these two pathologies. In our patient with a previously occluded inferior mesenteric artery and a 90% superior mesenteric artery stenosis, celiac compression by the diaphragm, worsened with exercise, caused severe abdominal pain. This exercise-induced pain resolved completely with endovascular treatment of the superior mesenteric artery stenosis. PMID:26184369

  18. 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.

  19. 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...

  20. Exercise-induced asthma. What family physicians should do.

    PubMed Central

    D'Urzo, A.

    1995-01-01

    Exercise-induced asthma is described as a transitory increase in airway resistance during or after vigorous exercise. Nearly 90% of patients with chronic asthma and 40% of allergic nonasthmatic patients have the condition. Family physicians should try to educate patients about their asthma and, barring contraindications, encourage them to participate in regular physical activity. PMID:8563507

  1. CARDIOMYOPATHY Exercise-Induced Left Ventricular Systolic Dysfunction

    E-print Network

    Campbell, Kevin P.

    CARDIOMYOPATHY Exercise-Induced Left Ventricular Systolic Dysfunction in Women Heterozygous women each underwent standard exercise stress echocardiography. Results: Heterozygotes demonstrated.62 6 0.07, P = .02). After exercise, the mean LVEF fell to 0.53 6 0.14 in heterozygotes but rose to 0

  2. Exercise?Induced growth hormone during acute sleep deprivation

    PubMed Central

    Ritsche, Kevin; Nindl, Bradly C.; Wideman, Laurie

    2014-01-01

    Abstract The effect of acute (24?h) sleep deprivation on exercise?induced growth hormone (GH) and insulin?like growth factor?1 (IGF?1) was examined. Ten men (20.6 ± 1.4 years) completed two randomized 24?h sessions including a brief, high?intensity exercise bout following either a night of sleep (SLEEP) or (24?h) sleep deprivation (SLD). Anaerobic performance (mean power [MP], peak power [PP], minimum power [MinP], time to peak power [TTPP], fatigue index, [FI]) and total work per sprint [TWPS]) was determined from four maximal 30?sec Wingate sprints on a cycle ergometer. Self?reported sleep 7 days prior to each session was similar between SLEEP and SLD sessions (7.92 ± 0.33 vs. 7.98 ± 0.39 h, P =0.656, respectively) and during the actual SLEEP session in the lab, the total amount of sleep was similar to the 7 days leading up to the lab session (7.72 ± 0.14 h vs. 7.92 ± 0.33 h, respectively) (P =0.166). No differences existed in MP, PP, MinP, TTPP, FI, TWPS, resting GH concentrations, time to reach exercise?induced peak GH concentration (TTP), or free IGF?1 between sessions. GH area under the curve (AUC) (825.0 ± 199.8 vs. 2212.9 ± 441.9 ?g/L*min, P <0.01), exercise?induced peak GH concentration (17.8 ± 3.7 vs. 39.6 ± 7.1 ?g/L, P <0.01) and ?GH (peak GH – resting GH) (17.2 ± 3.7 vs. 38.2 ± 7.3 ?g/L, P <0.01) were significantly lower during the SLEEP versus SLD session. Our results indicate that the exercise?induced GH response was significantly augmented in sleep?deprived individuals. PMID:25281616

  3. Exercise-Induced growth hormone during acute sleep deprivation.

    PubMed

    Ritsche, Kevin; Nindl, Bradly C; Wideman, Laurie

    2014-10-01

    The effect of acute (24-h) sleep deprivation on exercise-induced growth hormone (GH) and insulin-like growth factor-1 (IGF-1) was examined. Ten men (20.6 ± 1.4 years) completed two randomized 24-h sessions including a brief, high-intensity exercise bout following either a night of sleep (SLEEP) or (24-h) sleep deprivation (SLD). Anaerobic performance (mean power [MP], peak power [PP], minimum power [MinP], time to peak power [TTPP], fatigue index, [FI]) and total work per sprint [TWPS]) was determined from four maximal 30-sec Wingate sprints on a cycle ergometer. Self-reported sleep 7 days prior to each session was similar between SLEEP and SLD sessions (7.92 ± 0.33 vs. 7.98 ± 0.39 h, P = 0.656, respectively) and during the actual SLEEP session in the lab, the total amount of sleep was similar to the 7 days leading up to the lab session (7.72 ± 0.14 h vs. 7.92 ± 0.33 h, respectively) (P = 0.166). No differences existed in MP, PP, MinP, TTPP, FI, TWPS, resting GH concentrations, time to reach exercise-induced peak GH concentration (TTP), or free IGF-1 between sessions. GH area under the curve (AUC) (825.0 ± 199.8 vs. 2212.9 ± 441.9 ?g/L*min, P < 0.01), exercise-induced peak GH concentration (17.8 ± 3.7 vs. 39.6 ± 7.1 ?g/L, P < 0.01) and ?GH (peak GH - resting GH) (17.2 ± 3.7 vs. 38.2 ± 7.3 ?g/L, P < 0.01) were significantly lower during the SLEEP versus SLD session. Our results indicate that the exercise-induced GH response was significantly augmented in sleep-deprived individuals. PMID:25281616

  4. 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…

  5. Erythropoiesis and Iron Sulfur Cluster Biogenesis

    PubMed Central

    Ye, Hong; Rouault, Tracey A.

    2010-01-01

    Erythropoiesis in animals is a synchronized process of erythroid cell differentiation that depends on successful acquisition of iron. Heme synthesis depends on iron through its dependence on iron sulfur (Fe-S) cluster biogenesis. Here, we review the relationship between Fe-S biogenesis and heme synthesis in erythropoiesis, with emphasis on the proteins, GLRX5, ABCB7, ISCA, and C1orf69. These Fe-S biosynthesis proteins are highly expressed in erythroid tissues, and deficiency of each of these proteins has been shown to cause anemia in zebrafish model. GLRX5 is involved in the production and ABCB7 in the export of an unknown factor that may function as a gauge of mitochondrial iron status, which may indirectly modulate activity of iron regulatory proteins (IRPs). ALAS2, the enzyme catalyzing the first step in heme synthesis, is translationally controlled by IRPs. GLRX5 may also provide Fe-S cofactor for ferrochelatase, the last enzyme in heme synthesis. ISCA and C1orf69 are thought to assemble Fe-S clusters for mitochondrial aconitase and for lipoate synthase, the enzyme producing lipoate for pyruvate dehydrogenase complex (PDC). PDC and aconitase are involved in the production of succinyl-CoA, a substrate for heme biosynthesis. Thus, many steps of heme synthesis depend on Fe-S cluster assembly. PMID:20862391

  6. Pathophysiology of Acute Exercise-Induced Muscular Injury: Clinical Implications

    PubMed Central

    Page, Phillip

    1995-01-01

    Acute muscular injury is the most common injury affecting athletes and those participating in exercise. Nearly everyone has experienced soreness after unaccustomed or intense exercise. Clinically, acute strains and delayed-onset muscle soreness are very similar. The purpose of this paper is to review the predisposing factors, mechanisms of injury, structural changes, and biochemical changes associated with these injuries. Laboratory and clinical findings are discussed to help athletic trainers differentiate between the two conditions and to provide a background knowledge for evaluation, prevention, and treatment of exercise-induced muscular injury. PMID:16558305

  7. Nutritional strategies to minimise exercise-induced immunosuppression in athletes.

    PubMed

    Gleeson, M; Lancaster, G I; Bishop, N C

    2001-01-01

    Strenuous prolonged exertion and heavy training are associated with depressed immune function. Furthermore, improper nutrition can compound the negative influence of heavy exertion on immunocompetence. Dietary deficiencies of protein and specific micronutrients have long been associated with immune dysfunction. An adequate intake of iron, zinc, and vitamins A, E, B6 and B12 is particularly important but excess intakes can also impair immune function. Immune system impairment has also been associated with excess intake of fat. To maintain immune function, athletes should eat a well balanced diet sufficient to meet their energy requirements. An athlete exercising in a carbohydrate-depleted state experiences larger increases in circulating stress hormones and a greater perturbation of several immune function indices. Conversely, consuming carbohydrate during exercise attenuates rises in stress hormones such as cortisol and appears to limit the degree of exercise-induced immunosuppression, at least for non-fatiguing bouts of exercise. Strong evidence that high doses of antioxidant vitamins, glutamine supplementation or echinacea extracts can prevent exercise-induced immunosuppression is lacking. PMID:11897880

  8. Exercise-Induced Oxidative Stress and Dietary Antioxidants

    PubMed Central

    Yavari, Abbas; Javadi, Maryam; Mirmiran, Parvin; Bahadoran, Zahra

    2015-01-01

    Context: Overproduction of reactive oxygen and nitrogen species during physical exercise, exercise induced oxidative stress and antioxidant supplementation is interesting and controversial concepts that have been considered during the past decades. Evidence Acquisition: In this review, we aimed to summarize current evidence in relation to antioxidant supplementation outcomes during exercise and physical activity. For this aim, we obtained relevant articles through searches of the Medline and PubMed databases between 1980 to 2013. Although major studies have indicated that antioxidants could attenuate biomarkers of exercise-induced oxidative stress and the use of antioxidant supplement is a common phenomenon among athletes and physically active people, there are some doubts regarding the benefits of these. Results: It seems that the best recommendations regarding antioxidants and exercise are having a balanced diet rich in natural antioxidants and phytochemicals. Conclusions: Regular consumption of various fresh fruits and vegetables, whole grains, legumes and beans, sprouts and seeds is an effective and safe way to meet all antioxidant requirements in physically active persons and athletes. PMID:25883776

  9. 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.

  10. Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans.

    PubMed

    Layec, Gwenael; Trinity, Joel D; Hart, Corey R; Kim, Seong-Eun; Groot, H Jonathan; Le Fur, Yann; Sorensen, Jacob R; Jeong, Eun-Kee; Richardson, Russell S

    2015-08-15

    Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min(-1)·W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age. PMID:26041112

  11. 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…

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

    ERIC Educational Resources Information Center

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

    2010-01-01

    Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…

  13. Peroxisome Biogenesis and Function

    PubMed Central

    Kaur, Navneet; Reumann, Sigrun; Hu, Jianping

    2009-01-01

    Peroxisomes are small and single membrane-delimited organelles that execute numerous metabolic reactions and have pivotal roles in plant growth and development. In recent years, forward and reverse genetic studies along with biochemical and cell biological analyses in Arabidopsis have enabled researchers to identify many peroxisome proteins and elucidate their functions. This review focuses on the advances in our understanding of peroxisome biogenesis and metabolism, and further explores the contribution of large-scale analysis, such as in sillco predictions and proteomics, in augmenting our knowledge of peroxisome function In Arabidopsis. PMID:22303249

  14. Dietary strategies to recover from exercise-induced muscle damage.

    PubMed

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

    2014-03-01

    Exhaustive or unaccustomed intense exercise can cause exercise-induced muscle damage (EIMD) and its undesirable consequences may decrease the ability to exercise and to adhere to a training programme. This review briefly summarises the muscle damage process, focusing predominantly on oxidative stress and inflammation as contributing factors, and describes how nutrition may be positively used to recover from EIMD. The combined intake of carbohydrates and proteins and the use of antioxidants and/or anti-inflammatory nutrients within physiological ranges are interventions that may assist the recovery process. Although the works studying food instead of nutritional supplements are very scarce, their results seem to indicate that food might be a favourable option as a recovery strategy. To date, the only tested foods were milk, cherries, blueberries and pomegranate with promising results. Other potential solutions are foods rich in protein, carbohydrates, antioxidants and/or anti-inflammatory nutrients. PMID:24180469

  15. Exercise-induced brachial artery vasodilation: role of free radicals.

    PubMed

    Richardson, Russell S; Donato, Anthony J; Uberoi, Abhimanyu; Wray, D Walter; Lawrenson, Lesley; Nishiyama, Steven; Bailey, Damian M

    2007-03-01

    Originally thought of as simply damaging or toxic "accidents" of in vivo chemistry, free radicals are becoming increasingly recognized as redox signaling molecules implicit in cellular homeostasis. Indeed, at the vascular level, it is plausible that oxidative stress plays a regulatory role in normal vascular function. Using electron paramagnetic resonance (EPR) spectroscopy, we sought to document the ability of an oral antioxidant cocktail (vitamins C, E, and alpha-lipoic acid) to reduce circulating free radicals, and we employed Doppler ultrasound to examine the consequence of an antioxidant-mediated reduction in oxidative stress on exercise-induced vasodilation. A total of 25 young (18-31 yr) healthy male subjects partook in these studies. EPR spectroscopy revealed a reduction in circulating free radicals following antioxidant administration at rest ( approximately 98%) and as a consequence of exercise ( approximately 85%). Plasma total antioxidant capacity and vitamin C both increased following the ingestion of the antioxidant cocktail, whereas vitamin E levels were not influenced by the ingestion of the antioxidants. Brachial artery vasodilation during submaximal forearm handgrip exercise was greater with the placebo (7.4 +/- 1.8%) than with the antioxidant cocktail (2.3 +/- 0.7%). These data document the efficacy of an oral antioxidant cocktail in reducing free radicals and suggest that, in a healthy state, the aggressive disruption of the delicate balance between pro- and antioxidant forces can negatively impact vascular function. These findings implicate an exercise-induced reliance upon pro-oxidant-stimulated vasodilation, thereby revealing an important and positive vascular role for free radicals. PMID:17114239

  16. 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

  17. 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

  18. Exercise-Induced Pulmonary Edema in a Triathlon

    PubMed Central

    Yamanashi, Hirotomo; Koyamatsu, Jun; Nobuyoshi, Masaharu; Murase, Kunihiko; Maeda, Takahiro

    2015-01-01

    Introduction. Family physicians have more opportunities to attend athletic competitions as medical staff at first-aid centers because of the increasing popularity of endurance sports. Case. A 38-year-old man who participated in a triathlon race experienced difficulty in breathing after swimming and was moved to a first-aid center. His initial oxygen saturation was 82% and a thoracic computed tomography scan showed bilateral ground glass opacity in the peripheral lungs. His diagnosis was noncardiogenic pulmonary edema associated with exercise or swimming: exercise-induced pulmonary edema (EIPE) or swimming-induced pulmonary edema (SIPE). Treatment with furosemide and corticosteroid relieved his symptoms of pulmonary edema. Discussion. Noncardiogenic pulmonary edema associated with endurance sports is not common, but knowledge about EIPE/SIPE or neurogenic pulmonary edema associated with hyponatremia, which is called Ayus-Arieff syndrome, is crucial. Knowledge and caution for possible risk factors, such as exposure to cold water or overhydration, are essential for both medical staff and endurance athletes. Conclusion. To determine the presence of pulmonary edema associated with strenuous exercise, oxygen saturation should be used as a screening tool at a first-aid center. To avoid risks for EIPE/SIPE, knowledge about these diseases is essential for medical staff and for athletes who perform extreme exercise. PMID:26229538

  19. Lycium barbarum Polysaccharides Reduce Exercise-Induced Oxidative Stress

    PubMed Central

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

    2011-01-01

    The purpose of the present study was to investigate the effects of Lycium barbarum polysaccharides (LBP) on exercise-induced oxidative stress in rats. Rats were divided into four groups, i.e., one control group and three LBP treated groups. The animals received an oral administration of physiological saline or LBP (100, 200 and 400 mg/kg body weight) for 28 days. On the day of the exercise test, rats were required to run to exhaustion on the treadmill. Body weight, endurance time, malondialdehyde (MDA), super oxide dismutase (SOD) and glutathione peroxidase (GPX) level of rats were measured. The results showed that the body weight of rats in LBP treated groups were not significantly different from that in the normal control group before and after the experiment (P > 0.05). After exhaustive exercise, the mean endurance time of treadmill running to exhaustion of rats in LBP treated groups were significantly prolonged compared with that in the normal control group. MDA levels of rats in LBP treated groups were significantly decreased compared with that in the normal control group (P < 0.05). SOD and GPX levels of rats in LBP treated groups were significantly increased compared with that in the normal control group (P < 0.05). Together, these results indicate that LBP was effective in preventing oxidative stress after exhaustive exercise. PMID:21541044

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

    PubMed Central

    Rouault, Tracey A.

    2012-01-01

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

  1. Iron–sulfur cluster biogenesis and human disease

    PubMed Central

    Rouault, Tracey A.; Tong, Wing Hang

    2008-01-01

    Iron–sulfur (Fe–S) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Human Fe–S cluster assembly proteins are frequently encoded by single genes, and inherited defects in some of these genes cause disease. Recently, the spectrum of diseases attributable to abnormal Fe–S cluster biogenesis has extended beyond Friedreich ataxia to include a sideroblastic anemia with deficiency of glutaredoxin 5 and a myopathy associated with a deficiency of a Fe–S cluster assembly scaffold protein, ISCU. Mutations within other mammalian Fe–S cluster assembly genes could be causative for human diseases that manifest distinctive combinations of tissue-specific impairments. Thus, defects in the iron–sulfur cluster biogenesis pathway could underlie many human diseases. PMID:18606475

  2. Exercise-induced neuromuscular dysfunction under reflex conditions.

    PubMed

    Kaufman, T; Burke, J R; Davis, J M; Durstine, J L

    2001-06-01

    The purpose of this research was to describe further the effects of exercise-induced muscle damage on reflex sensitivity. The subjects were eight physically active, but untrained males, between the ages of 18 and 29 years. The effects of eccentric and concentric exercise on patellar tendon reflex responses were determined. The 8 week experiment consisted of two, 5 day, test protocols with a 6 week wash-out period between test protocols. Each 5 day test protocol consisted of the following six test sessions: (1) day 1--baseline, (2) day 2 baseline, (3) day 2--immediate post-exercise, and (4-6) days 3-5: 24, 48, and 72 h post-exercise. On day 2, the subjects made either 100 fatiguing concentric or eccentric isotonic contractions using the right leg at 75% of the corresponding repetition maximum values. During each test session, the electromyogram (EMG) and force-time characteristics of basic and conditioned patellar tendon reflex responses were measured. The reflex amplitudes of basic and conditioned patellar tendon reflex responses were decreased following fatiguing concentric exercise. There were no immediate effects of fatiguing eccentric exercise on the basic and conditioned patellar tendon reflex responses, but the EMG amplitudes of these reflex responses were reduced on the days following eccentric exercise. The amount of conditioned patellar tendon reflex facilitation was decreased following the concentric exercise protocol and at 48 h post-eccentric exercise. Our conditioned reflex data suggest that post-exercise changes to the physiological mechanisms that modulate the recruitment gain of the alpha-motoneuron pool may depend upon the type of fatiguing exercise. PMID:11482545

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

    PubMed

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

    2015-04-01

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

  4. Intensity Thresholds for Aerobic Exercise–Induced Hypoalgesia

    PubMed Central

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

    2014-01-01

    Despite many studies investigating exercise-induced hypoalgesia, there is limited understanding of the optimal intensity of aerobic exercise in producing hypoalgesic effects across different types of pain stimuli. Given that not all individuals are willing or capable of engaging in high intensity aerobic exercise, whether moderate intensity aerobic exercise is associated with a hypoalgesic response and whether this response generalizes to multiple pain induction techniques needs to be substantiated. Purpose This study’s purpose is to test for differences in the magnitude of pressure and heat pain modulation induced by moderate (MAE) and vigorous (VAE) intensity aerobic exercise. Methods Twelve healthy young males and 15 females completed one training session and three testing sessions consisting of 25 minutes of either 1) stationary cycling at 70% heart rate reserve (HRR), 2) stationary cycling at 50% HRR, or 3) quiet rest (control). Pain testing was conducted on both forearms prior to and immediately following each condition and included the following tests: pressure pain thresholds (PPT), suprathreshold pressure pain test, static continuous heat test, and repetitive pulse heat pain test. Repeated measures ANOVAs were conducted on each pain measure. Results VAE and MAE reduced pain ratings during static continuous heat stimuli and repetitive heat pulse stimuli, with VAE producing larger effects. VAE also increased PPTs, while neither exercise influenced suprathreshold pressure pain ratings. Conclusion These results suggest that MAE is capable of producing a hypoalgesic effect using continuous and repetitive pulse heat stimuli. However, a dose-response effect was evident as VAE produced larger effects than MAE. PMID:24002342

  5. Mitochondrial donation Mitochondrial donation

    E-print Network

    Rambaut, Andrew

    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

  6. mCSF1, a nucleus-encoded CRM protein required for the processing of many mitochondrial introns, is involved in the biogenesis of respiratory complexes I and IV in Arabidopsis.

    PubMed

    Zmudjak, Michal; Colas des Francs-Small, Catherine; Keren, Ido; Shaya, Felix; Belausov, Eduard; Small, Ian; Ostersetzer-Biran, Oren

    2013-07-01

    The coding regions of many mitochondrial genes in plants are interrupted by intervening sequences that are classified as group II introns. Their splicing is essential for the expression of the genes they interrupt and hence for respiratory function, and is facilitated by various protein cofactors. Despite the importance of these cofactors, only a few of them have been characterized. CRS1-YhbY domain (CRM) is a recently recognized RNA-binding domain that is present in several characterized splicing factors in plant chloroplasts. The Arabidopsis genome encodes 16 CRM proteins, but these are largely uncharacterized. Here, we analyzed the intracellular location of one of these hypothetical proteins in Arabidopsis, mitochondrial CAF-like splicing factor 1 (mCSF1; At4 g31010), and analyzed the growth phenotypes and organellar activities associated with mcsf1 mutants in plants. Our data indicated that mCSF1 resides within mitochondria and its functions are essential during embryogenesis. Mutant plants with reduced mCSF1 displayed inhibited germination and retarded growth phenotypes that were tightly associated with reduced complex I and IV activities. Analogously to the functions of plastid-localized CRM proteins, analysis of the RNA profiles in wildtype and mcsf1 plants showed that mCSF1 acts in the splicing of many of the group II intron RNAs in Arabidopsis mitochondria. PMID:23646912

  7. 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

  8. 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.

  9. Coronary arteriography and left ventriculography during spontaneous and exercise-induced ST segment elevation in patients with variant angina

    SciTech Connect

    Matsuda, Y.; Ozaki, M.; Ogawa, H.; Naito, H.; Yoshino, F.; Katayama, K.; Fujii, T.; Matsuzaki, M.; Kusukawa, R.

    1983-09-01

    The present study is an angiographic demonstration of coronary artery spasm during both spontaneous and exercise-induced angina in three patients with variant angina. In each case, clinical, ECG, coronary angiographic, and left ventriculographic observations were made at rest, during spontaneous angina, and during exercise-induced angina. The character of chest pain was similar during spontaneous and exercise-induced episodes. ST segment elevation was present in the anterior ECG leads during both episodes. The left anterior descending coronary artery became partially or totally obstructed during both types of attacks. When coronary spasm was demonstrated during both types of attacks, left ventriculography disclosed akinetic or dyskinetic wall motion in the area supplied by the involved artery. In those patients with reproducible exercise-induced ST segment elevation and chest pain, thallium-201 scintigraphy showed areas of reversible anteroseptal hypoperfusion. Thus in selected patients exercise-induced attacks of angina were similar to spontaneous episodes.

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

    ERIC Educational Resources Information Center

    Kaplan, Ted A.

    1995-01-01

    Exercise-induced bronchospasm commonly strikes young people, keeping many away from activity. The exercise challenge test (a powerful tool in diagnosing the condition, fine-tuning treatment, and improving patient compliance) can help get patients back in action. Knowing how to interpret and use test results helps physicians expedite effective…

  11. High protein diet maintains glucose production during exercise-induced energy deficit: a controlled trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inadequate energy intake induces changes in endogenous glucose production (GP) to preserve muscle mass. Whether addition provision of dietary protein modulates GP response to energy deficit is unclear. The objective was to determine whether exercise-induced energy deficit effects on glucose metaboli...

  12. Increased Protein Maintains Nitrogen Balance during Exercise-Induced Energy Deficit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE: This study examined how a high-protein diet affected nitrogen balance and protein turnover during an exercise-induced energy deficit. METHODS: Twenty-two men completed a 4-d (D1-4) baseline period (BL) of an energy balance diet while maintaining usual physical activity level, followed by 7 ...

  13. Update on Exercise-Induced Asthma. A Report of the Olympic Exercise Asthma Summit Conference.

    ERIC Educational Resources Information Center

    Storms, William W.; Joyner, David M.

    1997-01-01

    Summarizes results from the Olympic Exercise Asthma Summit Conference, offering the latest on identifying and managing exercise-induced asthma (EIA). Concludes that effective pharmacologic and nonpharmacologic treatment is available, but EIA is underrecognized and underdiagnosed. Physicians should look for it in all patients, including school…

  14. 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...

  15. Exercise Induced Nausea and Vomiting: Another Sign of Pheochromocytoma and Paraganglioma Preferably in Young Patients?

    PubMed Central

    King, Kathryn S.; Darmani, Nissar; Adams, Karen T.; Pacak, Karel

    2012-01-01

    Objective A cohort of nine patients, mostly young adults, presented with a new symptom of pheochromocytoma/paraganglioma: exercise induced nausea and vomiting. The aim of this report is to present this symptom of pheochromocytoma/paraganglioma and to suggest a hypothesis for the observation. Design This is a prospective study looking at the patient accounts of the reported symptom and the clinical data on the patients disease. Methods Following a 2000 report from a paraganglioma patient of the experience of exercise induced nausea and vomiting, researchers and clinicians at the National Institutes of Health (NIH), pheochromocytoma/paraganglioma protocol, began asking patients about instances of nausea and vomiting induced through exercise. A cohort of nine patients reporting exercise induced nausea and vomiting was found and their clinical data are analyzed and presented here. Results Exercise induced nausea and vomiting in pheochromocytoma/paraganglioma patients is most likely due to the elevation of circulating catecholamines that activate adrenergic receptors of the area postrema, which induces nausea and vomiting. Succinate dehydrogenase subunit B mutations/deletions were prevalent in the patients described. Conclusions Post exercise nausea and vomiting should be considered as a symptom of pheochromocytoma/paraganglioma and should be addressed in the clinical evaluation of these patients, especially in young adults. PMID:20960160

  16. The Effects of Creatine Supplementation on Exercise-Induced Muscle Damage.

    ERIC Educational Resources Information Center

    Rawson, Eric S.; Gunn, Bridget; Clarkson, Priscilla M.

    2001-01-01

    Investigated the effects of oral creatine (Cr) supplementation on markers of exercise-induced muscle damage following high-force eccentric exercise in men randomly administered Cr or placebo. Results indicated that 5 days of Cr supplementation did not reduce indirect makers of muscle damage or enhance recovery from high-force eccentric exercise.…

  17. 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

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

    PubMed

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

    2014-06-01

    Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans. PMID:24814483

  19. 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

  20. Mitochondrial Dysfunction in Cancer

    PubMed Central

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

    2013-01-01

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

  1. EVALUATION OF THE BIOGENESIS SOIL WASHING TECHNOLOGY

    EPA Science Inventory

    The BioGenesis Enterprises, Inc. (BioGenesis) soil washing technology was demonstrated as part of the US Environmental Protection Agency's (EPA) Superfund Innovative Technology Evaluation (SITE) program in November 1992. The demonstration was conducted over three days at a petrol...

  2. Phosphatidylserine Decarboxylase 1 (Psd1) Promotes Mitochondrial Fusion by Regulating the Biophysical Properties of the Mitochondrial Membrane and Alternative Topogenesis of Mitochondrial Genome Maintenance Protein 1 (Mgm1)*

    PubMed Central

    Chan, Eliana Y. L.; McQuibban, G. Angus

    2012-01-01

    Non–bilayer-forming lipids such as cardiolipin, phosphatidic acid, and phosphatidylethanolamine (PE) are proposed to generate negative membrane curvature, promoting membrane fusion. However, the mechanism by which lipids regulate mitochondrial fusion remains poorly understood. Here, we show that mitochondrial-localized Psd1, the key yeast enzyme that synthesizes PE, is required for proper mitochondrial morphology and fusion. Yeast cells lacking Psd1 exhibit fragmented and aggregated mitochondria with impaired mitochondrial fusion during mating. More importantly, we demonstrate that a reduction in PE reduces the rate of lipid mixing during fusion of liposomes with lipid compositions reflecting the mitochondrial membrane. This suggests that the mitochondrial fusion defect in the ?psd1 strain could be due to the altered biophysical properties of the mitochondrial membrane, resulting in reduced fusion kinetics. The ?psd1 strain also has impaired mitochondrial activity such as oxidative phosphorylation and reduced mitochondrial ATP levels which are due to a reduction in mitochondrial PE. The loss of Psd1 also impairs the biogenesis of s-Mgm1, a protein essential for mitochondrial fusion, further exacerbating the mitochondrial fusion defect of the ?psd1 strain. Increasing s-Mgm1 levels in ?psd1 cells markedly reduced mitochondrial aggregation. Our results demonstrate that mitochondrial PE regulates mitochondrial fusion by regulating the biophysical properties of the mitochondrial membrane and by enhancing the biogenesis of s-Mgm1. While several proteins are required to orchestrate the intricate process of membrane fusion, we propose that specific phospholipids of the mitochondrial membrane promote fusion by enhancing lipid mixing kinetics and by regulating the action of profusion proteins. PMID:23045528

  3. Mitochondrial protein translocases for survival and wellbeing.

    PubMed

    Sokol, Anna Magdalena; Sztolsztener, Malgorzata Eliza; Wasilewski, Michal; Heinz, Eva; Chacinska, Agnieszka

    2014-08-01

    Mitochondria are involved in many essential cellular activities. These broad functions explicate the need for the well-orchestrated biogenesis of mitochondrial proteins to avoid death and pathological consequences, both in unicellular and more complex organisms. Yeast as a model organism has been pivotal in identifying components and mechanisms that drive the transport and sorting of nuclear-encoded mitochondrial proteins. The machinery components that are involved in the import of mitochondrial proteins are generally evolutionarily conserved within the eukaryotic kingdom. However, topological and functional differences have been observed. We review the similarities and differences in mitochondrial translocases from yeast to human. Additionally, we provide a systematic overview of the contribution of mitochondrial import machineries to human pathologies, including cancer, mitochondrial diseases, and neurodegeneration. PMID:24866464

  4. 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

  5. Impact-driven, pulmonary emboli of osseous fat in exercise-induced bronchospasm.

    PubMed

    Simkin, Peter A; Snitily, Brian K

    2015-11-01

    Exercise induced bronchospasm (EIB) affects approximately 10% of normal individuals with higher prevalence rates among children, obese adults, and competitive athletes. Although hyperpnea with dry air is the best known cause, the problem is multifactorial with atopy, asthma and chlorine all playing established roles. To date, no clear mechanism has connected musculoskeletal loading with the ensuing pulmonary compromise. This paper reviews evidence that impact-driven pulses in subchondral bone pressure may push osseous fat cells into the local venous sinusoids. The resultant showers of microemboli must then travel to the lung where lysis of membrane phospholipids leads to leukotriene formation with resultant inflammation and bronchial hypersensitivity. Concurrently, the same emboli deliver triglyceride fuels for further physical activity. Thus, pulmonary microemboli derived from osseous fat may resolve the seeming paradox of athletic excellence in persons afflicted with exercise-induced bronchospasm. PMID:26328480

  6. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk.

    PubMed

    Malin, Steven K; Braun, Barry

    2016-01-01

    Combining metformin with exercise has been proposed to improve glucose homeostasis. However, we primarily discuss evidence suggesting that metformin and other pharmacological agents/dietary supplements (e.g., statins, resveratol, or antioxidants) may in fact oppose exercise-induced benefits on insulin sensitivity and cardiometabolic health. We explore the novel hypothesis that attenuation of oxidative stress from exercise by these exogenous compounds blunts metabolic adaptation. PMID:26583801

  7. Exercise excess pressure and exercise-induced albuminuria in patients with type 2 diabetes mellitus.

    PubMed

    Climie, Rachel E D; Srikanth, Velandai; Keith, Laura J; Davies, Justin E; Sharman, James E

    2015-05-01

    Exercise-induced albuminuria is common in patients with type 2 diabetes mellitus (T2DM) in response to maximal exercise, but the response to light-moderate exercise is unclear. Patients with T2DM have abnormal central hemodynamics and greater propensity for exercise hypertension. This study sought to determine the relationship between light-moderate exercise central hemodynamics (including aortic reservoir and excess pressure) and exercise-induced albuminuria. Thirty-nine T2DM (62 ± 9 yr; 49% male) and 39 nondiabetic controls (53 ± 9 yr; 51% male) were examined at rest and during 20 min of light-moderate cycle exercise (30 W; 50 revolutions/min). Albuminuria was assessed by the albumin-creatinine ratio (ACR) at rest and 30 min postexercise. Hemodynamics recorded included brachial and central blood pressure (BP), aortic stiffness, augmented pressure (AP), aortic reservoir pressure, and excess pressure integral (Pexcess). There was no difference in ACR between groups before exercise (P > 0.05). Exercise induced a significant rise in ACR in T2DM but not controls (1.73 ± 1.43 vs. 0.53 ± 1.0 mg/mol, P = 0.002). All central hemodynamic variables were significantly higher during exercise in T2DM (i.e., Pexcess, systolic BP and AP; P < 0.01 all). In T2DM (but not controls), exercise Pexcess was associated with postexercise ACR (r = 0.51, P = 0.002), and this relationship was independent of age, sex, body mass index, heart rate, aortic stiffness, antihypertensive medication, and ambulatory daytime systolic BP (? = 0.003, P = 0.003). Light-moderate exercise induced a significant rise in ACR in T2DM, and this was independently associated with Pexcess, a potential marker of vascular dysfunction. These novel findings suggest that Pexcess could be important for appropriate renal function in T2DM. PMID:25724495

  8. Clinical significance of plasminogen activator inhibitor activity in patients with exercise-induced ischemia

    SciTech Connect

    Sakata, K.; Kurata, C.; Taguchi, T.; Suzuki, S.; Kobayashi, A.; Yamazaki, N.; Rydzewski, A.; Takada, Y.; Takada, A. )

    1990-10-01

    To assess the fibrinolytic system in patients with exercise-induced ischemia and its relation to ischemia and severity of coronary artery disease (CAD), 47 patients with CAD confirmed by results of coronary angiography underwent symptom-limited multistage exercise thallium-201 emission computed tomography. All patients with CAD had exercise-induced ischemia as assessed from thallium-201 images. Pre- and peak exercise blood samples from each patient and preexercise blood samples from control subjects were assayed for several fibrinolytic components and were also assayed for plasma adrenaline. The extent of ischemia was defined as delta visual uptake score (total visual uptake score in delayed images minus total visual uptake score in initial images) and the severity of CAD as the number of diseased vessels. In the basal condition, plasminogen activator inhibitor (PAI) activity was significantly higher in patients with exercise-induced ischemia as compared to control subjects (p less than 0.01), although there were no significant differences in other fibrinolytic variables between the two groups. Moreover, PAI activity in the basal condition displayed a significantly positive correlation with the extent of ischemia (r = 0.47, p less than 0.01). Patients with exercise-induced ischemia were divided into two groups (24 with single-vessel disease and 23 with multivessel disease). There were no significant differences in coronary risk factors, hemodynamics, or plasma adrenaline levels during exercise between single-vessel and multivessel disease except that delta visual uptake score was significantly higher in multivessel disease (p less than 0.01).

  9. The Role of Exercise-Induced Cardiovascular Adaptation in Brain Health.

    PubMed

    Tarumi, Takashi; Zhang, Rong

    2015-10-01

    Regular aerobic exercise improves brain health; however, a potential dose-response relationship and the underling physiological mechanisms remain unclear. Existing data support the following hypotheses: 1) exercise-induced cardiovascular adaptation plays an important role in improving brain perfusion, structure, and function, and 2) a hormetic relation seems to exist between the intensity of exercise and brain health, which needs to be further elucidated. PMID:26196870

  10. Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes

    PubMed Central

    da Cunha, Fernanda Marques; Torelli, Nicole Quesada; Kowaltowski, Alicia J.

    2015-01-01

    Mitochondria are essential organelles for eukaryotic homeostasis. Although these organelles possess their own DNA, the vast majority (>99%) of mitochondrial proteins are encoded in the nucleus. This situation makes systems that allow the communication between mitochondria and the nucleus a requirement not only to coordinate mitochondrial protein synthesis during biogenesis but also to communicate eventual mitochondrial malfunctions, triggering compensatory responses in the nucleus. Mitochondria-to-nucleus retrograde signaling has been described in various organisms, albeit with differences in effector pathways, molecules, and outcomes, as discussed in this review. PMID:26583058

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

    PubMed Central

    Carver, Terrence W

    2009-01-01

    Exercise-induced asthma/exercise-induced bronchospasm (EIA/EIB) is a prevalent and clinically important disease affecting young children through older adulthood. These terms are often used interchangeably and the differences are not clearly defined in the literature. The pathogenesis of EIA/EIB may be different in those with persistent asthma compared to those with exercise-induced symptoms only. The natural history of EIA is unclear and may be different for elite athletes. Leukotriene biology has helped the understanding of EIB. The type and intensity of exercise are important factors for EIB. Exercise participation is necessary for proper development and control of EIA is recommended. Symptoms of EIB should be confirmed by proper testing. Biologic markers may also be helpful in diagnosis. Not all exercise symptoms are from EIB. Many medication and nonpharmacologic treatments are available. Asthma education is an important component of managing EIA. Many medications have been tested and the comparisons are complicated. Montelukast is a US Food and Drug Administration-approved asthma and EIB controller and has a number of potential advantages to other asthma medications including short onset of action, ease of use, and lack of tolerance. Not all patients improve with montelukast and rescue medication should be available. PMID:21437147

  12. Ultra-endurance exercise induces stress and inflammation and affects circulating hematopoietic progenitor cell function.

    PubMed

    Stelzer, I; Kröpfl, J M; Fuchs, R; Pekovits, K; Mangge, H; Raggam, R B; Gruber, H-J; Prüller, F; Hofmann, P; Truschnig-Wilders, M; Obermayer-Pietsch, B; Haushofer, A C; Kessler, H H; Mächler, P

    2015-10-01

    Although amateur sports have become increasingly competitive within recent decades, there are as yet few studies on the possible health risks for athletes. This study aims to determine the impact of ultra-endurance exercise-induced stress on the number and function of circulating hematopoietic progenitor cells (CPCs) and hematological, inflammatory, clinical, metabolic, and stress parameters in moderately trained amateur athletes. Following ultra-endurance exercise, there were significant increases in leukocytes, platelets, interleukin-6, fibrinogen, tissue enzymes, blood lactate, serum cortisol, and matrix metalloproteinase-9. Ultra-endurance exercise did not influence the number of CPCs but resulted in a highly significant decline of CPC functionality after the competition. Furthermore, Epstein-Barr virus was seen to be reactivated in one of seven athletes. The link between exercise-induced stress and decline of CPC functionality is supported by a negative correlation between cortisol and CPC function. We conclude that ultra-endurance exercise induces metabolic stress and an inflammatory response that affects not only mature hematopoietic cells but also the function of the immature hematopoietic stem and progenitor cell fraction, which make up the immune system and provide for regeneration. PMID:25438993

  13. 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

  14. Hemodynamic effects of high intensity interval training in COPD patients exhibiting exercise-induced dynamic hyperinflation.

    PubMed

    Nasis, I; Kortianou, E; Vasilopoulou, ?; Spetsioti, S; Louvaris, Z; Kaltsakas, G; Davos, C H; Zakynthinos, S; Koulouris, N G; Vogiatzis, I

    2015-10-01

    Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function during exercise in COPD patients. COPD patients with (n = 25) and without (n = 11) exercise-induced DH undertook an incremental (IET) and a constant-load exercise test (CLET) sustained at 75% peak work (WRpeak) prior to and following an interval cycling exercise training regime (set at 100% WRpeak with 30-s work/30-s rest intervals) lasting for 12 weeks. Cardiac output (Q) was assessed by cardio-bio-impedance (PhysioFlow, enduro, PF-O7) to determine Q mean response time (QMRT) at onset (QMRT(ON)) and offset (QMRT(OFF)) of CLET. Post-rehabilitation only those patients exhibiting exercise-induced DH demonstrated significant reductions in QMRT(ON) (from 82.2 ± 4.3 to 61.7 ± 4.2 s) and QMRT(OFF) (from 80.5 ± 3.8 to 57.2 ± 4.9 s ). These post-rehabilitation adaptations were associated with improvements in inspiratory capacity, thereby suggesting that mitigation of the degree of exercise-induced DH improves central hemodynamic responses in COPD patients. PMID:26112284

  15. [Exercise-induced asthma in children and oral terbutaline. A dose-response relationship study].

    PubMed

    Hertz, B; Fuglsang, G; Holm, E B

    1994-09-26

    We wanted to assess the protective effects on exercise-induced asthma as well as the clinical efficacy and safety of increasing doses of a new sustained-release formulation of terbutaline sulphate in 17 asthmatic children aged 6-12 years (mean 9 years). Placebo, 2, 4, and 6 mg terbutaline were given b.i.d. for 14 days in a randomized, double-blind, cross-over design. At the end of each two week period, an exercise test was performed and plasma terbutaline was measured. Compared with placebo, no significant effect was seen on asthma symptoms monitored at home, or on exercise-induced asthma. The percentage falls in FEV1 after the exercise test were 36, 35, 27 and 28%, after placebo, 4, 8 and 12 mg terbutaline/day, respectively. A small but statistically significant dose-related increase was seen in morning and evening peak expiratory flow (PEF) recordings. It is concluded that continuous treatment, even with high doses or oral terbutaline, does not offer clinically useful protection against exercise-induced asthma. PMID:7985255

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

    SciTech Connect

    Ikeda, Shin-ichi; Kizaki, Takako; Haga, Shukoh; Ohno, Hideki; Takemasa, Tohru

    2008-04-04

    Peroxisome proliferator-activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}) promotes the expression of oxidative enzymes in skeletal muscle. We hypothesized that activation of the p38 MAPK (mitogen-activated protein kinase) in response to exercise was associated with exercise-induced PGC-1{alpha} and respiratory enzymes expression and aimed to demonstrate this under the physiological level. We subjected mice to a single bout of treadmill running and found that the exercise induced a biphasic increase in the expression of respiratory enzymes mRNA. The second phase of the increase was accompanied by an increase in PGC-1{alpha} protein, but the other was not. Administration of SB203580 (SB), an inhibitor of p38 MAPK, suppressed the increase in PGC-1{alpha} expression and respiratory enzymes mRNA in both phases. These data suggest that p38 MAPK is associated with the exercise-induced expression of PGC-1{alpha} and biphasic increase in respiratory enzyme mRNAs in mouse skeletal muscle under physiological conditions.

  17. 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

  18. Mitochondrial Quality Control as a Therapeutic Target.

    PubMed

    Suliman, Hagir B; Piantadosi, Claude A

    2016-01-01

    In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control. PMID:26589414

  19. Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration.

    PubMed

    Stevens, Daniel A; Lee, Yunjong; Kang, Ho Chul; Lee, Byoung Dae; Lee, Yun-Il; Bower, Aaron; Jiang, Haisong; Kang, Sung-Ung; Andrabi, Shaida A; Dawson, Valina L; Shin, Joo-Ho; Dawson, Ted M

    2015-09-15

    Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1?. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1?-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death. PMID:26324925

  20. The Role of Mitochondria in Cellular Iron–Sulfur Protein Biogenesis: Mechanisms, Connected Processes, and Diseases

    PubMed Central

    Stehling, Oliver; Lill, Roland

    2013-01-01

    Iron–sulfur (Fe/S) clusters belong to the most ancient protein cofactors in life, and fulfill functions in electron transport, enzyme catalysis, homeostatic regulation, and sulfur activation. The synthesis of Fe/S clusters and their insertion into apoproteins requires almost 30 proteins in the mitochondria and cytosol of eukaryotic cells. This review summarizes our current biochemical knowledge of mitochondrial Fe/S protein maturation. Because this pathway is essential for various extramitochondrial processes, we then explain how mitochondria contribute to the mechanism of cytosolic and nuclear Fe/S protein biogenesis, and to other connected processes including nuclear DNA replication and repair, telomere maintenance, and transcription. We next describe how the efficiency of mitochondria to assemble Fe/S proteins is used to regulate cellular iron homeostasis. Finally, we briefly summarize a number of mitochondrial “Fe/S diseases” in which various biogenesis components are functionally impaired owing to genetic mutations. The thorough understanding of the diverse biochemical disease phenotypes helps with testing the current working model for the molecular mechanism of Fe/S protein biogenesis and its connected processes. PMID:23906713

  1. Distinct Pathways Mediate the Sorting of Tail-anchored Mitochondrial Outer Membrane Proteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about the biogenesis of tail-anchored (TA) proteins localized to the mitochondrial outer membrane in plant cells. To address this issue, we screened all of the (>500) known and predicted TA proteins in Arabidopsis for those annotated, based on Gene Ontology, to possess mitochondrial...

  2. Analysis of exercise-induced Na+-K+ exchange in rat skeletal muscle in vivo.

    PubMed

    Murphy, K T; Nielsen, O B; Clausen, T

    2008-12-01

    We aimed to quantify the Na(+)-K(+) exchange occurring during exercise in rat skeletal muscle in vivo. Intracellular Na(+) and K(+) content, Na(+) permeability ((22)Na(+) influx), Na(+)-K(+) pump activity (ouabain-sensitive (86)Rb(+) uptake) and Na(+)-K(+) pump alpha(2) subunit content ([(3)H]ouabain binding) were measured. Six-week-old rats rested (control animals) or performed intermittent running for 10-60 min and were then killed or were killed at 15 or 90 min following 60 min exercise. In the soleus muscle, intracellular Na(+) was 80% higher than in control rats after 60 min exercise, was still elevated (38%) after 15 min rest and returned to control levels after 90 min rest. Intracellular K(+) showed corresponding decreases after 15-60 min exercise, returning to control levels 90 min postexercise. Exercise induced little change in Na(+) and K(+) in the extensor digitorum longus muscle (EDL). In soleus, the exercise-induced rise in Na(+) and reduction in K(+) were augmented by pretreatment with ouabain or by reducing the content of muscular Na(+)-K(+) pumps by prior K(+) depletion of the animals. Fifteen minutes after 60 min exercise, ouabain-sensitive (86)Rb(+) uptake in the soleus was increased by 30% but was unchanged in EDL, and there was no effect of exercise on [(3)H]ouabain binding measured in vitro or in vivo in either muscle. In conclusion, in the soleus, in vivo exercise induces a rise in intracellular Na(+), which reflects the excitation-induced increase in Na(+) influx and leads to augmented Na(+)-K(+) pump activity without apparent change in Na(+)-K(+) pump capacity. PMID:18586859

  3. 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

  4. Role of creatine supplementation in exercise-induced muscle damage: A mini review

    PubMed Central

    Kim, Jooyoung; Lee, Joohyung; Kim, Seungho; Yoon, Daeyoung; Kim, Jieun; Sung, Dong Jun

    2015-01-01

    Muscle damage is induced by both high-intensity resistance and endurance exercise. Creatine is a widely used dietary supplement to improve exercise performance by reducing exercise-induced muscle damage. Many researchers have suggested that taking creatine reduces muscle damage by decreasing the inflammatory response and oxidative stress, regulating calcium homeostasis, and activating satellite cells. However, the underlying mechanisms of creatine and muscle damage have not been clarified. Therefore, this review discusses the regulatory effects of creatine on muscle damage by compiling the information collected from basic science and sports science research. PMID:26535213

  5. Role of creatine supplementation in exercise-induced muscle damage: A mini review.

    PubMed

    Kim, Jooyoung; Lee, Joohyung; Kim, Seungho; Yoon, Daeyoung; Kim, Jieun; Sung, Dong Jun

    2015-10-01

    Muscle damage is induced by both high-intensity resistance and endurance exercise. Creatine is a widely used dietary supplement to improve exercise performance by reducing exercise-induced muscle damage. Many researchers have suggested that taking creatine reduces muscle damage by decreasing the inflammatory response and oxidative stress, regulating calcium homeostasis, and activating satellite cells. However, the underlying mechanisms of creatine and muscle damage have not been clarified. Therefore, this review discusses the regulatory effects of creatine on muscle damage by compiling the information collected from basic science and sports science research. PMID:26535213

  6. Identification of three exercise-induced mortality risk factors in patients with COPD.

    PubMed

    Yoshimura, Kenji; Maekura, Ryoji; Hiraga, Toru; Miki, Keisuke; Kitada, Seigo; Miki, Mari; Tateishi, Yoshitaka; Mori, Masahide

    2014-12-01

    The survival rate of chronic obstructive pulmonary disease (COPD) patients with severely reduced exercise capacity is extremely low. We recently identified three life-threatening pathophysiological conditions during cardiopulmonary exercise testing (CPET): (1) exercise-induced hypoxemia, (2) sympathetic overactivity, and (3) progressive respiratory acidosis at low-intensity exercise. The present prospective observation study aimed to determine whether these parameters constitute risk factors of mortality in moderate-to-very severe COPD. Ninety-six COPD patients were followed-up, monthly, for >3 years. Subsequently, spirometry and CPET were performed to examine parameters of exercise-induced hypoxemia ([PaO2 slope, mmHg/L · min(-1)] = Decrease in PaO2/?V? O2 (Difference in ?V? O2 between at rest and at peak exercise)), progression of acidosis ([?pH/?V? O2,/L · min(-1)] = Decrease in pH/?V? O2), and sympathetic overactivity ([?norepinephrine (NE)/?V? O2, ng/mL/L · min(-1)] = Increase in NE/?V? O2). Univariate analysis revealed a significant association between the three conditions with increased mortality. Kaplan-Meier analysis showed that the quartile combining the steepest PaO2 slope (?-55 mmHg/?V? O2 [L/min]), steepest decrease in arterial blood pH (? -1.72/?V? O2 [L/min]), and most rapid increase in plasma NE level (? 5.2 ng/VO2 [L/min]) during incremental exercise was associated with higher all-cause mortality. These conditions showed cumulative effects on COPD patients' survival. Multivariate analyses revealed that these three life-threatening factors are also independent predictors of mortality based on age, heart rate and PaO2 at rest, body mass index, and forced expiratory volume in 1 s. Thus, these new exercise-induced mortality risk factors may lead to more efficient pulmonary rehabilitation programs for COPD patients based on patient-specific exercise-induced pathophysiological profiles. PMID:24914923

  7. Mitochondrial anomalies: driver to age associated degenerative human ailments.

    PubMed

    Bunkar, Neha; Bhargava, Arpit; Khare, Naveen Kumar; Mishra, Pradyumna Kumar

    2016-01-01

    Mitochondria play a fundamental role in regulating a variety of complex metabolic processes to maintain adequate energy balance for cellular existence. To orchestrate these functions, an undisturbed mitochondrial dynamics is imperative through a set of tightly guided mechanisms. Interference in key signature processes by several genetic, epigenetic and age-linked factors triggers mitochondrial dysfunction through decrease in mitochondrial biogenesis, reduced mitochondrial content, aberrant mtDNA mutations, increased oxidative stress, deficient mitophagy, energy dysfunction, decrease in anti oxidant defense and impaired calcium homeostasis. Mitochondrial dysfunction is widely implicated in origin and development of various age associated degenerative human ailments including metabolic syndromes, cardiovascular diseases, cancer, diabetes and neurodegenerative disorders. The present review revisits the mitochondrial anomalies involved in aetiology of different human diseases and also highlights the translational significance of nano-vectors aimed for selective mitochondrial engineering which might pave way for development of novel therapeutics. PMID:26709805

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

    SciTech Connect

    Sinha, Rohit Anthony; Pathak, Amrita; Mohan, Vishwa; Babu, Satish; Pal, Amit; Khare, Drirh; Godbole, Madan M.

    2010-07-02

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

  9. Irisin Controls Growth, Intracellular Ca2+ Signals, and Mitochondrial Thermogenesis in Cardiomyoblasts

    PubMed Central

    Xie, Chao; Zhang, Yuan; Tran, Tran D. N.; Wang, Hai; Li, Shiwu; George, Eva Vertes; Zhuang, Haoyang; Zhang, Peilan; Kandel, Avi; Lai, Yimu; Tang, Dongqi; Reeves, Westley H.; Cheng, Henrique; Ding, Yousong; Yang, Li-Jun

    2015-01-01

    Exercise offers short-term and long-term health benefits, including an increased metabolic rate and energy expenditure in myocardium. The newly-discovered exercise-induced myokine, irisin, stimulates conversion of white into brown adipocytes as well as increased mitochondrial biogenesis and energy expenditure. Remarkably, irisin is highly expressed in myocardium, but its physiological effects in the heart are unknown. The objective of this work is to investigate irisin’s potential multifaceted effects on cardiomyoblasts and myocardium. For this purpose, H9C2 cells were treated with recombinant irisin produced in yeast cells (r-irisin) and in HEK293 cells (hr-irisin) for examining its effects on cell proliferation by MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and on gene transcription profiles by qRT-PCR. R-irisin and hr-irisin both inhibited cell proliferation and activated genes related to cardiomyocyte metabolic function and differentiation, including myocardin, follistatin, smooth muscle actin, and nuclear respiratory factor-1. Signal transduction pathways affected by r-irisin in H9C2 cells and C57BL/6 mice were examined by detecting phosphorylation of PI3K-AKT, p38, ERK or STAT3. We also measured intracellular Ca2+ signaling and mitochondrial thermogenesis and energy expenditure in r-irisin-treated H9C2 cells. The results showed that r-irisin, in a certain concentration rage, could activate PI3K-AKT and intracellular Ca2+ signaling and increase cellular oxygen consumption in H9C2 cells. Our study also suggests the existence of irisin-specific receptor on the membrane of H9C2 cells. In conclusion, irisin in a certain concentration rage increased myocardial cell metabolism, inhibited cell proliferation and promoted cell differentiation. These effects might be mediated through PI3K-AKT and Ca2+ signaling, which are known to activate expression of exercise-related genes such as follistatin and myocardin. This work supports the value of exercise, which promotes irisin release. PMID:26305684

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

    PubMed

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

    2014-06-01

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

  11. The effect of interval training in children with exercise-induced asthma competing in soccer.

    PubMed

    Sidiropoulou, Maria P; Fotiadou, Eleni G; Tsimaras, Vasilios K; Zakas, Athanasios P; Angelopoulou, Nickoletta A

    2007-05-01

    A lot of emphasis has been placed in screening individuals with exercise-induced bronchospasm in order to avoid persistence bronchial hyperactivity and consequent chronic silent inflammation of the respiratory tract. The purpose of this study was to evaluate the effect of interval training on the respiratory function and endurance in children with exercise-induced asthma (EIA) participating in the sport of soccer. Twenty-nine boys ages 10-14, who developed EIA after a 6-minute free running test (decline in forced expiratory volume in 1 second: FEV(1)10%), participated in the study. They were divided into 2 groups (experimental: n = 18, and control: n = 11), fulfilling the same criteria (i.e., age, body height and weight, and severity of asthma). The experimental group exercised with the interval training method for a period of 8 weeks, (3 sessions per week), whereas the control group exercised with the usual football program. Measurements were made for FEV(1) and endurance in both groups, before and after the application of training (8 weeks). Following the implementation of the training program, a significant improvement in FEV(1) and endurance was documented in the experimental group, as well as significant differences between the 2 groups. In conclusion, duration and aerobic training via the interval method seems to be beneficial to soccer players with EIA. PMID:17530938

  12. Bricanyl Turbuhaler and Ventolin Rotahaler in exercise-induced asthma in children.

    PubMed

    dos Santos, J M; Costa, H; Ståhl, E; Wirén, J E

    1991-04-01

    Bricanyl Turbuhaler (0.5 mg terbutaline sulphate) and Ventolin Rotahaler (0.4 mg salbutamol) were compared in a randomized double-blind placebo controlled study on exercise-induced asthma in 19 children (14 boys) aged 7-14 years. The study was carried out on 3 separate days. Asthmatic attacks were provoked by free range running. Peak expiratory flow (PEF) was measured before and after exercise. If PEF decreased by greater than 20%, one inhalation from each of the inhalers was given under supervision of the investigator. Only one of the inhalers (none on the placebo day) delivered active drug. PEF was measured again 5 and 10 min after treatment. Already 5 min after treatment PEF had returned to baseline after active treatment. There was no statistically significant difference between the two active treatments. After placebo treatment, PEF did not return to baseline even at the 10 min post-exercise measurement. Ten children needed extra medication after the last PEF measurement on the placebo day, whereas no child needed extra medication after any of the active treatments. No adverse events were reported in this study. In conclusion, Bricanyl Turbuhaler (0.5 mg) and Ventolin Rotahaler (0.4 mg) were equally efficacious in the treatment of exercise-induced asthma in children. PMID:2058816

  13. Benefits of dietary phytochemical supplementation on eccentric exercise-induced muscle damage: Is including antioxidants enough?

    PubMed

    Pereira Panza, Vilma Simões; Diefenthaeler, Fernando; da Silva, Edson Luiz

    2015-09-01

    The purpose of this review was to critically discuss studies that investigated the effects of supplementation with dietary antioxidant phytochemicals on recovery from eccentric exercise-induced muscle damage. The performance of physical activities that involve unaccustomed eccentric muscle actions-such as lowering a weight or downhill walking-can result in muscle damage, oxidative stress, and inflammation. These events may be accompanied by muscle weakness and delayed-onset muscle soreness. According to the current evidences, supplementation with dietary antioxidant phytochemicals appears to have the potential to attenuate symptoms associated with eccentric exercise-induced muscle damage. However, there are inconsistencies regarding the relationship between muscle damage and blood markers of oxidative stress and inflammation. Furthermore, the effectiveness of strategies appear to depend on a number of aspects inherent to phytochemical compounds as well as its food matrix. Methodological issues also may interfere with the proper interpretation of supplementation effects. Thus, the study may contribute to updating professionals involved in sport nutrition as well as highlighting the interest of scientists in new perspectives that can widen dietary strategies applied to training. PMID:26233864

  14. 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

  15. Caloric Restriction and the Nutrient-Sensing PGC-1? in Mitochondrial Homeostasis: New Perspectives in Neurodegeneration

    PubMed Central

    Lettieri Barbato, Daniele; Baldelli, Sara; Pagliei, Beatrice; Aquilano, Katia; Ciriolo, Maria Rosa

    2012-01-01

    Mitochondrial activity progressively declines during ageing and in many neurodegenerative diseases. Caloric restriction (CR) has been suggested as a dietary intervention that is able to postpone the detrimental aspects of aging as it ameliorates mitochondrial performance. This effect is partially due to increased mitochondrial biogenesis. The nutrient-sensing PGC-1? is a transcriptional coactivator that promotes the expression of mitochondrial genes and is induced by CR. It is believed that many of the mitochondrial and metabolic benefits of CR are due to increased PGC-1? activity. The increase of PGC-1? is also positively linked to neuroprotection and its decrement has been involved in the pathogenesis of many neurodegenerative diseases. This paper aims to summarize the current knowledge about the role of PGC-1? in neuronal homeostasis and the beneficial effects of CR on mitochondrial biogenesis and function. We also discuss how PGC-1?-governed pathways could be used as target for nutritional intervention to prevent neurodegeneration. PMID:22829833

  16. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol.

    PubMed

    Wrobel, Lidia; Topf, Ulrike; Bragoszewski, Piotr; Wiese, Sebastian; Sztolsztener, Malgorzata E; Oeljeklaus, Silke; Varabyova, Aksana; Lirski, Maciej; Chroscicki, Piotr; Mroczek, Seweryn; Januszewicz, Elzbieta; Dziembowski, Andrzej; Koblowska, Marta; Warscheid, Bettina; Chacinska, Agnieszka

    2015-08-27

    Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction. PMID:26245374

  17. 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

  18. Plant-Specific Features of Ribosome Biogenesis.

    PubMed

    Weis, Benjamin L; Kovacevic, Jelena; Missbach, Sandra; Schleiff, Enrico

    2015-11-01

    The biogenesis of eukaryotic ribosomes is a fundamental process involving hundreds of ribosome biogenesis factors (RBFs) in three compartments of the cell, namely the nucleolus, nucleus, and cytoplasm. Many RBFs are involved in the processing of the primary ribosomal (r)RNA transcript, in which three of the four rRNAs are imbedded. While pre-rRNA processing is well described for yeast and mammals, a detailed processing scheme for plants is lacking. Here, we discuss the emerging scheme of pre-rRNA processing in Arabidopsis thaliana in comparison to other eukaryotes, with a focus on plant characteristics. In addition, we highlight the impact of the ribosome and its biogenesis on developmental processes because common phenotypes can be observed for ribosomal protein and RBF mutants. PMID:26459664

  19. 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

  20. Exercise-Induced Cognitive Plasticity, Implications for Mild Cognitive Impairment and Alzheimer’s Disease

    PubMed Central

    Foster, Philip P.; Rosenblatt, Kevin P.; Kuljiš, Rodrigo O.

    2011-01-01

    Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer’s disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ?4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The “inward” continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal “outward” continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid ? (A?) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders. PMID:21602910

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

    PubMed Central

    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. The dying of the light: mitochondrial failure in Alzheimer's disease.

    PubMed

    Young-Collier, Kisha J; McArdle, Michael; Bennett, James P

    2012-01-01

    Impaired brain energy production, reflected by reduced cortical glucose metabolism seen on 2-FDG PET scans, has emerged as a robust biomarker of mild cognitive impairment (MCI). Progression from MCI to Alzheimer's disease (AD) shows further decline of cortical 2-FDG uptake, implying worsening bioenergetics. We characterized respiration, respiratory protein levels, and gene expressions for mitochondrial DNA (mtDNA), mitochondrial biogenesis, and antioxidative signaling in preparations from postmortem AD and control frontal cortex. Mitochondrial respiration was maintained in frozen brain mitochondria and reduced by approximately two-thirds in AD due to loss of mitochondrial mass. Levels of most respiratory proteins were preserved, but expressions of gene families for mtDNA, mitobiogenesis, and mitochondrial/cytosolic antioxidant enzymes were reduced in AD cortex. None of these changes in AD were related to elevated levels of amyoid-?1-42 peptide. For unclear reasons, mitochondrial biogenesis is suppressed in AD frontal cortex, leading to reduced mitochondrial mass and impaired mitochondrial respiratory capacity. Downregulation of antioxidant proteins further threatens neuronal function. Altering progression of AD appears to require both correction of impaired mitobiogenesis and restoration of antioxidant protection. PMID:22057028

  3. Iron-sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery.

    PubMed

    Maio, Nunziata; Rouault, Tracey A

    2015-06-01

    Iron-sulfur (Fe-S) clusters are ancient, ubiquitous cofactors composed of iron and inorganic sulfur. The combination of the chemical reactivity of iron and sulfur, together with many variations of cluster composition, oxidation states and protein environments, enables Fe-S clusters to participate in numerous biological processes. Fe-S clusters are essential to redox catalysis in nitrogen fixation, mitochondrial respiration and photosynthesis, to regulatory sensing in key metabolic pathways (i.e. cellular iron homeostasis and oxidative stress response), and to the replication and maintenance of the nuclear genome. Fe-S cluster biogenesis is a multistep process that involves a complex sequence of catalyzed protein-protein interactions and coupled conformational changes between the components of several dedicated multimeric complexes. Intensive studies of the assembly process have clarified key points in the biogenesis of Fe-S proteins. However several critical questions still remain, such as: what is the role of frataxin? Why do some defects of Fe-S cluster biogenesis cause mitochondrial iron overload? How are specific Fe-S recipient proteins recognized in the process of Fe-S transfer? This review focuses on the basic steps of Fe-S cluster biogenesis, drawing attention to recent advances achieved on the identification of molecular features that guide selection of specific subsets of nascent Fe-S recipients by the cochaperone HSC20. Additionally, it outlines the distinctive phenotypes of human diseases due to mutations in the components of the basic pathway. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID:25245479

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

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

  5. Acute Exercise-Induced Response of Monocyte Subtypes in Chronic Heart and Renal Failure

    PubMed Central

    Van Craenenbroeck, Amaryllis H.; Hoymans, Vicky Y.; Verpooten, Gert A.; Vrints, Christiaan J.; Couttenye, Marie M.; Van Craenenbroeck, Emeline M.

    2014-01-01

    Purpose. Monocytes (Mon1-2-3) play a substantial role in low-grade inflammation associated with high cardiovascular morbidity and mortality of patients with chronic kidney disease (CKD) and chronic heart failure (CHF). The effect of an acute exercise bout on monocyte subsets in the setting of systemic inflammation is currently unknown. This study aims (1) to evaluate baseline distribution of monocyte subsets in CHF and CKD versus healthy subjects (HS) and (2) to evaluate the effect of an acute exercise bout. Exercise-induced IL-6 and MCP-1 release are related to the Mon1-2-3 response. Methods. Twenty CHF patients, 20 CKD patients, and 15 HS were included. Before and after a maximal cardiopulmonary exercise test, monocyte subsets were quantified by flow cytometry: CD14++CD16?CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2), and CD14+CD16++CCR2? (Mon3). Serum levels of IL-6 and MCP-1 were determined by ELISA. Results. Baseline distribution of Mon1-2-3 was comparable between the 3 groups. Following acute exercise, %Mon2 and %Mon3 increased significantly at the expense of a decrease in %Mon1 in HS and in CKD. This response was significantly attenuated in CHF (P < 0.05). In HS only, MCP-1 levels increased following exercise; IL-6 levels were unchanged. Circulatory power was a strong and independent predictor of the changes in Mon1 (? = ?0.461, P < 0.001) and Mon3 (? = 0.449, P < 0.001); and baseline LVEF of the change in Mon2 (? = 0.441, P < 0.001). Conclusion. The response of monocytes to acute exercise is characterized by an increase in proangiogenic and proinflammatory Mon2 and Mon3 at the expense of phagocytic Mon1. This exercise-induced monocyte subset response is mainly driven by hemodynamic changes and not by preexistent low-grade inflammation. PMID:25587208

  6. Effects of Massage on Muscular Strength and Proprioception After Exercise-Induced Muscle Damage.

    PubMed

    Shin, Mal-Soon; Sung, Yun-Hee

    2015-08-01

    Exercise-induced muscle damage (EIMD), which is commonly associated with eccentric exercise, unaccustomed exercise, and resistance training, may lead to delayed onset muscle soreness, swelling, decreased muscle strength, and range of motion. Many researchers have evaluated various interventions to treat the signs and symptoms of EIMD. However, the effects of massage after EIMD are unclear. Here, we investigated the effect of massage on muscle strength and proprioception after EIMD. All subjects randomly were divided into an EIMD-treated control group (n = 10) and a massage-treated after EIMD experimental group (n = 11). Exercise-induced muscle damage was induced by repeated exercise. Massage treatment was provided by physiotherapist for 15 minutes. It consists of light stroking, milking, friction, and skin rolling. Lactate was evaluated by Lactate Pro analyzer in pre- and postexercise. Surface electromyography (muscle activity) and sonography (muscle thickness) were used to confirm the muscular characteristics. Proprioception was investigated by dual inclinometer. As a result, massage treatment on the gastrocnemius after EIMD increased activation of the medial gastrocnemius during contraction (p ? 0.05). In the lateral and medial gastrocnemius, the ?s, which is the angle between muscle fibers and superficial aponeurosis, showed a significant change (p ? 0.05). However, there are no differences in the ?d, which is the angle between muscle fibers and deep aponeurosis. We also found that proprioceptive acuity in the ankle joint was significantly greater in the massage-treated experimental group compared with that in the control group (p ? 0.05). These findings suggest that massage of the gastrocnemius after EIMD can improve muscle strength and proprioception by influencing the superficial layer of the gastrocnemius. PMID:25226328

  7. 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…

  8. 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)

  9. 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...

  10. BIOGENESIS OF TELOMERASE RNA IN FISSION YEAST

    E-print Network

    Tang, Wen

    2012-08-31

    roles on telomerase RNA biogenesis. Sm and Lsm proteins belong to an ancient family of RNA binding proteins represented in all three domains of life. They form multimeric complexes on specific sets of non-coding RNAs and play critical roles...

  11. Unravelling mitochondrial pathways to Parkinson's disease

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    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

    2013-07-01

    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

  13. Acute and chronic watercress supplementation attenuates exercise-induced peripheral mononuclear cell DNA damage and lipid peroxidation.

    PubMed

    Fogarty, Mark C; Hughes, Ciara M; Burke, George; Brown, John C; Davison, Gareth W

    2013-01-28

    Pharmacological antioxidant vitamins have previously been investigated for a prophylactic effect against exercise-induced oxidative stress. However, large doses are often required and may lead to a state of pro-oxidation and oxidative damage. Watercress contains an array of nutritional compounds such as ?-carotene and ?-tocopherol which may increase protection against exercise-induced oxidative stress. The present randomised controlled investigation was designed to test the hypothesis that acute (consumption 2 h before exercise) and chronic (8 weeks consumption) watercress supplementation can attenuate exercise-induced oxidative stress. A total of ten apparently healthy male subjects (age 23 (SD 4) years, stature 179 (SD 10) cm and body mass 74 (SD 15) kg) were recruited to complete the 8-week chronic watercress intervention period (and then 8 weeks of control, with no ingestion) of the experiment before crossing over in order to compete the single-dose acute phase (with control, no ingestion). Blood samples were taken at baseline (pre-supplementation), at rest (pre-exercise) and following exercise. Each subject completed an incremental exercise test to volitional exhaustion following chronic and acute watercress supplementation or control. The main findings show an exercise-induced increase in DNA damage and lipid peroxidation over both acute and chronic control supplementation phases (P< 0.05 v. supplementation), while acute and chronic watercress attenuated DNA damage and lipid peroxidation and decreased H?O? accumulation following exhaustive exercise (P< 0.05 v. control). A marked increase in the main lipid-soluble antioxidants (?-tocopherol, ?-tocopherol and xanthophyll) was observed following watercress supplementation (P< 0.05 v. control) in both experimental phases. These findings suggest that short- and long-term watercress ingestion has potential antioxidant effects against exercise-induced DNA damage and lipid peroxidation. PMID:22475430

  14. Cooperation of protein machineries in mitochondrial protein sorting.

    PubMed

    Wenz, Lena-Sophie; Opali?ski, ?ukasz; Wiedemann, Nils; Becker, Thomas

    2015-05-01

    The function of mitochondria depends on the import of proteins, which are synthesized as precursors on cytosolic ribosomes. The majority of the precursor proteins are sorted into the mitochondrial subcompartments via five distinct routes. Recent studies revealed that molecular cooperation between protein machineries is a central feature of mitochondrial protein biogenesis. First, coupling to various partner proteins affects the substrate specificity of translocases and single translocation steps. Second, there is a substantial cooperation between different protein translocases in the import of specific precursor proteins. Third, protein transport is intimately linked to processing, folding and assembly reactions. Fourth, sorting of precursor proteins is functionally and physically connected to protein machineries, which fulfill central functions for respiration, maintenance of membrane architecture and form contacts to the endoplasmic reticulum. Therefore, we propose that the protein transport systems are part of a complicated protein network for mitochondrial biogenesis. PMID:25633533

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

    PubMed

    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

  16. 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

  17. Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver.

    PubMed

    Ni, Hong-Min; Williams, Jessica A; Jaeschke, Hartmut; Ding, Wen-Xing

    2013-01-01

    Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the US and many western countries. It is well known that APAP induces mitochondrial damage to trigger centrilobular necrosis. Emerging evidence suggests that autophagic removal of damaged mitochondria may protect against APAP-induced liver injury. Electron and confocal microscopy analysis of liver tissues revealed that APAP overdose triggers unique biochemical and pathological zonated changes in the mouse liver, which includes necrosis (zone 1), mitochondrial spheroid formation (zone 2), autophagy (zone 3) and mitochondrial biogenesis (zone 4). In this graphic review, we discuss the role of autophagy/mitophagy in limiting the expansion of necrosis and promoting mitochondrial biogenesis and liver regeneration for the recovery of APAP-induced liver injury. We also discuss possible mechanisms that could be involved in regulating APAP-induced autophagy/mitophagy and the formation of mitochondrial spheroids. PMID:24191236

  18. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function

    PubMed Central

    Dugan, Laura L.; You, Young-Hyun; Ali, Sameh S.; Diamond-Stanic, Maggie; Miyamoto, Satoshi; DeCleves, Anne-Emilie; Andreyev, Aleksander; Quach, Tammy; Ly, San; Shekhtman, Grigory; Nguyen, William; Chepetan, Andre; Le, Thuy P.; Wang, Lin; Xu, Ming; Paik, Kacie P.; Fogo, Agnes; Viollet, Benoit; Murphy, Anne; Brosius, Frank; Naviaux, Robert K.; Sharma, Kumar

    2013-01-01

    Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-?-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2+/–) mice had no evidence of increased renal disease, and Ampka2–/– mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity. PMID:24135141

  19. Dual Localized AtHscB Involved in Iron Sulfur Protein Biogenesis in Arabidopsis

    PubMed Central

    Xu, Xiang Ming; Lin, Hong; Latijnhouwers, Maita; Møller, Simon Geir

    2009-01-01

    Background Iron-sulfur clusters are ubiquitous structures which act as prosthetic groups for numerous proteins involved in several fundamental biological processes including respiration and photosynthesis. Although simple in structure both the assembly and insertion of clusters into apoproteins requires complex biochemical pathways involving a diverse set of proteins. In yeast, the J-type chaperone Jac1 plays a key role in the biogenesis of iron sulfur clusters in mitochondria. Methodology/Principal Findings In this study we demonstrate that AtHscB from Arabidopsis can rescue the Jac1 yeast knockout mutant suggesting a role for AtHscB in iron sulfur protein biogenesis in plants. In contrast to mitochondrial Jac1, AtHscB localizes to both mitochondria and the cytosol. AtHscB interacts with AtIscU1, an Isu-like scaffold protein involved in iron-sulfur cluster biogenesis, and through this interaction AtIscU1 is most probably retained in the cytosol. The chaperone AtHscA can functionally complement the yeast Ssq1knockout mutant and its ATPase activity is enhanced by AtHscB and AtIscU1. Interestingly, AtHscA is also localized in both mitochondria and the cytosol. Furthermore, AtHscB is highly expressed in anthers and trichomes and an AtHscB T-DNA insertion mutant shows reduced seed set, a waxless phenotype and inappropriate trichome development as well as dramatically reduced activities of the iron-sulfur enzymes aconitase and succinate dehydrogenase. Conclusions Our data suggest that AtHscB together with AtHscA and AtIscU1 plays an important role in the biogenesis of iron-sulfur proteins in both mitochondria and the cytosol. PMID:19865480

  20. Redox mechanisms of cardiomyocyte mitochondrial protection

    PubMed Central

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

    2015-01-01

    Oxidative and nitrosative stress are primary contributors to the loss of myocardial tissue in insults ranging from ischemia/reperfusion injury from coronary artery disease and heart transplantation to sepsis-induced myocardial dysfunction and drug-induced myocardial damage. This cell damage caused by oxidative and nitrosative stress leads to mitochondrial protein, DNA, and lipid modifications, which inhibits energy production and contractile function, potentially leading to cell necrosis and/or apoptosis. However, cardiomyocytes have evolved an elegant set of redox-sensitive mechanisms that respond to and contain oxidative and nitrosative damage. These responses include the rapid induction of antioxidant enzymes, mitochondrial DNA repair mechanisms, selective mitochondrial autophagy (mitophagy), and mitochondrial biogenesis. Coordinated cytoplasmic to nuclear cell-signaling and mitochondrial transcriptional responses to the presence of elevated cytoplasmic oxidant production, e.g., H2O2, allows nuclear translocation of the Nfe2l2 transcription factor and up-regulation of downstream cytoprotective genes such as heme oxygenase-1 which generates physiologic signals, such as CO that up-regulates Nfe212 gene transcription. Simultaneously, a number of other DNA binding transcription factors are expressed and/or activated under redox control, such as Nuclear Respiratory Factor-1 (NRF-1), and lead to the induction of genes involved in both intracellular and mitochondria-specific repair mechanisms. The same insults, particularly those related to vascular stress and inflammation also produce elevated levels of nitric oxide, which also has mitochondrial protein thiol-protective functions and induces mitochondrial biogenesis through cyclic GMP-dependent and perhaps other pathways. This brief review provides an overview of these pathways and interconnected cardiac repair mechanisms. PMID:26578967

  1. Impaired mitochondrial function in human placenta with increased maternal adiposity.

    PubMed

    Mele, James; Muralimanoharan, Sribalasubashini; Maloyan, Alina; Myatt, Leslie

    2014-09-01

    The placenta plays a key role in regulation of fetal growth and development and in mediating in utero developmental programming. Obesity, which is associated with chronic inflammation and mitochondrial dysfunction in many tissues, exerts a programming effect in pregnancy. We determined the effect of increasing maternal adiposity and of fetal sex on placental ATP generation, mitochondrial biogenesis, expression of electron transport chain subunits, and mitochondrial function in isolated trophoblasts. Placental tissue was collected from women with prepregnancy BMI ranging from 18.5 to 45 following C-section at term with no labor. Increasing maternal adiposity was associated with excessive production of reactive oxygen species and a significant reduction in placental ATP levels in placentae with male and female fetuses. To explore the potential mechanism of placental mitochondrial dysfunction, levels of transcription factors regulating the expression of genes involved in electron transport and mitochondrial biogenesis were measured. Our in vitro studies showed significant reduction in mitochondrial respiration in cultured primary trophoblasts with increasing maternal obesity along with an abnormal metabolic flexibility of these cells. This reduction in placental mitochondrial respiration in pregnancies complicated by maternal obesity could compromise placental function and potentially underlie the increased susceptibility of these pregnancies to fetal demise in late gestation and to developmental programming. PMID:25028397

  2. Impaired mitochondrial function in human placenta with increased maternal adiposity

    PubMed Central

    Mele, James; Muralimanoharan, Sribalasubashini; Maloyan, Alina

    2014-01-01

    The placenta plays a key role in regulation of fetal growth and development and in mediating in utero developmental programming. Obesity, which is associated with chronic inflammation and mitochondrial dysfunction in many tissues, exerts a programming effect in pregnancy. We determined the effect of increasing maternal adiposity and of fetal sex on placental ATP generation, mitochondrial biogenesis, expression of electron transport chain subunits, and mitochondrial function in isolated trophoblasts. Placental tissue was collected from women with prepregnancy BMI ranging from 18.5 to 45 following C-section at term with no labor. Increasing maternal adiposity was associated with excessive production of reactive oxygen species and a significant reduction in placental ATP levels in placentae with male and female fetuses. To explore the potential mechanism of placental mitochondrial dysfunction, levels of transcription factors regulating the expression of genes involved in electron transport and mitochondrial biogenesis were measured. Our in vitro studies showed significant reduction in mitochondrial respiration in cultured primary trophoblasts with increasing maternal obesity along with an abnormal metabolic flexibility of these cells. This reduction in placental mitochondrial respiration in pregnancies complicated by maternal obesity could compromise placental function and potentially underlie the increased susceptibility of these pregnancies to fetal demise in late gestation and to developmental programming. PMID:25028397

  3. The Potential Use of PGC-1? and PGC-1? to Protect the Retina by Stimulating Mitochondrial Repair.

    PubMed

    Ash, John D

    2016-01-01

    Damage to mitochondria is a common mechanism of cell death in inherited neurodegenerative disorders. Therefore, mitochondrial protection and mitochondrial repair are promising strategies to induce retinal neuroprotection. Peroxisome proliferator-activated receptor ? coactivator-? (PGC-1?) and ? (PGC-1?) are transcriptional coactivators that are the main regulators of mitochondrial biogenesis. We propose that PGC-1? and PGC-1? could play a role in regulating retina cell survival, and may be important therapeutic targets to prevent retinal degeneration. PMID:26427438

  4. Caenorhabditis elegans neuron degeneration and mitochondrial suppression caused by selected environmental chemicals

    PubMed Central

    Zhou, Shaoyu; Wang, Zemin; Klaunig, James E

    2013-01-01

    Mitochondrial alterations have been documented for many years in the brains of Parkinson’s disease (PD), a disorder that is characterized by the selective loss of dopamine neurons. Recent studies have demonstrated that Parkinson’s disease-associated proteins are either present in mitochondria or translocated into mitochondria in response to stress, further reinforcing the importance of the mitochondrial function in the pathogenesis of Parkinson’s disease. Exposure to environmental chemicals such as pesticides and heavy metals has been suggested as risk factors in the development of Parkinson’s disease. It has been reported that a number of environmental agents including tobacco smoke and perfluorinated compounds, pesticides, as well as metals (Mn2+ and Pb2+) modulate mitochondrial function. However the exact mechanism of mitochondrial alteration has not been defined in the context of the development and progression of Parkinson’s disease. The complexity of the mammalian system has made it difficult to dissect the molecular components involved in the pathogenesis of Parkinson’s disease. In the present study we used the nematode Caenorhabditis elegans (C. elegans) model of neuron degeneration and investigated the effect of environmental chemicals on mitochondrial biogenesis and mitochondrial gene regulation. Chronic exposure to low concentration (2 or 4 ?M) of pesticide rotenone, resulted in significant loss of dopamine neuron in C. elegans, a classic feature of Parkinson’s disease. We then determined if the rotenone-induced neuron degeneration is accompanied by a change in mitochondria biogenesis. Analysis of mitochondrial genomic replication by quantitative PCR showed a dramatic decrease in mitochondrial DNA (mtDNA) copies of rotenone-treated C. elegans compared to control. This decreased mitochondrial biogenesis occurred prior to the development of loss of dopamine neurons, and was persistent. The inhibition of mtDNA replication was also found in C. elegans exposed to another neuron toxicant Mn2+ at the concentration 50 or 100 mM. We further examined the mitochondrial gene expression and found significant lower level of mitochondrial complex IV subunits COI and COII in C. elegans exposed to rotenone. These results demonstrate that environmental chemicals cause persistent suppression of mitochondrial biogenesis and mitochondrial gene expression, and suggest a critical role of modifying mitochondrial biogenesis in toxicants-induced neuron degeneration in C. elegans model. PMID:24380023

  5. Cholesterol in myelin biogenesis and hypomyelinating disorders.

    PubMed

    Saher, Gesine; Stumpf, Sina Kristin

    2015-08-01

    The largest pool of free cholesterol in mammals resides in myelin membranes. Myelin facilitates rapid saltatory impulse propagation by electrical insulation of axons. This function is achieved by ensheathing axons with a tightly compacted stack of membranes. Cholesterol influences myelination at many steps, from the differentiation of myelinating glial cells, over the process of myelin membrane biogenesis, to the functionality of mature myelin. Cholesterol emerged as the only integral myelin component that is essential and rate-limiting for the development of myelin in the central and peripheral nervous system. Moreover, disorders that interfere with sterol synthesis or intracellular trafficking of cholesterol and other lipids cause hypomyelination and neurodegeneration. This review summarizes recent results on the roles of cholesterol in CNS myelin biogenesis in normal development and under different pathological conditions. This article is part of a Special Issue entitled Brain Lipids. PMID:25724171

  6. Oil body biogenesis during Brassica napus embryogenesis.

    PubMed

    He, Yu-Qing; Wu, Yan

    2009-08-01

    Although the oil body is known to be an important membrane enclosed compartment for oil storage in seeds, we have little understanding about its biogenesis during embryogenesis. In the present study we investigated the oil body emergence and variations in Brassica napus cv. Topas. The results demonstrate that the oil bodies could be detected already at the heart stage, at the same time as the embryos began to turn green, and the starch grains accumulated in the chloroplast stroma. In comparison, we have studied the development of oil bodies between Arabidopsis thaliana wild type (Col) and the low-seed-oil mutant wrinkled1-3. We observed that the oil body development in the embryos of Col is similar to that of B. napus cv. Topas, and that the size of the oil bodies was obviously smaller in the embryos of wrinkled1-3. Our results suggest that the oil body biogenesis might be coupled with the embryo chloroplast. PMID:19686376

  7. Enantiomeric Natural Products: Occurrence and Biogenesis**

    PubMed Central

    Finefield, Jennifer M.; Sherman, David H.; Kreitman, Martin; Williams, Robert M.

    2012-01-01

    In Nature, chiral natural products are usually produced in optically pure form; however, on occasion Nature is known to produce enantiomerically opposite metabolites. These enantiomeric natural products can arise in Nature from a single species, or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers, however, many fascinating puzzles and stereochemical anomalies still remain. PMID:22555867

  8. Exercise-induced changes in blood zinc and related proteins in humans.

    PubMed

    Ohno, H; Yamashita, K; Doi, R; Yamamura, K; Kondo, T; Taniguchi, N

    1985-05-01

    Effects of cycle ergometer exercise (approximately 75% maximum ventilatory O2 consumption for 30 min) on the concentrations of zinc and related proteins in erythrocytes and/or plasma were studied on 11 sedentary male students. Lower concentrations of total zinc and of zinc derived from carbonic anhydrase I type (CA-I) in erythrocytes were observed immediately after exercise, but they disappeared after 30 min of rest. The change in total zinc concentration in erythrocytes correlated well with that in CA-I concentration immediately after exercise, as well as after rest. The concentration of carbonic anhydrase II type (CA-II)-derived zinc did not vary substantially at any time. On the other hand, there were significant increases in the plasma concentrations of total zinc and of alpha 2-macroglobulin (alpha 2-MG)-bound zinc immediately after exercise, whereas no such effect was noted in albumin-bound zinc. A positive correlation was found between total zinc and alpha 2-MG concentrations in plasma immediately after exercise. In addition, the change in the activity of alkaline phosphatase, a zinc metalloenzyme, correlated well with that in the total zinc concentration in plasma. These results suggest that a brief physical exercise induces the movement of zinc into plasma. PMID:2581927

  9. 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

  10. Attenuation of eccentric exercise-induced muscle damage conferred by maximal isometric contractions: a mini review

    PubMed Central

    Lima, Leonardo C. R.; Denadai, Benedito S.

    2015-01-01

    Although, beneficial in determined contexts, eccentric exercise-induced muscle damage (EIMD) might be unwanted during training regimens, competitions and daily activities. There are a vast number of studies investigating strategies to attenuate EIMD response after damaging exercise bouts. Many of them consist of performing exercises that induce EIMD, consuming supplements or using equipment that are not accessible for most people. It appears that performing maximal isometric contractions (ISOs) 2–4 days prior to damaging bouts promotes significant attenuation of EIMD symptoms that are not related to muscle function. It has been shown that the volume of ISOs, muscle length in which they are performed, and interval between them and the damaging bout influence the magnitude of this protection. In addition, it appears that this protection is not long-lived, lasting no longer than 4 days. Although no particular mechanisms for these adaptations were identified, professionals should consider applying this non-damaging stimulus before submitting their patients to unaccustomed exercised. However, it seems not to be the best option for athletes or relatively trained individuals. Future, studies should focus on establishing if ISOs protect other populations (i.e., trained individuals) or muscle groups (i.e., knee extensors) against EIMD, as well as investigate different mechanisms for ISO-induced protection. PMID:26578972

  11. Effects of eccentric exercise-induced muscle damage on intramyocellular lipid concentration and high energy phosphates.

    PubMed

    Hughes, Jonathan D; Johnson, Nathan A; Brown, Stephen J; Sachinwalla, Toos; Walton, David W; Stannard, Stephen R

    2010-12-01

    Eccentric exercise is known to cause changes to the ultrastructure of skeletal muscle and, in turn, may alter the ability of the muscle to store and utilise intracellular substrates such as intramyocellular lipid (IMCL). The purpose of this study was to test the hypothesis that exercise-induced muscle damage (EIMD) results in IMCL accumulation. Six males (31 ± 6 years; mean ± SD, and 72.3 ± 9.7 kg body mass) performed 300 unilateral, maximal, isokinetic, eccentric contractions (Ecc) (30° s(-1)) of the quadriceps on an isokinetic dynamometer, followed immediately by an equal amount of work by the contralateral leg but with concentric action (Con). Phosphate compounds and IMCL content of the vastus lateralis of both legs were measured using (31)P and (1)H magnetic resonance spectroscopy. IMCL content was higher in Ecc than Con 24 h post but the reverse was evident 48 h post-exercise (P = 0.046). A significant time × trial interaction for resting [P(i)] (P = 0.045), showed increases in Ecc across time but no change in Con. A significant main effect of trial (P = 0.002) was apparent indicating the Ecc leg had marked metabolic dysfunction. The P(i)/PCr ratio showed a significant effect of trial (P = 0.001) with an increase evident in Ecc leg, primarily due to increases in [P(i)]. The present study highlights changes in IMCL content of skeletal muscle following EIMD. PMID:20706732

  12. 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

  13. Exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-?1 mediated pathways.

    PubMed

    Nikooie, Rohollah; Samaneh, Sajadian

    2016-01-01

    The mechanism regulating the utilization of intramuscular triacylglycerol (IMTG) during high-intensity interval training (HIIT) and post-exercise recovery period remains elusive. In this study, the acute and long-term effects of HIIT on transforming growth factor beta 1 (TGF-?1) abundance in rat skeletal muscle and role of lactate and TGF-?1 in IMTG lipolysis during post-exercise recovery period were examined. TGF-?1 and Adipose triacylglycerol lipase (ATGL) abundance as well as total lipase activity in the gastrocnemius muscle significantly increased to a maximum value 10 h after acute bout of HIIT. Inhibition of TGF-?1 signaling by intramuscular injection of SB431542 30 min prior to the acute exercise attenuated ATGL abundance and total lipase activity in the gastrocnemius muscle in response to acute exercise. Intramuscular acute injection of lactate increased TGF-?1 and ATGL abundance in the gastrocnemius muscle and there were a significant increase in Muscle TGF-?1 and ATGL abundance after 5 weeks of HIIT/lactate treatment. These results indicate that exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-?1 mediated pathways during post-exercise recovery from strenuous exercise. PMID:26522131

  14. Hyperthermia, dehydration, and osmotic stress: unconventional sources of exercise-induced reactive oxygen species.

    PubMed

    King, Michelle A; Clanton, Thomas L; Laitano, Orlando

    2016-01-15

    Evidence of increased reactive oxygen species (ROS) production is observed in the circulation during exercise in humans. This is exacerbated at elevated body temperatures and attenuated when normal exercise-induced body temperature elevations are suppressed. Why ROS production during exercise is temperature dependent is entirely unknown. This review covers the human exercise studies to date that provide evidence that oxidant and antioxidant changes observed in the blood during exercise are dependent on temperature and fluid balance. We then address possible mechanisms linking exercise with these variables that include shear stress, effects of hemoconcentration, and signaling pathways involving muscle osmoregulation. Since pathways of muscle osmoregulation are rarely discussed in this context, we provide a brief review of what is currently known and unknown about muscle osmoregulation and how it may be linked to oxidant production in exercise and hyperthermia. Both the circulation and the exercising muscle fibers become concentrated with osmolytes during exercise in the heat, resulting in a competition for available water across the muscle sarcolemma and other tissues. We conclude that though multiple mechanisms may be responsible for the changes in oxidant/antioxidant balance in the blood during exercise, a strong case can be made that a significant component of ROS produced during some forms of exercise reflect requirements of adapting to osmotic challenges, hyperthermia challenges, and loss of circulating fluid volume. PMID:26561649

  15. Impact of an endurance training program on exercise-induced cardiac biomarker release.

    PubMed

    Legaz-Arrese, Alejandro; López-Laval, Isaac; George, Keith; Puente-Lanzarote, Juan José; Mayolas-Pi, Carmen; Serrano-Ostáriz, Enrique; Revilla-Martí, Pablo; Moliner-Urdiales, Diego; Reverter-Masià, Joaquín

    2015-04-15

    We evaluated the influence of a 14-wk endurance running program on the exercise-induced release of high-sensitivity cardiac troponin T (hs-cTnT) and NH2-terminal pro-brain natriuretic peptide (NT-proBNP). Fifty-eight untrained participants were randomized to supervised endurance exercise (14 wk, 3-4 days/wk, 120-240 min/wk, 65-85% of maximum heart rate) or a control group. At baseline and after the training program, hs-cTnT and NT-proBNP were assessed before and 5 min, 1 h, 3 h, 6 h, 12 h, and 24 h after a 60-min maximal running test. Before training, hs-cTnT was significantly elevated in both groups with acute exercise (P < 0.0001) with no between-group differences. There was considerable heterogeneity in peak hs-cTnT concentration with the upper reference limit exceeded in 71% of the exercise tests. After training, both baseline and postexercise hs-cTnT were significantly higher compared with pretraining and the response of the control group (P = 0.008). Acute exercise led to a small but significant increase in NT-proBNP, but this was not mediated by training (P = 0.121). In summary, a controlled endurance training intervention resulted in higher pre- and postexercise values of hs-cTnT with no changes in NT-proBNP. PMID:25681432

  16. Exercise-induced inverted U wave in asymptomatic high-risk subjects. A preliminary study.

    PubMed

    Salmasi, A M; Abraham, R; al-Kutoubi, A; Nicolaides, A N

    1994-09-01

    The sixteen-lead ECG chest wall mapping was used to investigate the significance of inverted U waves during exercise in diagnosing occult coronary artery disease (CAD) in asymptomatic high-risk subjects. For this purpose 100 patients with various types of hyperlipidemia and 33 patients with diabetes mellitus were studied. None of these patients had a history of angina pectoris or myocardial infarction and all had normal resting ECG. Exercise was carried out on a bicycle ergometer to an end point, and ECG recordings were made from all sixteen chest leads. Inverted U waves developed during the early minutes of exercise in 8 patients (6 hyperlipidemics and 2 diabetics), indicating disease in 11 coronary artery territories (7 in the left anterior descending/diagonal coronary artery, 3 in the circumflex, and 1 in the right coronary artery territories). Subsequent coronary arteriography confirmed the territorial distribution of the inverted U waves in all the cases. Following coronary artery bypass grafting in 2 of these patients no U wave inversion developed during stress testing. It is concluded that exercise-induced inverted U wave is a reliable indicator of silent myocardial ischemia due to occult CAD in asymptomatic high-risk subjects. Its distribution on the ECG chest wall map is highly predictive of significant disease in the individual coronary artery territory. The disappearance of this ECG sign following myocardial revascularization is a further proof of its myocardial ischemic origin. PMID:8092544

  17. Contrast Water Therapy and Exercise Induced Muscle Damage: A Systematic Review and Meta-Analysis

    PubMed Central

    Bieuzen, François; Bleakley, Chris M.; Costello, Joseph Thomas

    2013-01-01

    The aim of this systematic review was to examine the effect of Contrast Water Therapy (CWT) on recovery following exercise induced muscle damage. Controlled trials were identified from computerized literature searching and citation tracking performed up to February 2013. Eighteen trials met the inclusion criteria; all had a high risk of bias. Pooled data from 13 studies showed that CWT resulted in significantly greater improvements in muscle soreness at the five follow-up time points (<6, 24, 48, 72 and 96 hours) in comparison to passive recovery. Pooled data also showed that CWT significantly reduced muscle strength loss at each follow-up time (<6, 24, 48, 72 and 96 hours) in comparison to passive recovery. Despite comparing CWT to a large number of other recovery interventions, including cold water immersion, warm water immersion, compression, active recovery and stretching, there was little evidence for a superior treatment intervention. The current evidence base shows that CWT is superior to using passive recovery or rest after exercise; the magnitudes of these effects may be most relevant to an elite sporting population. There seems to be little difference in recovery outcome between CWT and other popular recovery interventions. PMID:23626806

  18. Exercise-induced hemolysis in xerocytosis. Erythrocyte dehydration and shear sensitivity.

    PubMed Central

    Platt, O S; Lux, S E; Nathan, D G

    1981-01-01

    A patient with xerocytosis was found to have swimming-induced intravascular hemolysis and shortening of erythrocyte life-span. In a microviscometer, xerocytes were more susceptible than normal erythrocytes to hemolysis by shear stress. Fractionation of normal and abnormal cells on discontinuous Stractan density gradients revealed that increasingly dehydrated cells were increasingly more shear sensitive. This sensitivity was partially corrected by rehydrating xerocytic erythrocytes by means of the cation-ionophore nystatin in a high potassium buffer. Conversely, normal erythrocytes were rendered shear sensitive by dehydrating them with nystatin in a low potassium buffer. This effect of dehydration was entirely reversible if normal cells were dehydrated for less than 4 h but was only partially reversed after more prolonged dehydration. It is likely that dehydration of erythrocytes results in shear sensitivity primarily because of concentration of cell contents and reduced cellular deformability. With prolonged dehydration, secondary membrane changes may potentiate the primary effect. This increased shear sensitivity of dehydrated cells may explain atraumatic exercise-induced hemolysis in xerocytosis as cardiac output is shifted to vessels of exercising muscles with small diameters and high shear rates. PMID:7276163

  19. Acute hypervolaemia improves arterial oxygen pressure in athletes with exercise-induced hypoxaemia.

    PubMed

    Zavorsky, Gerald S; Walley, Keith R; Hunte, Garth S; McKenzie, Donald C; Sexsmith, George P; Russell, James A

    2003-07-01

    The aim of this study was to determine the effect of acute plasma volume expansion on arterial blood-gas status during 6.5 min strenuous cycling exercise comparing six athletes with and six athletes without exercise-induced arterial hypoxaemia (EIAH). We hypothesized that plasma volume expansion could improve arterial oxygen pressure in a homogeneous sample of athletes - those with EIAH. In this paper we have extended the analysis and results of our recently published surprising findings that lengthening cardiopulmonary transit time did not improve arterial blood-gas status in a heterogeneous sample of endurance cyclists. One 500 ml bag of 10 % Pentastarch (infusion condition) or 60 ml 0.9 % saline (placebo) was infused prior to exercise in a randomized, double-blind fashion on two different days. Power output, cardiac output, oxygen consumption and arterial blood gases were measured during strenuous exercise. Cardiac output and oxygen consumption were not affected by acute hypervolaemia. There were group x condition interaction effects for arterial oxygen pressure and alveolar-arterial oxygen pressure difference, suggesting that those with hypoxaemia experienced improved arterial oxygen pressure (+4 mmHg) and lower alveolar-arterial oxygen pressure difference (-2 mmHg) with infusion. In conclusion, acute hypervolaemia improves blood-gas status in athletes with EIAH. The impairment of gas exchange occurs within the first minute of exercise, and is not impaired further throughout the remaining duration of exercise. This suggests that arterial oxygen pressure is only minimally mediated by cardiac output. PMID:12861344

  20. [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

  1. Hyperoxia prevents exercise-induced intrapulmonary arteriovenous shunt in healthy humans

    PubMed Central

    Lovering, Andrew T; Stickland, Michael K; Amann, Markus; Murphy, Joan C; O'Brien, Matthew J; Hokanson, John S; Eldridge, Marlowe W

    2008-01-01

    The 100% oxygen (O2) technique has been used to detect and quantify right-to-left shunt for more than 50 years. The goal of this study was to determine if breathing 100% O2 affected intrapulmonary arteriovenous pathways during exercise. Seven healthy subjects (3 females) performed two exercise protocols. In Protocol I subjects performed an incremental cycle ergometer test (60 W + 30 W/2 min; breathing room air, ) and arteriovenous shunting was evaluated using saline contrast echocardiography at each stage. Once significant arteriovenous shunting was documented (bubble score = 2), workload was held constant for the remainder of the protocol and was alternated between 1.0 (hyperoxia) and 0.209 (normoxia) as follows: hyperoxia for 180 s, normoxia for 120 s, hyperoxia for 120 s, normoxia for 120 s, hyperoxia for 60 s and normoxia for 120 s. For Protocol II, subjects performed an incremental cycle ergometer test until volitional exhaustion while continuously breathing 100% O2. In Protocol I, shunting was seen in all subjects at 120–300 W. Breathing oxygen for 1 min reduced shunting, and breathing oxygen for 2 min eliminated shunting in all subjects. Shunting promptly resumed upon breathing room air. Similarly, in Protocol II, breathing 100% O2 substantially decreased or eliminated exercise-induced arteriovenous shunting in all subjects at submaximal and in 4/7 subjects at maximal exercise intensities. Our results suggest that alveolar hyperoxia prevents or reduces blood flow through arteriovenous shunt pathways. PMID:18687713

  2. The effect of exercise-induced arousal on chosen tempi for familiar melodies.

    PubMed

    Jakubowski, Kelly; Halpern, Andrea R; Grierson, Mick; Stewart, Lauren

    2015-04-01

    Many previous studies have shown that arousal affects time perception, suggesting a direct influence of arousal on the speed of the pacemaker of the internal clock. However, it is unknown whether arousal influences the mental representation of tempo (speed) for highly familiar and complex stimuli, such as well-known melodies, that have long-term representations in memory. Previous research suggests that mental representations of the tempo of familiar melodies are stable over time; the aim of the present study was to investigate whether these representations can be systematically altered via an increase in physiological arousal. Participants adjusted the tempo of 14 familiar melodies in real time until they found a tempo that matched their internal representation of the appropriate tempo for that piece. The task was carried out before and after a physiologically arousing (exercise) or nonarousing (anagrams) manipulation. Participants completed this task both while hearing the melodies aloud and while imagining them. Chosen tempi increased significantly following exercise-induced arousal, regardless of whether a melody was heard aloud or imagined. These findings suggest that a change in internal clock speed affects temporal judgments even for highly familiar and complex stimuli such as music. PMID:25056004

  3. Dunbar syndrome as an unusual cause of exercise-induced retrosternal pain.

    PubMed

    Karavelio?lu, Yusuf; Kalç?k, Macit; Sarak, Taner

    2015-07-01

    The median arcuate ligament is a fibrous band connecting the left and right diaphragmatic crura across the aortic hiatus at the level of the T12/L1 vertebral bodies. The low insertion point of this ligament causes significant stenosis of the proximal portion of the coeliac artery in a small group of patients, and contributes to ischemic symptoms known as coeliac artery compression syndrome (CACS). It is also referred to as median arcuate ligament syndrome or Dunbar syndrome. Symptoms include especially postprandial epigastric or retrosternal pain, weight loss, nausea, vomiting, diarrhea and reduced appetite. In severe cases, exercise related abdominal pain may be caused by steal phenomenon, whereby blood is shunted to the skin and relevant muscles during exercise. Computed tomographic angiography and mesenteric angiography are the gold standard diagnostic modalities to confirm diagnosis of CACS. Surgical therapy with release of the median arcuate ligament usually is the primary treatment of choice. Here, we present a 46-year-old male CACS patient with postprandial and especially exercise-induced retrosternal pain radiating to the epigastric region, which may be misperceived as a coronary symptom. PMID:26148079

  4. A 45-Year-Old Man With Recurrent Dyspnea and Hemoptysis during Exercise: Exercise-Induced Pulmonary Hemorrhage/Edema

    PubMed Central

    Kim, Dae Sung; Lee, Minhyeok; Kwon, Oh Jung; Jeong, Inbeom; Son, Ji Woong; Na, Moon Jun

    2015-01-01

    A 45-year-old man presented with dyspnea and hemoptysis during exercise. A chest computed tomography (CT) revealed multifocal diffuse patchy ground glass opacity and interlobular septal thickening in both the lungs. Permeability pulmonary edema or pulmonary hemorrhage was suspected. Serologic studies for autoimmune disorders and vasculitis were negative. There was no laboratory evidence of coagulopathy, other hematopoietic disease or infectious disease. Considering correlation with exercise, we diagnosed exercise-induced pulmonary hemorrhage (EIPH) or exercise-induced pulmonary edema (EIPE). The patient was managed with antifibrinolytics, antibiotics, and antitussive agent. After a week, follow-up chest CT revealed completely resolved pulmonary hemorrhage. About 2 months after the first event, he visited again with dyspnea and hemoptysis during running. In the present study, we report a case of recurrent pulmonary hemorrhage after exercise. PMID:26508928

  5. Mitophagy and mitochondrial dynamics in Saccharomyces cerevisiae.

    PubMed

    Müller, Matthias; Lu, Kaihui; Reichert, Andreas S

    2015-10-01

    Mitochondria fulfill central cellular functions including energy metabolism, iron-sulfur biogenesis, and regulation of apoptosis and calcium homeostasis. Accumulation of dysfunctional mitochondria is observed in ageing and many human diseases such as cancer and various neurodegenerative disorders. Appropriate quality control of mitochondria is important for cell survival in most eukaryotic cells. One important pathway in this respect is mitophagy, a selective form of autophagy which removes excess and dysfunctional mitochondria. In the past decades a series of essential factors for mitophagy have been identified and characterized. However, little is known about the molecular mechanisms regulating mitophagy. The role of mitochondrial dynamics in mitophagy is controversially discussed. Here we will review recent advances in this context promoting our understanding on the molecular regulation of mitophagy in Saccharomyces cerevisiae and on the role of mitochondrial dynamics in mitochondrial quality control. PMID:25753536

  6. 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...

  7. 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

  8. Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate.

    PubMed

    Foryst-Ludwig, Anna; Kreissl, Michael C; Benz, Verena; Brix, Sarah; Smeir, Elia; Ban, Zsofia; Januszewicz, El?bieta; Salatzki, Janek; Grune, Jana; Schwanstecher, Anne-Kathrin; Blumrich, Annelie; Schirbel, Andreas; Klopfleisch, Robert; Rothe, Michael; Blume, Katharina; Halle, Martin; Wolfarth, Bernd; Kershaw, Erin E; Kintscher, Ulrich

    2015-09-25

    Endurance exercise training induces substantial adaptive cardiac modifications such as left ventricular hypertrophy (LVH). Simultaneously to the development of LVH, adipose tissue (AT) lipolysis becomes elevated upon endurance training to cope with enhanced energy demands. In this study, we investigated the impact of adipose tissue lipolysis on the development of exercise-induced cardiac hypertrophy. Mice deficient for adipose triglyceride lipase (Atgl) in AT (atATGL-KO) were challenged with chronic treadmill running. Exercise-induced AT lipolytic activity was significantly reduced in atATGL-KO mice accompanied by the absence of a plasma fatty acid (FA) increase. These processes were directly associated with a prominent attenuation of myocardial FA uptake in atATGL-KO and a significant reduction of the cardiac hypertrophic response to exercise. FA serum profiling revealed palmitoleic acid (C16:1n7) as a new molecular co-mediator of exercise-induced cardiac hypertrophy by inducing nonproliferative cardiomyocyte growth. In parallel, serum FA analysis and echocardiography were performed in 25 endurance athletes. In consonance, the serum C16:1n7 palmitoleate level exhibited a significantly positive correlation with diastolic interventricular septum thickness in those athletes. No correlation existed between linoleic acid (18:2n6) and diastolic interventricular septum thickness. Collectively, our data provide the first evidence that adipose tissue lipolysis directly promotes the development of exercise-induced cardiac hypertrophy involving the lipokine C16:1n7 palmitoleate as a molecular co-mediator. The identification of a lipokine involved in physiological cardiac growth may help to develop future lipid-based therapies for pathological LVH or heart failure. PMID:26260790

  9. Mitochondrial protein quality control in health and disease

    PubMed Central

    Baker, Michael J; Palmer, Catherine S; Stojanovski, Diana

    2014-01-01

    Progressive mitochondrial dysfunction is linked with the onset of many age-related pathologies and neurological disorders. Mitochondrial damage can come in many forms and be induced by a variety of cellular insults. To preserve organelle function during biogenesis or times of stress, multiple surveillance systems work to ensure the persistence of a functional mitochondrial network. This review provides an overview of these processes, which collectively contribute to the maintenance of a healthy mitochondrial population, which is critical for cell physiology and survival. 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:24117041

  10. 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

  11. The cAMP phosphodiesterase Prune localizes to the mitochondrial matrix and promotes mtDNA replication by stabilizing TFAM

    PubMed Central

    Zhang, Fan; Qi, Yun; Zhou, Kiet; Zhang, Guofeng; Linask, Kaari; Xu, Hong

    2015-01-01

    Compartmentalized cAMP signaling regulates mitochondrial dynamics, morphology, and oxidative phosphorylation. However, regulators of the mitochondrial cAMP pathway, and its broad impact on organelle function, remain to be explored. Here, we report that Drosophila Prune is a cyclic nucleotide phosphodiesterase that localizes to the mitochondrial matrix. Knocking down prune in cultured cells reduces mitochondrial transcription factor A (TFAM) and mitochondrial DNA (mtDNA) levels. Our data suggest that Prune stabilizes TFAM and promotes mitochondrial DNA (mtDNA) replication through downregulation of mitochondrial cAMP signaling. In addition, our work demonstrates the prevalence of mitochondrial cAMP signaling in metazoan and its new role in mitochondrial biogenesis. PMID:25648146

  12. Exploring effects of a natural combination medicine on exercise-induced inflammatory immune response: A double-blind RCT.

    PubMed

    Pilat, C; Frech, T; Wagner, A; Krüger, K; Hillebrecht, A; Pons-Kühnemann, J; Scheibelhut, C; Bödeker, R-H; Mooren, F-C

    2015-08-01

    Traumeel (Tr14) is a natural, combination drug, which has been shown to modulate inflammation at the cytokine level. This study aimed to investigate potential effects of Tr14 on the exercise-induced immune response. In a double-blind, randomized, controlled trial, healthy, untrained male subjects received either Tr14 (n?=?40) or placebo (n?=?40) for 24?h after a strenuous experimental exercise trial on a bicycle (60?min at 80%VO2 max). A range of antigen-stimulated cytokines (in vitro), white blood cell count, lymphocyte activation and apoptosis markers, and indicators of muscle damage were assessed up to 24?h following exercise. The area under the curve with respect to the increase (AUCI ) was compared between both groups. The Tr14 group showed a reduced exercise-induced leukocytosis and neutrocytosis (P?exercise-induced immune response by (a) decreasing the inflammatory response of the innate immune system; and (b) augmenting the pro-inflammatory cytokine response. PMID:24924232

  13. No protection by oral terbutaline against exercise-induced asthma in children: a dose-response study.

    PubMed

    Fuglsang, G; Hertz, B; Holm, E B

    1993-04-01

    We wanted to assess the protective effects on exercise-induced asthma as well as the clinical efficacy and safety of increasing doses of a new sustained-release formulation of terbutaline sulphate, in 17 asthmatic children aged 6-12 yrs (mean 9 yrs). Placebo, 2, 4 and 6 mg terbutaline were given b.i.d. for 14 days, in a randomized, double-blind, cross-over design. At the end of each two week period, an exercise test was performed and plasma terbutaline was measured. Compared with placebo, no significant effect was seen on asthma symptoms monitored at home, or on exercise-induced asthma. The percentage falls in FEV1 after the exercise test were 36, 35, 27 and 28%, after placebo, 4, 8 and 12 mg terbutaline.day-1, respectively. There was no correlation between plasma terbutaline and dose of terbutaline. A small but statistically significant dose-related increase in morning and evening peak expiratory flow (PEF) recordings occurred, but the incidence of side-effects also increased with the dose given. There was a trend towards more side-effects when the high doses were used, and two patients withdrew from the study because of side-effects at this dose. It is concluded that continuous treatment, even with high doses of oral terbutaline, does not offer clinically useful protection against exercise-induced asthma. PMID:8491302

  14. Prevention of subsequent exercise-induced periinfarct ischemia by emergency coronary angioplasty in acute myocardial infarction: comparison with intracoronary streptokinase

    SciTech Connect

    Fung, A.Y.; Lai, P.; Juni, J.E.; Bourdillon, P.D.; Walton, J.A. Jr.; Laufer, N.; Buda, A.J.; Pitt, B.; O'Neill, W.W.

    1986-09-01

    To compare the efficacy of emergency percutaneous transluminal coronary angioplasty and intracoronary streptokinase in preventing exercise-induced periinfarct ischemia, 28 patients presenting within 12 hours of the onset of symptoms of acute myocardial infarction were prospectively randomized. Of these, 14 patients were treated with emergency angioplasty and 14 patients received intracoronary streptokinase. Recatheterization and submaximal exercise thallium-201 single photon emission computed tomography were performed before hospital discharge. Periinfarct ischemia was defined as a reversible thallium defect adjacent to a fixed defect assessed qualitatively. Successful reperfusion was achieved in 86% of patients treated with emergency angioplasty and 86% of patients treated with intracoronary streptokinase (p = NS). Residual stenosis of the infarct-related coronary artery shown at predischarge angiography was 43.8 +/- 31.4% for the angioplasty group and 75.0 +/- 15.6% for the streptokinase group (p less than 0.05). Of the angioplasty group, 9% developed exercise-induced periinfarct ischemia compared with 60% of the streptokinase group (p less than 0.05). Thus, patients with acute myocardial infarction treated with emergency angioplasty had significantly less severe residual coronary stenosis and exercise-induced periinfarct ischemia than did those treated with intracoronary streptokinase. These results suggest further application of coronary angioplasty in the management of acute myocardial infarction.

  15. 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 ...

  16. 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; Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan ; Jeong, Seon-Young; Department of Medical Genetics, Ajou University School of Medicine ; Yun, Jeanho; Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan

    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.

  17. 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

  18. Contribution of nitric oxide to exercise-induced hypotension in human sympathetic denervation.

    PubMed

    Akinola, A B; Land, J M; Mathias, C J; Giovannoni, G; Magnifico, F; Puvi-Rajasingham, S; Smith, G D; Watson, L

    1999-10-01

    The cardiovascular, catecholamine, and nitrate/nitrite (NO) responses to bicycle exercise were measured in 14 normal subjects (controls) and two groups with sympathetic denervation; 14 with peripheral autonomic failure (pure autonomic failure [PAF]); and 13 with central autonomic failure (multiple system atrophy [MSA]). With exercise, blood pressure increased in control subjects by 40 +/- 7/24 +/- 5 mm Hg (p < 0.001) and fell in PAF by 24 +/- 8/24 +/- 5 mm Hg (p < 0.02 and p < 0.007) and MSA by 31 +/- 7/11 +/- 3 mm Hg (p < 0.005 and p < 0.04). With exercise, the increase in heart rate was greater in control subjects (60 +/- 3 to 111 +/- 4/min; p < 0.0001) than in PAF (69 +/- 3 to 86 +/- 4/min; p < 0.0001) and MSA (70 +/- 4 to 90 +/- 4; p < 0.001). Resting plasma noradrenaline levels were similar in controls (291 +/- 51 pg ml(-1)) and MSA (257 +/- 49 pg ml(-1)), but lower in PAF (82 +/- 14 pg ml(-1)). With exercise, plasma noradrenaline increased in controls but was unchanged in PAF and MSA. Resting NOx was similar in controls (50 +/- 5 nmol/L; range, 23.3-87.6 nmol/L) and PAF patients (59+/-8 nmol/l; range, 19.3-116.4 nmol/L), but was higher in MSA patients (87 +/-14 nmol/L; p <0.025, range 15.4-157.2 nmol/L). With exercise, NOx was unchanged in control subjects and increased by 10% and 17% in PAF and MSA, respectively; these changes were not statistically significant. This study suggests that circulating changes in NOx levels do not exert a major role in exercise-induced hypotension in subjects with sympathetic denervation. PMID:10580878

  19. An Evaluation of Levalbuterol HFA in the Prevention of Exercise-Induced Bronchospasm

    PubMed Central

    Pearlman, D.S.; Rees, William; Schaefer, Kendyl; Huang, Holly; Andrews, William T.

    2007-01-01

    Background Exercise-induced bronchospasm (EIB) affects up to 90% of all patients with asthma. Objective This study evaluated the ability of levalbuterol hydrofluoroalkane (HFA) 90 ?g (two actuations of 45 ?g) administered via metered dose inhaler (MDI) to protect against EIB in mild-to-moderate asthmatics. Methods This was a randomized, double-blind, placebo-controlled, two-way cross-over study. Patients with asthma (n = 15) were ?18 years, had a ?6-month history of EIB, ?70% baseline predicted forced expiratory volume in 1 second (FEV1), and a 20% to 50% decrease in FEV1 after treadmill exercise challenge using single-blind placebo MDI. Levalbuterol or placebo was self-administered 30 minutes before exercise. Treatment sequences were separated by a 3-to 7-day washout period. Spirometry was performed predose, 20 minutes postdose/pre-exercise, and 5, 10, 15, 30, and 60 minutes post-exercise. The primary endpoint was the maximum percent decrease in FEV1 from baseline (postdose/pre-exercise). The percentage of protected (?20% decrease in post-exercise FEV1) patients was also assessed. Results Levalbuterol had significantly smaller maximum percent post-exercise decrease in FEV1 compared with placebo (LS mean ± SE; ?4.8% ± 2.8% versus ?22.5% ± 2.8%, respectively). For levalbuterol, 14/15 (93.3%) patients had <20% decrease in post-exercise FEV1 compared with 8/15 (53.3%) for placebo (p = 0.0143). Treatment was well tolerated. Conclusion Levalbuterol HFA MDI (90 ?g) administered 30 minutes before exercise was significantly more effective than placebo in protecting against EIB after a single exercise challenge and was well tolerated. Clinical Implications Levalbuterol HFA MDI when administered before exercise was effective in protecting adults with asthma from EIB. PMID:17994402

  20. Voluntary exercise-induced changes in ?2-adrenoceptor signalling in rat ventricular myocytes

    PubMed Central

    Stones, Rachel; Natali, Antonio; Billeter, Rudolf; Harrison, Simon; White, Ed

    2008-01-01

    Regular exercise is beneficial to cardiovascular health. We tested whether mild voluntary exercise training modifies key myocardial parameters [ventricular mass, intracellular calcium ([Ca2+]i) handling and the response to ?-adrenoceptor (?-AR) stimulation] in a manner distinct from that reported for beneficial, intensive training and pathological hypertrophic stimuli. Female rats performed voluntary wheel-running exercise for 6–7 weeks. The mRNA expression of target proteins was measured in left ventricular tissue using real-time reverse transcriptase-polymerase chain reaction. Simultaneous measurement of cell shortening and [Ca2+]i transients were made in single left ventricular myocytes and the inotropic response to ?1- and ?2-AR stimulation was measured. Voluntary exercise training resulted in cardiac hypertrophy, the heart weight to body weight ratio being significantly greater in trained compared with sedentary animals. However, voluntary exercise caused no significant alteration in the size or time course of myocyte shortening and [Ca2+]i transients or in the mRNA levels of key proteins that regulate Ca2+ handling. The positive inotropic response to ?1-AR stimulation and the level of ?1-AR mRNA were unaltered by voluntary exercise but both mRNA levels and inotropic response to ?2-AR stimulation were significantly reduced in trained animals. The ?2-AR inotropic response was restored by exposure to pertussis toxin. We propose that in contrast to pathological stimuli and to beneficial, intense exercise training, modulation of Ca2+ handling is not a major adaptive mechanism in the response to mild voluntary exercise. In addition, and in a reversal of the situation seen in heart failure, voluntary exercise training maintains the ?1-AR response but reduces the ?2-AR response. Therefore, although voluntary exercise induces cardiac hypertrophy, there are distinct differences between its effects on key myocardial regulatory mechanisms and those of hypertrophic stimuli that eventually cause cardiac decompensation. PMID:18487315

  1. Resistance exercise-induced fluid shifts: change in active muscle size and plasma volume

    NASA Technical Reports Server (NTRS)

    Ploutz-Snyder, L. L.; Convertino, V. A.; Dudley, G. A.

    1995-01-01

    The purpose of this study was to test the hypothesis that the reduction in plasma volume (PV) induced by resistance exercise reflects fluid loss to the extravascular space and subsequently selective increase in cross-sectional area (CSA) of active but not inactive skeletal muscle. We compared changes in active and inactive muscle CSA and PV after barbell squat exercise. Magnetic resonance imaging (MRI) was used to quantify muscle involvement in exercise and to determine CSA of muscle groups or individual muscles [vasti (VS), adductor (Add), hamstring (Ham), and rectus femoris (RF)]. Muscle involvement in exercise was determined using exercise-induced contrast shift in spin-spin relaxation time (T2)-weighted MR images immediately postexercise. Alterations in muscle size were based on the mean CSA of individual slices. Hematocrit, hemoglobin, and Evans blue dye were used to estimate changes in PV. Muscle CSA and PV data were obtained preexercise and immediately postexercise and 15 and 45 min thereafter. A hierarchy of muscle involvement in exercise was found such that VS > Add > Ham > RF, with the Ham and RF showing essentially no involvement. CSA of the VS and Add muscle groups were increased 10 and 5%, respectively, immediately after exercise in each thigh with no changes in Ham and RF CSA. PV was decreased 22% immediately following exercise. The absolute loss of PV was correlated (r2 = 0.75) with absolute increase in muscle CSA immediately postexercise, supporting the notion that increased muscle size after resistance exercise reflects primarily fluid movement from the vascular space into active but not inactive muscle.

  2. Effects of allopurinol on exercise-induced muscle damage: new therapeutic approaches?

    PubMed

    Sanchis-Gomar, F; Pareja-Galeano, H; Perez-Quilis, C; Santos-Lozano, A; Fiuza-Luces, C; Garatachea, N; Lippi, G; Lucia, A

    2015-01-01

    Intensive muscular activity can trigger oxidative stress, and free radicals may hence be generated by working skeletal muscle. The role of the enzyme xanthine oxidase as a generating source of free radicals is well documented and therefore is involved in the skeletal muscle damage as well as in the potential transient cardiovascular damage induced by high-intensity physical exercise. Allopurinol is a purine hypoxanthine-based structural analog and a well-known inhibitor of xanthine oxidase. The administration of the xanthine oxidase inhibitor allopurinol may hence be regarded as promising, safe, and an economic strategy to decrease transient skeletal muscle damage (as well as heart damage, when occurring) in top-level athletes when administered before a competition or a particularly high-intensity training session. Although continuous administration of allopurinol in high-level athletes is not recommended due to its possible role in hampering training-induced adaptations, the drug might be useful in non-athletes. Exertional rhabdomyolysis is the most common form of rhabdomyolysis and affects individuals participating in a type of intense exercise to which they are not accustomed. This condition can cause exercise-related myoglobinuria, thus increasing the risk of acute renal failure and is also associated with sickle cell trait. In this manuscript, we have reviewed the recent evidence about the effects of allopurinol on exercise-induced muscle damage. More research is needed to determine whether allopurinol may be useful for preventing not only exertional rhabdomyolysis and acute renal damage but also skeletal muscle wasting in critical illness as well as in immobilized, bedridden, sarcopenic or cachectic patients. PMID:25181966

  3. Evaluation of Exercise-Induced Hypertension Post Endovascular Stenting of Coarctation of Aorta

    PubMed Central

    Mortazaeian, Hojat; Moghadam, Mohammad Yoosef Aarabi; Ghaderian, Mehdi; Davary, Paridokht Nakhostin; Meraji, Mohmood; Mohammadi, Akbar Shah

    2010-01-01

    Background: Coarctation of the aorta (COA) is a defect that accounts for 5–8% of all congenital heart diseases. Balloon angioplasty as a treatment for COA is increasingly performed, with endovascular stents having been proposed as a means of improving the efficacy and safety of the procedure. The aim of this study was to evaluate the systolic blood pressure gradient at rest and during maximal exercise at follow-up in patients post endovascular stenting of COA. Methods: Thirteen patients (4 native and 9 re-coarctation cases of COA after surgery or balloon angioplasty) with a mean age of 11.1 ± 4.7 years underwent endovascular stenting between November 2007 and December 2009 via standard techniques for native COA as an alternative to surgical repair. Doppler echocardiography was performed pre and post stenting. Resting and exercise assessment of blood pressure was performed at follow-up. Results: Post stent implantation, no angiographic major complications were evident. Systolic blood pressure gradient decreased from 42 ± 8.8 mm Hg before stent placement to 7 ± 10 mm Hg at follow-up (p value < 0.001). Peak Doppler pressure gradient decreased from 30 ± 14 mm Hg to 14 ± 10 mm Hg at follow-up (p value < 0.007). One case of exercise-induced hypertension was seen in patients. Conclusion: Endovascular stenting for native COA in older children and post-surgical COA repair in patients with residual COA and re-coarctation is a reasonable alternative to surgical correction. During early follow-up, stenting effectively alleviates the aortic arch obstruction with normalization of the systemic blood pressure both at rest and during maximal exercise. PMID:23074582

  4. Vitamin D2 Supplementation Amplifies Eccentric Exercise-Induced Muscle Damage in NASCAR Pit Crew Athletes

    PubMed Central

    Nieman, David C.; Gillitt, Nicholas D.; Shanely, R. Andrew; Dew, Dustin; Meaney, Mary Pat; Luo, Beibei

    2013-01-01

    This study determined if 6-weeks vitamin D2 supplementation (vitD2, 3800 IU/day) had an influence on muscle function, eccentric exercise-induced muscle damage (EIMD), and delayed onset of muscle soreness (DOMS) in National Association for Stock Car Auto Racing (NASCAR) NASCAR pit crew athletes. Subjects were randomized to vitD2 (n = 13) and placebo (n = 15), and ingested supplements (double-blind) for six weeks. Blood samples were collected and muscle function tests conducted pre- and post-study (leg-back and hand grip dynamometer strength tests, body weight bench press to exhaustion, vertical jump, 30-s Wingate test). Post-study, subjects engaged in 90 min eccentric-based exercise, with blood samples and DOMS ratings obtained immediately after and 1- and 2-days post-exercise. Six weeks vitD2 increased serum 25(OH)D2 456% and decreased 25(OH)D3 21% versus placebo (p < 0.001, p = 0.036, respectively), with no influence on muscle function test scores. The post-study eccentric exercise bout induced EIMD and DOMS, with higher muscle damage biomarkers measured in vitD2 compared to placebo (myoglobin 252%, 122% increase, respectively, p = 0.001; creatine phosphokinase 24 h post-exercise, 169%, 32%, p < 0.001), with no differences for DOMS. In summary, 6-weeks vitD2 (3800 IU/day) significantly increased 25(OH)D2 and decreased 25(OH)D3, had no effect on muscle function tests, and amplified muscle damage markers in NASCAR pit crew athletes following eccentric exercise. PMID:24362707

  5. The Interplay of Neuronal Mitochondrial Dynamics and Bioenergetics: Implications for Parkinson’s Disease

    PubMed Central

    Van Laar, Victor S.; Berman, Sarah B.

    2012-01-01

    The dynamic properties of mitochondria (mitochondrial fission, fusion, transport biogenesis and degradation) are critical for neuronal function and health, and dysregulation of mitochondrial dynamics has been increasingly linked to the pathogenesis of Parkinson’s disease (PD). Mitochondrial dynamics and bioenergetics are interconnected, and this is of particular importance in neurons, which have a unique bioenergetic profile due to their energetic dependence on mitochondria and specialized, compartmentalized energetic needs. In this review, we summarize the interplay of mitochondrial dynamics and bioenergetics, and its particular relevance for neurodegeneration. Evidence linking dysregulation of mitochondrial dynamics to PD is presented from both toxin and genetic models, including newly emerging details of how PD-relevant genes PTEN-induced kinase 1 (PINK1) and Parkin regulate fission, fusion, mitophagy and transport. Finally, we discuss how neuronal bioenergetics may impact PD-relevant regulation of mitochondrial dynamics, and possible implications for understanding the role of mitochondrial dynamics in PD. PMID:22668779

  6. Biosynthesis and Roles of Phospholipids in Mitochondrial Fusion, Division and Mitophagy

    PubMed Central

    Zhang, Qiang; Tamura, Yasushi; Roy, Madhuparna; Adachi, Yoshihiro; Iijima, Miho; Sesaki, Hiromi

    2014-01-01

    Mitochondria move, fuse and divide in cells. The dynamic behavior of mitochondria is central to the control of their structure and function. Three conserved mitochondrial dynamin-related GTPases (i.e., mitofusin, Opa1 and Drp1 in mammals and Fzo1, Mgm1 and Dnm1 in yeast) mediate mitochondrial fusion and division. In addition to dynamins, recent studies demonstrated that phospholipids in mitochondria also play key roles in mitochondrial dynamics by interacting with dynamin GTPases and by directly changing the biophysical properties of the mitochondrial membranes. Changes in phospholipid composition also promote mitophagy, which is a selective mitochondrial degradation process that is mechanistically coupled to mitochondrial division. In this review, we will discuss the biogenesis and function of mitochondrial phospholipids. PMID:24866973

  7. Biogenesis, delivery, and function of extracellular RNA

    PubMed Central

    Patton, James G.; Franklin, Jeffrey L.; Weaver, Alissa M.; Vickers, Kasey; Zhang, Bing; Coffey, Robert J.; Ansel, K. Mark; Blelloch, Robert; Goga, Andrei; Huang, Bo; L'Etoille, Noelle; Raffai, Robert L.; Lai, Charles P.; Krichevsky, Anna M.; Mateescu, Bogdan; Greiner, Vanille J.; Hunter, Craig; Voinnet, Olivier; McManus, Michael T.

    2015-01-01

    The Extracellular RNA (exRNA) Communication Consortium was launched by the National Institutes of Health to focus on the extent to which RNA might function in a non-cell-autonomous manner. With the availability of increasingly sensitive tools, small amounts of RNA can be detected in serum, plasma, and other bodily fluids. The exact mechanism(s) by which RNA can be secreted from cells and the mechanisms for the delivery and uptake by recipient cells remain to be determined. This review will summarize current knowledge about the biogenesis and delivery of exRNA and outline projects seeking to understand the functional impact of exRNA. PMID:26320939

  8. Human telomerase: biogenesis, trafficking, recruitment, and activation.

    PubMed

    Schmidt, Jens C; Cech, Thomas R

    2015-06-01

    Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species. PMID:26063571

  9. Human telomerase: biogenesis, trafficking, recruitment, and activation

    PubMed Central

    Schmidt, Jens C.

    2015-01-01

    Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species. PMID:26063571

  10. Insulin resistance by TNF-? is associated with mitochondrial dysfunction in 3T3-L1 adipocytes and is ameliorated by punicic acid, a PPAR? agonist.

    PubMed

    Anusree, S S; Nisha, V M; Priyanka, A; Raghu, K G

    2015-09-15

    Punicic acid (PA), a poly unsaturated fatty acid found abundantly in pomegranate seed oil is reported to have PPAR? agonist property. TNF-? mediated insulin resistance plays an important role in the pathogenesis of diabetes and is associated with severe mitochondrial impairment. In this study, PA was evaluated for its ability to ameliorate TNF-? induced mitochondrial dysfunctions in 3T3-L1 adipocytes. For this, we examined the alterations in mitochondrial energetics, biogenesis, transmembrane potential and dynamics in TNF-? induced insulin resistant model of 3T3-L1 adipocytes. PA improved glucose uptake, ROS accumulation, mitochondrial biogenesis and energetics in TNF-? treated cells. In addition, treatment with PA was found to ameliorate TNF-? induced alterations in proteins associated with mitochondrial dynamics like FIS1 and OPA1. These findings suggest that PA can be considered as an active lead for the management of insulin resistance and associated mitochondrial dysfunctions. PMID:26116231

  11. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

    PubMed

    Khan, Nahid A; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J; Auwerx, Johan; Suomalainen, Anu

    2014-06-01

    Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy. PMID:24711540

  12. Distinct Pathways Mediate the Sorting of Tail-anchored Mitochondrial Outer Membrane Proteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about the biogenesis of tail-anchored (TA) proteins localized to the mitochondrial outer membrane in plant cells. To address this issue, we screened all of the (>600) known and predicted TA proteins in Arabidopsis thaliana for those annotated, based on Gene Ontology, to possess mitoc...

  13. 1985 Elsevier Science Publishers B.V. (Biomedical Division) Achievements and Perspectives of Mitochondrial Research

    E-print Network

    Simpson, Larry

    for Crithidia fasciculata (15), Leptomonas (unpublished results), and Trypanosoma cruzi and Herpetomonas of Mitochondrial Research Volume II: Biogenesis, E. Quagliariello et al. editors 99 GENOMIC ORGANIZATION diverse organisms may lead to a deeper'understanding of the mode of evolution of this originally endosym

  14. Mitochondria-associated Yeast mRNAs and the Biogenesis of Molecular Complexes

    PubMed Central

    Garcia, M.; Darzacq, X.; Delaveau, T.; Jourdren, L.; Singer, R. H.

    2007-01-01

    The coherence of mitochondrial biogenesis relies on spatiotemporally coordinated associations of 800–1000 proteins mostly encoded in the nuclear genome. We report the development of new quantitative analyses to assess the role of local protein translation in the construction of molecular complexes. We used real-time PCR to determine the cellular location of 112 mRNAs involved in seven mitochondrial complexes. Five typical cases were examined by an improved FISH protocol. The proteins produced in the vicinity of mitochondria (MLR proteins) were, almost exclusively, of prokaryotic origin and are key elements of the core construction of the molecular complexes; the accessory proteins were translated on free cytoplasmic polysomes. These two classes of proteins correspond, at least as far as intermembrane space (IMS) proteins are concerned, to two different import pathways. Import of MLR proteins involves both TOM and TIM23 complexes whereas non-MLR proteins only interact with the TOM complex. Site-specific translation loci, both outside and inside mitochondria, may coordinate the construction of molecular complexes composed of both nuclearly and mitochondrially encoded subunits. PMID:17108321

  15. Exercise-induced apoptosis of rat skeletal muscle and the effect of meloxicam.

    PubMed

    Arslan, Sule; Erdem, Sevim; Sivri, Aysen; Hasçelik, Zafer; Tan, Ersin

    2002-01-01

    The aim of this study was to evaluate the effect of exercise on apoptosis in rat gastrocnemius and soleus muscle tissue and to determine the effect of meloxicam, a novel non-steroidal anti-inflammatory drug (NSAID), on the ratio of exercise-induced apoptosis. Forty male Wistar rats were used in the experiments. Spontaneous wheel-running was used as an exercise protocol. Rats were divided randomly into four groups. Group A (n = 10) was the control group, in which rats did not perform any exercise. In group B (n = 10), gastrocnemius and soleus muscles were biopsied immediately after exercise. The rats in group C (n = 10) were placed back in their cages after exercise and allowed to rest for 48 h, after which the gastrocnemius and soleus muscles were biopsied. In group D (n = 10), rats were given 11 mg meloxicam (Mobic, Boehringer Ingelheim) per kilogram body weight per day p.o. for 2 days, after which gastrocnemius and soleus muscles were biopsied 48 h after exercise. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labelling (TUNEL) technique was used to detect DNA fragmentation in situ. TUNEL-positive nuclei were identified and counted. The apoptosis ratio in gastrocnemius muscle was 0.50x10(-3)+/-0.96x10(-3) in group A, 5.42x10(-3)+/-3.58x10(-3) in group B, 3.55x10(-3)+/-3.23x10(-3) in Group C and 3.52x10(-3)+/-1.00 in Group D; the ratios in soleus muscle were 0.98x10(-3)+/-1.83x10(-3), 3.03x10(-3)+/-2.78x10(-3), 4.48x10(-3)+/-3.32x10(-3) and 2.91x10(-3) 1.98x10(-3), respectively. The differences between the apoptosis ratios in group A and B, Group A and C, and Group A and D were statistically significant (P < 0.05). There was no statistically significant difference between group C and D. In conclusion, exercise increased apoptosis in gastrocnemius and soleus muscle tissue, and the apoptosis ratios were not affected by meloxicam. PMID:11843167

  16. Carbohydrate exerts a mild influence on fluid retention following exercise-induced dehydration.

    PubMed

    Osterberg, Kristin L; Pallardy, Shannon E; Johnson, Richard J; Horswill, Craig A

    2010-02-01

    Rapid and complete rehydration, or restoration of fluid spaces, is important when acute illness or excessive sweating has compromised hydration status. Many studies have investigated the effects of graded concentrations of sodium and other electrolytes in rehydration solutions; however, no study to date has determined the effect of carbohydrate on fluid retention when electrolyte concentrations are held constant. The purpose of this study was to determine the effect of graded levels of carbohydrate on fluid retention following exercise-induced dehydration. Fifteen heat-acclimatized men exercised in the heat for 90 min with no fluid to induce 2-3% dehydration. After a 30-min equilibration period, they received, over the course of 60 min, one of five test beverages equal to 100% of the acute change in body mass. The experimental beverages consisted of a flavored placebo with no electrolytes (P), placebo with electrolytes (P + E), 3%, 6%, and 12% carbohydrate solutions with electrolytes. All beverages contained the same type and concentration of electrolytes (18 meq/l Na(+), 3 meq/l K(+), 11 meq/l Cl(-)). Subjects voided their bladders at 60, 90, 120, 180, and 240 min, and urine specific gravity and urine volume were measured. Blood samples were taken before exercise and 30, 90, 180, and 240 min following exercise and were analyzed for glucose, sodium, hemoglobin, hematocrit, renin, aldosterone, and osmolality. Body mass was measured before and after exercise and a final body mass was taken at 240 min. There were no differences in percent dehydration, sweat loss, or fluid intake between trials. Fluid retention was significantly greater for all carbohydrate beverages compared with P (66.3 +/- 14.4%). P + E (71.8 +/- 9.9%) was not different from water, 3% (75.4 +/- 7.8%) or 6% (75.4 +/- 16.4%) but was significantly less than 12% (82.4 +/- 9.2%) retention of the ingested fluid. No difference was found between the carbohydrate beverages. Carbohydrate at the levels measured exerts a mild influence on fluid retention in postexercise recovery. PMID:19940093

  17. Effect of New Zealand blueberry consumption on recovery from eccentric exercise-induced muscle damage

    PubMed Central

    2012-01-01

    Background Exercise-induced muscle damage (EIMD) is accompanied by localized oxidative stress / inflammation which, in the short-term at least, is associated with impaired muscular performance. Dietary antioxidants have been shown to reduce excessive oxidative stress; however, their effectiveness in facilitating recovery following EIMD is not clear. Blueberries demonstrate antioxidant and anti-inflammatory properties. In this study we examine the effect of New Zealand blueberries on EIMD after strenuous eccentric exercise. Methods In a randomized cross-over design, 10 females consumed a blueberry smoothie or placebo of a similar antioxidant capacity 5 and 10 hours prior to and then immediately, 12 and 36 hours after EIMD induced by 300 strenuous eccentric contractions of the quadriceps. Absolute peak and average peak torque across the knee, during concentric, isometric, and eccentric actions were measured. Blood biomarkers of oxidative stress, antioxidant capacity, and inflammation were assessed at 12, 36 and 60 hours post exercise. Data were analyzed using a two-way ANOVA. Results A significant (p?

  18. Exercise-induced GH secretion is enhanced by the oral ingestion of melatonin in healthy adult male subjects.

    PubMed

    Meeking, D R; Wallace, J D; Cuneo, R C; Forsling, M; Russell-Jones, D L

    1999-07-01

    There is evidence that melatonin may play a role in modulating pituitary secretion, although the mechanisms are unclear. We examined the effects of a single dose of oral melatonin (5mg) on exercise-induced GH secretion. In a randomised, double-blind, placebo-controlled study, seven healthy male subjects undertook an initial period of graded bicycle ergometric exercise to determine maximum workload and oxygen uptake (VO(2max)). Subjects were subsequently studied on two further occasions, receiving either melatonin or placebo in random order at the onset of each study (-60min). At 0 min a period of bicycle exercise was performed for 8 min at a workload corresponding to 70% of that achieved at VO(2max). Serum GH and IGF-binding protein-1 (IGFBP-1) concentration was measured at 15-min intervals from the onset of the study until 120 min post-exercise. Blood was also sampled for the measurement of plasma glucose, insulin, non-esterified fatty acids, IGFBP-3, melatonin and vasopressin concentration. There was an exercise-induced increase in GH concentration following melatonin which was greater compared with placebo as assessed by both area under the curve (P<0.01) and peak increase in GH levels (P<0.01). The peak increase in IGFBP-1 levels post-exercise was also significantly greater following melatonin compared with placebo (P<0. 01) but did not quite reach levels of significance as measured by area under the curve (P=0.07). Since exercise-induced GH secretion is thought to be mediated predominantly through a hypothalamic pathway, it seems likely that melatonin facilitates GH secretion at a hypothalamic level. PMID:10407218

  19. Tissue factor-dependent pathway is not involved in exercise-induced formation of thrombin and fibrin.

    PubMed

    Weiss, Claus; Bierhaus, Angelika; Kinscherf, Ralf; Hack, Volker; Luther, Thomas; Nawroth, Peter Paul; Bärtsch, Peter

    2002-01-01

    In healthy individuals, prolonged intensive physical exercise leads to an activation of blood coagulation that results in the formation of thrombin and fibrin. This study investigated whether oxidative stress during intensive physical exercise induces tissue factor (TF) via activation of the redox-responsive transcription factor nuclear factor-kappaB (NF-kappaB). Twelve young men performed a standardized 1-h maximal run on a treadmill that gave rise to significant increases of markers of thrombin and fibrin formation. The ratio of intracellular reduced to oxidized glutathione as measured by HPLC decreased from 23.3 +/- 10.7 to 14.2 +/- 6.5 (P < 0.05), indicating the generation of free radicals during exercise. Electrophoretic mobility shift assays from nuclear extracts of peripheral blood mononuclear cells revealed that exercise testing increased NF-kappaB (p50/p65) binding activity to a NF-kappaB consensus sequence by 105 +/- 68% (P < 0.01) but did not affect NF-kappaB (p65/c-Rel) binding to a nonconsensus-kappaB-like site present in the TF promoter. Consistently, there was no exercise-induced increase in TF expression as demonstrated by TF-specific immunofluorescence staining and ELISA. Thus selective activation of NF-kappaB (p50/p65) during intensive physical exercise does not result in the expression of TF, suggesting that the TF-dependent pathway in peripheral blood mononuclear cells does not account for exercise-induced formation of thrombin and fibrin. PMID:11744662

  20. Transcranial magnetic stimulation intensity affects exercise-induced changes in corticomotoneuronal excitability and inhibition and voluntary activation.

    PubMed

    Bachasson, D; Temesi, J; Gruet, M; Yokoyama, K; Rupp, T; Millet, G Y; Verges, Samuel

    2016-02-01

    Transcranial magnetic stimulation (TMS) of the motor cortex during voluntary contractions elicits electrophysiological and mechanical responses in the target muscle. The effect of different TMS intensities on exercise-induced changes in TMS-elicited variables is unknown, impairing data interpretation. This study aimed to investigate TMS intensity effects on maximal voluntary activation (VATMS), motor-evoked potentials (MEPs), and silent periods (SPs) in the quadriceps muscles before, during, and after exhaustive isometric exercise. Eleven subjects performed sets of ten 5-s submaximal isometric quadriceps contractions at 40% of maximal voluntary contraction (MVC) strength until task failure. Three different TMS intensities (I100, I75, I50) eliciting MEPs of 53±6%, 38±5% and 25±3% of maximal compound action potential (Mmax) at 20% MVC were used. MEPs and SPs were assessed at both absolute (40% baseline MVC) and relative (50%, 75%, and 100% MVC) force levels. VATMS was assessed with I100 and I75. When measured at absolute force level, MEP/Mmax increased during exercise at I50, decreased at I100 and remained unchanged at I75. No TMS intensity effect was observed at relative force levels. At both absolute and relative force levels, SPs increased at I100 and remained stable at I75 and I50. VATMS assessed at I75 tended to be lower than at I100. TMS intensity affects exercise-induced changes in MEP/Mmax (only when measured at absolute force level), SPs, and VATMS. These results indicate a single TMS intensity assessing maximal voluntary activation and exercise-induced changes in corticomotoneuronal excitability/inhibition may be inappropriate. PMID:26642805

  1. [Wheat dependent exercise induced anaphylaxis possibly sensitized by the hydrolyzed wheat proteins in a facial cleansing soap].

    PubMed

    Kobayashi, Miwa; Okura, Risa; Yoshioka, Haruna; Hiromasa, Kana; Yoshioka, Manabu; Nakamura, Motonobu

    2012-03-01

    There are increasing cases of wheat dependent exercise-induced anaphylaxis (WDEIA) with transcutaneous or transmucosal sensitization. Hydrolyzed wheat included in a certain brand of soap was identified as a cause of sensitization. The useful clues to detect this disorder consist of the patient's past usage of a soap containing hydrolyzed wheat, the appearance of cutaneous or mucosal symptoms after the intake of wheat or washing with this soap, and a high level of specific IgE for wheat gluten. Because hydrolyzed wheat is used as an additive in a wide variety of cosmetics, we should pay careful attention to the ingredients of cosmetics when observing WDEIA. PMID:22428462

  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. PMID:26157720

  3. Alpha-Synuclein Abnormalities in Mouse Models of Peroxisome Biogenesis Disorders

    PubMed Central

    Yakunin, Eugenia; Moser, Ann; Loeb, Virginie; Reisch, Ann Saada; Faust, Phyllis; Crane, Denis I.; Baes, Myriam; Sharon, Ronit

    2009-01-01

    alpha-Synuclein (?S) is a presynaptic protein implicated in Parkinson’s disease (PD). Growing evidence implicates mitochondrial dysfunction, oxidative stress and ?S-lipids interactions in the gradual accumulation of ?S in pathogenic forms and its deposition in Lewy bodies, the pathological hallmark of PD and related synucleinopathies. The peroxisomal biogenesis disorders (PBD), with Zellweger syndrome serving as the prototype of this group, are characterized by malformed and functionally impaired peroxisomes. Here we utilized the PBD mouse models, Pex2-/-, Pex5-/- and Pex13-/-, to study the potential effects of peroxisomal dysfunction on ?S–related pathogenesis. We found increased ?S oligomerization and phosphorylation and its increased deposition in cytoplasmic inclusions in these PBD mouse models. Further, we show that ?S abnormalities correlate with the altered lipid metabolism and specifically, with accumulation of long chain, n-6 polyunsaturated fatty acids, that occurs in the PBD models. PMID:19830841

  4. Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis

    PubMed Central

    Liao, Xudong; Zhang, Rongli; Lu, Yuan; Prosdocimo, Domenick A.; Sangwung, Panjamaporn; Zhang, Lilei; Zhou, Guangjin; Anand, Puneet; Lai, Ling; Leone, Teresa C.; Fujioka, Hisashi; Ye, Fang; Rosca, Mariana G.; Hoppel, Charles L.; Schulze, P. Christian; Abel, E. Dale; Stamler, Jonathan S.; Kelly, Daniel P.; Jain, Mukesh K.

    2015-01-01

    Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac-specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPAR? coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis. PMID:26241060

  5. Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis.

    PubMed

    Liao, Xudong; Zhang, Rongli; Lu, Yuan; Prosdocimo, Domenick A; Sangwung, Panjamaporn; Zhang, Lilei; Zhou, Guangjin; Anand, Puneet; Lai, Ling; Leone, Teresa C; Fujioka, Hisashi; Ye, Fang; Rosca, Mariana G; Hoppel, Charles L; Schulze, P Christian; Abel, E Dale; Stamler, Jonathan S; Kelly, Daniel P; Jain, Mukesh K

    2015-09-01

    Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac-specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPAR? coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis. PMID:26241060

  6. 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

  7. Evolution of the holozoan ribosome biogenesis regulon

    PubMed Central

    Brown, Seth J; Cole, Michael D; Erives, Albert J

    2008-01-01

    Background The ribosome biogenesis (RiBi) genes encode a highly-conserved eukaryotic set of nucleolar proteins involved in rRNA transcription, assembly, processing, and export from the nucleus. While the mode of regulation of this suite of genes has been studied in the yeast, Saccharomyces cerevisiae, how this gene set is coordinately regulated in the larger and more complex metazoan genomes is not understood. Results Here we present genome-wide analyses indicating that a distinct mode of RiBi regulation co-evolved with the E(CG)-binding, Myc:Max bHLH heterodimer complex in a stem-holozoan, the ancestor of both Metazoa and Choanoflagellata, the protozoan group most closely related to animals. These results show that this mode of regulation, characterized by an E(CG)-bearing core-promoter, is specific to almost all of the known genes involved in ribosome biogenesis in these genomes. Interestingly, this holozoan RiBi promoter signature is absent in nematode genomes, which have not only secondarily lost Myc but are marked by invariant cell lineages typically producing small body plans of 1000 somatic cells. Furthermore, a detailed analysis of 10 fungal genomes shows that this holozoan signature in RiBi genes is not found in hemiascomycete fungi, which evolved their own unique regulatory signature for the RiBi regulon. Conclusion These results indicate that a Myc regulon, which is activated in proliferating cells during normal development as well as during tumor progression, has primordial roots in the evolution of an inducible growth regime in a protozoan ancestor of animals. Furthermore, by comparing divergent bHLH repertoires, we conclude that regulation by Myc but not by other bHLH genes is responsible for the evolutionary maintenance of E(CG) sites across the RiBi suite of genes. PMID:18816399

  8. Biogenesis of respiratory cytochromes in bacteria.

    PubMed Central

    Thöny-Meyer, L

    1997-01-01

    Biogenesis of respiratory cytochromes is defined as consisting of the posttranslational processes that are necessary to assemble apoprotein, heme, and sometimes additional cofactors into mature enzyme complexes with electron transfer functions. Different biochemical reactions take place during maturation: (i) targeting of the apoprotein to or through the cytoplasmic membrane to its subcellular destination; (ii) proteolytic processing of precursor forms; (iii) assembly of subunits in the membrane and oligomerization; (iv) translocation and/or modification of heme and covalent or noncovalent binding to the protein moiety; (v) transport, processing, and incorporation of other cofactors; and (vi) folding and stabilization of the protein. These steps are discussed for the maturation of different oxidoreductase complexes, and they are arranged in a linear pathway to best account for experimental findings from studies concerning cytochrome biogenesis. The example of the best-studied case, i.e., maturation of cytochrome c, appears to consist of a pathway that requires at least nine specific genes and more general cellular functions such as protein secretion or the control of the redox state in the periplasm. Covalent attachment of heme appears to be enzyme catalyzed and takes place in the periplasm after translocation of the precursor through the membrane. The genetic characterization and the putative biochemical functions of cytochrome c-specific maturation proteins suggest that they may be organized in a membrane-bound maturase complex. Formation of the multisubunit cytochrome bc, complex and several terminal oxidases of the bo3, bd, aa3, and cbb3 types is discussed in detail, and models for linear maturation pathways are proposed wherever possible. PMID:9293186

  9. Type V secretion: from biogenesis to biotechnology.

    PubMed

    van Ulsen, Peter; Rahman, Sadeeq ur; Jong, Wouter S P; Daleke-Schermerhorn, Maria H; Luirink, Joen

    2014-08-01

    The two membranes of Gram-negative bacteria contain protein machines that have a general function in their assembly. To interact with the extra-cellular milieu, Gram-negatives target proteins to their cell surface and beyond. Many specialized secretion systems have evolved with dedicated translocation machines that either span the entire cell envelope or localize to the outer membrane. The latter act in concert with inner-membrane transport systems (i.e. Sec or Tat). Secretion via the Type V secretion system follows a two-step mechanism that appears relatively simple. Proteins secreted via this pathway are important for the Gram-negative life-style, either as virulence factors for pathogens or by contributing to the survival of non-invasive environmental species. Furthermore, this system appears well suited for the secretion of biotechnologically relevant proteins. In this review we focus on the biogenesis and application of two Type V subtypes, the autotransporters and two-partner secretion (TPS) systems. For translocation across the outer membrane the autotransporters require the assistance of the Bam complex that also plays a generic role in the assembly of outer membrane proteins. The TPS systems do use a dedicated translocator, but this protein shows resemblance to BamA, the major component of the Bam complex. Interestingly, both the mechanistic and more applied studies on these systems have provided a better understanding of the secretion mechanism and the biogenesis of outer membrane proteins. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. PMID:24269841

  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. Fatty Acid Synthase as a Factor Required for Exercise-Induced Cognitive Enhancement and Dentate Gyrus Cellular Proliferation

    PubMed Central

    Chorna, Nataliya E.; Santos-Soto, Iván J.; Carballeira, Nestor M.; Morales, Joan L.; de la Nuez, Janneliz; Cátala-Valentin, Alma; Chornyy, Anatoliy P.; Vázquez-Montes, Adrinel; De Ortiz, Sandra Peña

    2013-01-01

    Voluntary running is a robust inducer of adult hippocampal neurogenesis. Given that fatty acid synthase (FASN), the key enzyme for de novo fatty acid biosynthesis, is critically involved in proliferation of embryonic and adult neural stem cells, we hypothesized that FASN could mediate both exercise-induced cell proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhancement of spatial learning and memory. In 20 week-old male mice, voluntary running-induced hippocampal-specific upregulation of FASN was accompanied also by hippocampal-specific accumulation of palmitate and stearate saturated fatty acids. In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze. Unlike the vehicle-injected mice, the C75 group adopted a non-spatial serial escape strategy and displayed delayed escape latencies during acquisition and memory tests. Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ. Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis. PMID:24223732

  12. The protective effects of a polyphenol-enriched protein powder on exercise-induced susceptibility to virus infection.

    PubMed

    Ahmed, Maryam; Henson, Dru A; Sanderson, Matthew C; Nieman, David C; Gillitt, Nicholas D; Lila, Mary Ann

    2014-12-01

    Prolonged and intensive exercise induces transient immunosuppression and is associated with an increased risk and severity of infections. The goal of this study was to characterize the antiviral and antibacterial properties of the bioactive metabolites of a blueberry-green tea-polyphenol soy protein complex (PSPC) in the serum of supplemented subjects during a 3-day intensified training period. Long-distance runners, randomly divided into two groups, ingested 40?g/day PSPC or placebo (soy protein and colorings) for 17?days, with a 3-day running period inserted at day 14. Blood serum samples were collected pre-14?days and post-14?days supplementation, and immediately and 14?h after the third day of running. The post-exercise serum from both groups significantly promoted the growth of Escherichia coli and Staphylococcus aureus in culture by 20-70%, but returned to normal levels following recovery. Furthermore, the serum from subjects ingesting PSPC did not display antibacterial properties at any time point. In contrast, there was a significant difference in the ability of serum from PSPC-supplemented versus placebo-supplemented athletes to protect cells in culture from killing by vesicular stomatitis virus following strenuous exercise. In addition, the serum of subjects who ingested PSPC significantly delayed an exercise-induced increase in virus replication. These results indicate that polyphenol complexes containing blueberry and green tea have the potential to protect athletes from virus infections following rigorous exercise. PMID:25088029

  13. IHG-1 increases mitochondrial fusion and bioenergetic function.

    PubMed

    Hickey, Fionnuala B; Corcoran, James B; Griffin, Brenda; Bhreathnach, Una; Mortiboys, Heather; Reid, Helen M; Andrews, Darrell; Byrne, Shane; Furlong, Fiona; Martin, Finian; Godson, Catherine; Murphy, Madeline

    2014-12-01

    Induced in high glucose-1 (IHG-1) is a conserved mitochondrial protein associated with diabetic nephropathy (DN) that amplifies profibrotic transforming growth factor (TGF)-?1 signaling and increases mitochondrial biogenesis. Here we report that inhibition of endogenous IHG-1 expression results in reduced mitochondrial respiratory capacity, ATP production, and mitochondrial fusion. Conversely, overexpression of IHG-1 leads to increased mitochondrial fusion and also protects cells from reactive oxygen species-induced apoptosis. IHG-1 forms complexes with known mediators of mitochondrial fusion-mitofusins (Mfns) 1 and 2-and enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as a guanine nucleotide exchange factor. IHG-1 must be localized to mitochondria to interact with Mfn1 and Mfn2, and this interaction is necessary for increased IHG-1-mediated mitochondrial fusion. Together, these findings indicate that IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. We propose that in diabetic kidney disease increased IHG-1 expression protects cell viability and enhances the actions of TGF-?, leading to renal proximal tubule dedifferentiation, an important event in the pathogenesis of this devastating condition. PMID:25008184

  14. Mitochondrial Myopathy

    MedlinePLUS

    ... with ragged-red fibers, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. The symptoms of ... riboflavin, coenzyme Q, and carnitine (a specialized amino acid) may provide subjective improvement in fatigue and energy ...

  15. Mitochondrial DNA.

    ERIC Educational Resources Information Center

    Wright, Russell G.; Bottino, Paul J.

    1986-01-01

    Provides background information for teachers on mitochondrial DNA, pointing out that it may have once been a free-living organism. Includes a ready-to-duplicate exercise titled "Using Microchondrial DNA to Measure Evolutionary Distance." (JN)

  16. Mitochondrial Myopathies

    MedlinePLUS

    ... muscle cells and nerve cells have especially high energy needs, muscular and ease), mitochondrial diseases are so- ... and coordination, sei- eases affect the mitochondria — tiny energy zures and learning deficits — are common factories found ...

  17. Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9.

    PubMed

    Schmitz-Abe, Klaus; Ciesielski, Szymon J; Schmidt, Paul J; Campagna, Dean R; Rahimov, Fedik; Schilke, Brenda A; Cuijpers, Marloes; Rieneck, Klaus; Lausen, Birgitte; Linenberger, Michael L; Sendamarai, Anoop K; Guo, Chaoshe; Hofmann, Inga; Newburger, Peter E; Matthews, Dana; Shimamura, Akiko; Snijders, Pieter J L M; Towne, Meghan C; Niemeyer, Charlotte M; Watson, Henry G; Dziegiel, Morten H; Heeney, Matthew M; May, Alison; Bottomley, Sylvia S; Swinkels, Dorine W; Markianos, Kyriacos; Craig, Elizabeth A; Fleming, Mark D

    2015-12-17

    The congenital sideroblastic anemias (CSAs) are relatively uncommon diseases characterized by defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Here we demonstrate that mutations in HSPA9, a mitochondrial HSP70 homolog located in the chromosome 5q deletion syndrome 5q33 critical deletion interval and involved in mitochondrial Fe-S biogenesis, result in CSA inherited as an autosomal recessive trait. In a fraction of patients with just 1 severe loss-of-function allele, expression of the clinical phenotype is associated with a common coding single nucleotide polymorphism in trans that correlates with reduced messenger RNA expression and results in a pseudodominant pattern of inheritance. PMID:26491070

  18. Application of cytoplasmic Ca2+ fluorescence imaging techniques to study the molecular mechanisms of exercise-induced fatigue eliminated by Chinese medicine ginseng extract

    NASA Astrophysics Data System (ADS)

    Liu, Yi; Zhao, Yanping; Zhang, Heming; Liu, Songhao

    2009-11-01

    The exercise-induced fatigue eliminated by Chinese medicine offers advantages including good efficiency and smaller side-effects, however, the exact mechanisms have not been classified. A lot of literatures indicated the cytosolic free Ca2+ concentrations of skeletal muscle cells increased significantly during exercise-induced fatigue. This study is aimed to establish a rat skeletal muscle cell model of exercise-induced fatigue. We applied cytoplasmic Ca2+ fluorescence imaging techniques to study the molecular mechanisms of exercise-induced fatigue eliminated by Chinese medicine ginseng extract. In our research, the muscle tissues from the newborn 3 days rats were taken out and digested into cells. The cells were randomly divided into the ginseng extract group and the control group. The cells from the two groups were cultured in the medium respectively added 2mg/ml ginseng extract and 2mg/ml D-hanks solution. After differentiating into myotubes, the two groups of cells treated with a fluorescent probe Fluo-3 AM were put on the confocal microscope and the fluorescence intensity of cells pre- and post- stimulation with dexamethasone were detected. It was found that cytoplasmic Ca2+ concentrations of the two groups of cells both increased post-stimulation, however, the increasing amplitude of fluorescence intensity of the ginseng extract group was significantly lower than that of the control group. In conclusion, stimulating the cells with dexamethasone is a kind of workable cell models of exercise-induced fatigue, and the molecular mechanisms of exercise-induced fatigue eliminated by ginseng extract may be connected to regulatating cytosolic free Ca2+ concentrations.

  19. Magnetoencephalography to investigate central perception of exercise-induced breathlessness in people with chronic lung disease: a feasibility pilot

    PubMed Central

    Johnson, Miriam J; Simpson, Michael IG; Currow, David C; Millman, Rebecca E; Hart, Simon P; Green, Gary

    2015-01-01

    Objectives Neuroimaging in chronic breathlessness is challenging. The study objective was to test the feasibility of magnetoencephalography (MEG) for functional neuroimaging of people with chronic breathlessness. Design Feasibility pilot study. Setting Respiratory clinic out-patients. Participants 8 patients (mean age=62; (range 47–83); 4 men) with chronic non-malignant lung disease; modified MRC breathlessness score ?3 (median mMRC=4), intensity of exercise-induced breathlessness >3/10; no contraindication to MRI scanning. Methods and measures 4 MEG scans were conducted for each participant: (1) at rest (5?mins), (2) postseated leg exercise-induced breathlessness during recovery (10?mins). Recovery scans (2) were conducted with/without facial airflow in random order; both scans were repeated 1?h later. Participants rated breathlessness intensity (0–10 Numerical Rating Scale (NRS)) at baseline, maximal exertion and every minute during recovery, and rated acceptability of study procedures at the end of the study (0–10 NRS). A structural MRI scan was conducted for MEG coregistration and source-space analyses. Rest data were compared with data from healthy volunteers (N=6; 5 men; mean age=30.7?years±3.9?years). Results Exercises and MEG scanning were acceptable to all participants; 7/8 completed the MRI scans. Maximum breathlessness intensity was induced by 5?min’ exercise. The same level was induced for repeat scans (median=8; IQR=7–8). All recovered to baseline by 10?min. Time-frequency profiles of data from the first and last 3?min were analysed in MEG source space based on breathlessness location estimates. Source localisation was performed, but anatomical source inference was limited to the level of the lobe. Differences in areas of activity were seen: during recovery scans; with and without airflow; and between participants/normal volunteers at rest. Conclusions MEG is a feasible method to investigate exercise-induced breathlessness in people breathless with chronic lung disease, and able to identify neural activity related to changes in breathlessness. PMID:26063567

  20. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles

    PubMed Central

    Sugiura, Ayumu; McLelland, Gian-Luca; Fon, Edward A; McBride, Heidi M

    2014-01-01

    The last decade has been marked by tremendous progress in our understanding of the cell biology of mitochondria, with the identification of molecules and mechanisms that regulate their fusion, fission, motility, and the architectural transitions within the inner membrane. More importantly, the manipulation of these machineries in tissues has provided links between mitochondrial dynamics and physiology. Indeed, just as the proteins required for fusion and fission were identified, they were quickly linked to both rare and common human diseases. This highlighted the critical importance of this emerging field to medicine, with new hopes of finding drugable targets for numerous pathologies, from neurodegenerative diseases to inflammation and cancer. In the midst of these exciting new discoveries, an unexpected new aspect of mitochondrial cell biology has been uncovered; the generation of small vesicular carriers that transport mitochondrial proteins and lipids to other intracellular organelles. These mitochondrial-derived vesicles (MDVs) were first found to transport a mitochondrial outer membrane protein MAPL to a subpopulation of peroxisomes. However, other MDVs did not target peroxisomes and instead fused with the late endosome, or multivesicular body. The Parkinson's disease-associated proteins Vps35, Parkin, and PINK1 are involved in the biogenesis of a subset of these MDVs, linking this novel trafficking pathway to human disease. In this review, we outline what has been learned about the mechanisms and functional importance of MDV transport and speculate on the greater impact of these pathways in cellular physiology. PMID:25107473

  1. 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

  2. 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

  3. 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.

  4. Ribosome Biogenesis in the Yeast Saccharomyces cerevisiae

    PubMed Central

    Woolford, John L.; Baserga, Susan J.

    2013-01-01

    Ribosomes are highly conserved ribonucleoprotein nanomachines that translate information in the genome to create the proteome in all cells. In yeast these complex particles contain four RNAs (>5400 nucleotides) and 79 different proteins. During the past 25 years, studies in yeast have led the way to understanding how these molecules are assembled into ribosomes in vivo. Assembly begins with transcription of ribosomal RNA in the nucleolus, where the RNA then undergoes complex pathways of folding, coupled with nucleotide modification, removal of spacer sequences, and binding to ribosomal proteins. More than 200 assembly factors and 76 small nucleolar RNAs transiently associate with assembling ribosomes, to enable their accurate and efficient construction. Following export of preribosomes from the nucleus to the cytoplasm, they undergo final stages of maturation before entering the pool of functioning ribosomes. Elaborate mechanisms exist to monitor the formation of correct structural and functional neighborhoods within ribosomes and to destroy preribosomes that fail to assemble properly. Studies of yeast ribosome biogenesis provide useful models for ribosomopathies, diseases in humans that result from failure to properly assemble ribosomes. PMID:24190922

  5. Mechanistic aspects of GFP chromophore biogenesis

    NASA Astrophysics Data System (ADS)

    Wachter, Rebekka M.

    2006-02-01

    We have investigated the autocatalytic mechanism of green fluorescent protein (GFP) maturation. To this end, we have used techniques such as site-directed mutagenesis, X-ray crystallography and in vitro kinetics, and have monitored the reaction by fluorescence, HPLC and MALDI (matrix-assisted laser desorption ionization) mass spectrometry. In summary, we find that chromophore formation, which generally occurs within 40 to 60 min, can be accelerated dramatically under some conditions. In the E222Q variant, the rate-limiting process appears to be a function of slow proton transfer steps. Other mutagenesis data indicate that chromophore biogenesis is not driven by the aromatic character of residue 66. The GFP self-modification process involves a rate-limiting oxidation reaction that results in the production of H IIO II. The data are most consistent with a reaction mechanism that proceeds via cyclization-oxidation-dehydration during in vitro maturation under aerobic conditions. The ejection of water from the heterocycle that is formed from main chain protein atoms appears to depend on the degree of ?-overlap of the five-membered ring with the side chain adduct.

  6. Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers

    SciTech Connect

    Fleg, J.L.; Gerstenblith, G.; Zonderman, A.B.; Becker, L.C.; Weisfeldt, M.L.; Costa, P.T. Jr.; Lakatta, E.G. )

    1990-02-01

    Although a silent ischemic electrocardiographic response to treadmill exercise in clinically healthy populations is associated with an increased likelihood of future coronary events (i.e., angina pectoris, myocardial infarction, or cardiac death), such a response has a low predictive value for future events because of the low prevalence of disease in asymptomatic populations. To examine whether detection of reduced regional perfusion by thallium scintigraphy improved the predictive value of exercise-induced ST segment depression, we performed maximal treadmill exercise electrocardiography (ECG) and thallium scintigraphy (201Tl) in 407 asymptomatic volunteers 40-96 years of age (mean = 60) from the Baltimore Longitudinal Study on Aging. The prevalence of exercise-induced silent ischemia, defined by concordant ST segment depression and a thallium perfusion defect, increased more than sevenfold from 2% in the fifth and sixth decades to 15% in the ninth decade. Over a mean follow-up period of 4.6 years, cardiac events developed in 9.8% of subjects and consisted of 20 cases of new angina pectoris, 13 myocardial infarctions, and seven deaths. Events occurred in 7% of individuals with both negative 201Tl and ECG, 8% of those with either test positive, and 48% of those in whom both tests were positive (p less than 0.001). By proportional hazards analysis, age, hypertension, exercise duration, and a concordant positive ECG and 201Tl result were independent predictors of coronary events. Furthermore, those with positive ECG and 201Tl had a 3.6-fold relative risk for subsequent coronary events, independent of conventional risk factors.

  7. Impact of Percutaneous Coronary Intervention on Exercise-Induced Repolarization Changes in Patients With Stable Coronary Artery Disease.

    PubMed

    Juki?, Anita; Carevi?, Vedran; Zekanovi?, Dražen; Stojanovi?-Stipi?, Sanda; Runji?, Frane; Ljubkovi?, Marko; Fabijani?, Damir

    2015-09-15

    Recent reports suggest T peak to T end (Tpe) interval and Tpe/QT ratio as valuable indicators of increased arrhythmogenic risk in patients with coronary artery disease (CAD). We aimed to examine the exercise-induced changes in these indexes in patients with stable CAD, before and after percutaneous coronary intervention (PCI). Forty patients were consecutively included in the interventional group (n = 20), with significant lesions (?75% luminal narrowing) suitable for PCI and in the control group (n = 20), with no significant coronary artery lesions (<50% luminal narrowing). One day before and 30 days after the coronarography, all patients performed treadmill exercise stress testing, and the electrocardiographic (ECG) indexes of repolarization were assessed during baseline and at peak exercise intensity. In the control group, the QT interval, QTc (QT-corrected) interval, Tpe interval, and Tpe/QT ratio measured at peak exercise significantly decreased from baseline values (p = 0.001, p = 0.004, p <0.001, and p = 0.017, respectively). Conversely, in interventional patients before the PCI, an increase in the Tpe interval and the Tpe/QT ratio was observed at exercise (p = 0.009, and p <0.001, respectively), with only the QT interval exhibiting a significant decrease from baseline (p <0.001). Thirty days after the PCI, all the ECG arrhythmogenic indexes measured at peak exercise significantly decreased from baseline values, thus assuming the same trend as detected in controls. In conclusion, restoration of blood supply normalized exercise-induced repolarization changes, suggesting that revascularization of previously ischemic myocardium lowers the cardiac arrhythmogenic potential in patients with stable CAD. PMID:26174604

  8. The impact of a cold pressor test on brachial artery handgrip exercise-induced flow-mediated dilation.

    PubMed

    Stuckless, Troy J R; Pyke, Kyra E

    2015-10-01

    It is unknown how endothelial-dependent flow-mediated dilation (FMD) stimulated by a sustained, exercise-induced increase in shear stress (EX-FMD) is affected by a simultaneous sympathoexcitatory painful stimulus. The purpose of this study was to examine the impact of a cold pressor test (CPT) on brachial artery EX-FMD elicited by a handgrip exercise-induced increase in shear stress. Participants were healthy males (age 21±2 years) (n=28; 16 Experimental group, 12 Control). Brachial artery diameter and blood velocity were measured using echo and Doppler ultrasound, respectively. Shear stress was estimated by shear rate (shear rate = blood velocity / diameter) and targeted to reach 75 s(-1) in each of two EX-FMD trials in all subjects. In the Experimental group, the second EX-FMD trial was accompanied by simultaneous foot immersion in ice water (simultaneous CPT). The shear rate stimulus did not differ between groups (p=0.823) or trials (p=0.726) (group × trial interaction: p=0.646) (average exercise shear rate (mean ± SD): 67.6±6.2 s(-1)). The CPT (experienced during EX-FMD trial 2 in the Experimental group) increased mean arterial pressure (p<0.001) and heart rate (p=0.002) relative to the Control group. %EX-FMD was not different between groups (p=0.508) or trials (p=0.592) (group × trial interaction: p=0.879) (EX-FMD: Experimental group trial 1: 5.4±3.4%, trial 2: 5.6±2.6%; Control group trial 1: 6.0±3.7%, trial 2: 6.4±2.2%). In conclusion, the CPT did not impact concurrent EX-FMD, and this indicates that an acute painful stimulus does not interfere with conduit artery FMD responses during exercise in young healthy men. PMID:26021703

  9. Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'.

    PubMed

    Raichlen, David A; Foster, Adam D; Gerdeman, Gregory L; Seillier, Alexandre; Giuffrida, Andrea

    2012-04-15

    Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. Endocannabinoids (eCBs) are endogenous neurotransmitters that appear to play a major role in generating these rewards by activating cannabinoid receptors in brain reward regions during and after exercise. Other species also regularly engage in endurance exercise (cursorial mammals), and as humans share many morphological traits with these taxa, it is possible that exercise-induced eCB signaling motivates habitual high-intensity locomotor behaviors in cursorial mammals. If true, then neurobiological rewards may explain variation in habitual locomotor activity and performance across mammals. We measured circulating eCBs in humans, dogs (a cursorial mammal) and ferrets (a non-cursorial mammal) before and after treadmill exercise to test the hypothesis that neurobiological rewards are linked to high-intensity exercise in cursorial mammals. We show that humans and dogs share significantly increased exercise-induced eCB signaling following high-intensity endurance running. eCB signaling does not significantly increase following low-intensity walking in these taxa, and eCB signaling does not significantly increase in the non-cursorial ferrets following exercise at any intensity. This study provides the first evidence that inter-specific variation in neurotransmitter signaling may explain differences in locomotor behavior among mammals. Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks, and why non-cursorial mammals avoid such locomotor behaviors. PMID:22442371

  10. 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...

  11. Efficacy of whey protein supplementation on resistance exercise-induced changes in muscle strength, lean mass, and function in mobility-limited older adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Whey protein supplementation may augment resistance exercise-induced increases in muscle strength and mass. Further studies are required to determine whether this effect extends to functionally compromised older adults. The objectives of the study were to compare the effects of whey protein concent...

  12. Mitochondria. Cell cycle-dependent regulation of mitochondrial preprotein translocase.

    PubMed

    Harbauer, Angelika B; Opali?ska, Magdalena; Gerbeth, Carolin; Herman, Josip S; Rao, Sanjana; Schönfisch, Birgit; Guiard, Bernard; Schmidt, Oliver; Pfanner, Nikolaus; Meisinger, Chris

    2014-11-28

    Mitochondria play central roles in cellular energy conversion, metabolism, and apoptosis. Mitochondria import more than 1000 different proteins from the cytosol. It is unknown if the mitochondrial protein import machinery is connected to the cell division cycle. We found that the cyclin-dependent kinase Cdk1 stimulated assembly of the main mitochondrial entry gate, the translocase of the outer membrane (TOM), in mitosis. The molecular mechanism involved phosphorylation of the cytosolic precursor of Tom6 by cyclin Clb3-activated Cdk1, leading to enhanced import of Tom6 into mitochondria. Tom6 phosphorylation promoted assembly of the protein import channel Tom40 and import of fusion proteins, thus stimulating the respiratory activity of mitochondria in mitosis. Tom6 phosphorylation provides a direct means for regulating mitochondrial biogenesis and activity in a cell cycle-specific manner. PMID:25378463

  13. Mitochondrial emitted electromagnetic signals mediate retrograde signaling.

    PubMed

    Bagkos, Georgios; Koufopoulos, Kostas; Piperi, Christina

    2015-12-01

    Recent evidence shows that mitochondria regulate nuclear transcriptional activity both in normal and cell stress conditions, known as retrograde signaling. Under normal mitochondrial function, retrograde signaling is associated with mitochondrial biogenesis, normal cell phenotype and metabolic profile. In contrast, mitochondrial dysfunction leads to abnormal (oncogenic) cell phenotype and altered bio-energetic profile (nucleus reprogramming). Despite intense research efforts, a concrete mechanism through which mitochondria determine the group of genes expressed by the nucleus is still missing. The present paper proposes a novel hypothesis regarding retrograde signaling. More specifically, it reveals the mitochondrial membrane potential (MMP) and the accompanied strong electromagnetic field (EF) as key regulatory factors of nuclear activity. Mitochondrial emitted EFs extend in long distance and affect the function of nuclear membrane receptors. Depending on their frequencies, EFs can directly activate or deactivate different groups of nuclear receptors and so determine nuclear gene expression. One of the key features of the above hypothesis is that nuclear membrane receptors, besides their own endogenous or chemical ligands (hormones, lipids, etc.), can also be activated by electromagnetic signals. Moreover, normal MMP values (about -140mV) are associated with the production of high ATP quantities and small levels of reactive oxygen species (ROS) while the hyperpolarization observed in all cancer cell types leads to a dramatic fall in ATP production and an analogous increase in ROS. The diminished ATP and increased ROS production negatively affect the function of all cellular systems including nucleus. Restoration of mitochondrial function, which is characterized by the fluctuation of MMP and EF values within a certain (normal) range, is proposed as a necessary condition for normal nuclear function and cancer therapy. PMID:26474928

  14. Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration.

    PubMed

    Fourcade, Stéphane; Ferrer, Isidre; Pujol, Aurora

    2015-11-01

    Peroxisomal and mitochondrial malfunction, which are highly intertwined through redox regulation, in combination with defective proteostasis, are hallmarks of the most prevalent multifactorial neurodegenerative diseases-including Alzheimer's (AD) and Parkinson's disease (PD)-and of the aging process, and are also found in inherited conditions. Here we review the interplay between oxidative stress and axonal degeneration, taking as groundwork recent findings on pathomechanisms of the peroxisomal neurometabolic disease adrenoleukodystrophy (X-ALD). We explore the impact of chronic redox imbalance caused by the excess of very long-chain fatty acids (VLCFA) on mitochondrial respiration and biogenesis, and discuss how this impairs protein quality control mechanisms essential for neural cell survival, such as the proteasome and autophagy systems. As consequence, prime molecular targets in the pathogenetic cascade emerge, such as the SIRT1/PGC-1? axis of mitochondrial biogenesis, and the inhibitor of autophagy mTOR. Thus, we propose that mitochondria-targeted antioxidants; mitochondrial biogenesis boosters such as the antidiabetic pioglitazone and the SIRT1 ligand resveratrol; and the autophagy activator temsirolimus, a derivative of the mTOR inhibitor rapamycin, hold promise as disease-modifying therapies for X-ALD. PMID:26073123

  15. 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

  16. Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle.

    PubMed

    Drake, Joshua C; Wilson, Rebecca J; Yan, Zhen

    2016-01-01

    Exercise training enhances physical performance and confers health benefits, largely through adaptations in skeletal muscle. Mitochondrial adaptation, encompassing coordinated improvements in quantity (content) and quality (structure and function), is increasingly recognized as a key factor in the beneficial outcomes of exercise training. Exercise training has long been known to promote mitochondrial biogenesis, but recent work has demonstrated that it has a profound impact on mitochondrial dynamics (fusion and fission) and clearance (mitophagy), as well. In this review, we discuss the various mechanisms through which exercise training promotes mitochondrial quantity and quality in skeletal muscle.-Drake, J. C., Wilson, R. J., Yan, Z. Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle. PMID:26370848

  17. Polar Flagellum Biogenesis in Aeromonas hydrophila

    PubMed Central

    Canals, Rocío; Ramirez, Silvia; Vilches, Silvia; Horsburgh, Gavin; Shaw, Jonathan G.; Tomás, Juan M.; Merino, Susana

    2006-01-01

    Mesophilic Aeromonas spp. constitutively express a single polar flagellum that helps the bacteria move to more favorable environments and is an important virulence and colonization factor. Certain strains can also produce multiple lateral flagella in semisolid media or over surfaces. We have previously reported 16 genes (flgN to flgL) that constitute region 1 of the Aeromonas hydrophila AH-3 polar flagellum biogenesis gene clusters. We identified 39 new polar flagellum genes distributed in four noncontiguous chromosome regions (regions 2 to 5). Region 2 contained six genes (flaA to maf-1), including a modification accessory factor gene (maf-1) that has not been previously reported and is thought to be involved in glycosylation of polar flagellum filament. Region 3 contained 29 genes (fliE to orf29), most of which are involved in flagellum basal body formation and chemotaxis. Region 4 contained a single gene involved in the motor stator formation (motX), and region 5 contained the three master regulatory genes for the A. hydrophila polar flagella (flrA to flrC). Mutations in the flaH, maf-1, fliM, flhA, fliA, and flrC genes, as well as the double mutant flaA flaB, all caused loss of polar flagella and reduction in adherence and biofilm formation. A defined mutation in the pomB stator gene did not affect polar flagellum motility, in contrast to the motX mutant, which was unable to swim even though it expressed a polar flagellum. Mutations in all of these genes did not affect lateral flagellum synthesis or swarming motility, showing that both A. hydrophila flagellum systems are entirely distinct. PMID:16385045

  18. What can rapid terrestrial biogenesis tell us about life in the universe?

    E-print Network

    Charles H. Lineweaver; Tamara M. Davis

    2002-09-19

    It is sometimes asserted that the rapidity of biogenesis on Earth suggests that life is common in the Universe. We critically examine the assumptions inherent in this argument. Using a lottery model for biogenesis in the Universe, we convert the observational constraints on the rapidity of biogenesis on Earth into constraints on the probability of biogenesis on other terrestrial planets. For example, if terrestrial biogenesis took less than 200 Myr (and we assume that it could have taken 1 billion years) then we find the probability of biogenesis on terrestrial planets older than ~ 1 Gyr, is > 36% at the 95% confidence level. However, there are assumptions and selection effects that complicate this result: although we correct the analysis for the fact that biogenesis is a prerequisite for our existence, our result depends on the plausible assumption that rapid biogenesis is not such a prerequisite.

  19. A Role for IOP1 in Mammalian Cytosolic Iron-Sulfur Protein Biogenesis*S?

    PubMed Central

    Song, Daisheng; Lee, Frank S.

    2008-01-01

    The biogenesis of cytosolic iron-sulfur (Fe-S) proteins in mammalian cells is poorly understood. In Saccharomyces cerevisiae, there is a pathway dedicated to cytosolic Fe-S protein maturation that involves several essential proteins. One of these is Nar1, which intriguingly is homologous to iron-only hydrogenases, ancient enzymes that catalyze the formation of hydrogen gas in anaerobic bacteria. There are two orthologues of Nar1 in mammalian cells, iron-only hydrogenase-like protein 1 (IOP1) and IOP2 (also known as nuclear prelamin A recognition factor). We examined IOP1 for a potential role in mammalian cytosolic Fe-S protein biogenesis. We found that knockdown of IOP1 in both HeLa and Hep3B cells decreases the activity of cytosolic aconitase, an Fe-S protein, but not that of mitochondrial aconitase. Knockdown of IOP2, in contrast, had no effect on either. The decrease in aconitase activity upon IOP1 knockdown is rescued by expression of a small interference RNA-resistant version of IOP1. Upon loss of its Fe-S cluster, cytosolic aconitase is known to be converted to iron regulatory protein 1, and consistent with this, we found that IOP1 knockdown increases transferrin receptor 1 mRNA levels and decreases ferritin heavy chain protein levels. IOP1 knockdown also leads to a decrease in activity of xanthine oxidase, a distinct cytosolic Fe-S protein. Taken together, these results provide evidence that IOP1 is involved in mammalian cytosolic Fe-S protein maturation. PMID:18270200

  20. Chemical modulators of ribosome biogenesis as biological probes.

    PubMed

    Stokes, Jonathan M; Brown, Eric D

    2015-12-01

    Small-molecule inhibitors of protein biosynthesis have been instrumental in the dissection of the complexities of ribosome structure and function. Ribosome biogenesis, on the other hand, is a complex and largely enigmatic process for which there is a paucity of chemical probes. Indeed, ribosome biogenesis has been studied almost exclusively using genetic and biochemical approaches without the benefit of small-molecule inhibitors of this process. Here, we provide a perspective on the promise of chemical inhibitors of ribosome assembly for future research. We explore key obstacles that complicate the interpretation of studies aimed at perturbing ribosome biogenesis in vivo using genetic methods, and we argue that chemical inhibitors are especially powerful because they can be used to induce perturbations in a manner that obviates these difficulties. Thus, in combination with leading-edge biochemical and structural methods, chemical probes offer unique advantages toward elucidating the molecular events that define the assembly of ribosomes. PMID:26575239

  1. Biogenesis of mitochondria in cauliflower (Brassica oleracea var. botrytis) curds subjected to temperature stress and recovery involves regulation of the complexome, respiratory chain activity, organellar translation and ultrastructure.

    PubMed

    Rurek, Michal; Woyda-Ploszczyca, Andrzej M; Jarmuszkiewicz, Wieslawa

    2015-01-01

    The biogenesis of the cauliflower curd mitochondrial proteome was investigated under cold, heat and the recovery. For the first time, two dimensional fluorescence difference gel electrophoresis was used to study the plant mitochondrial complexome in heat and heat recovery. Particularly, changes in the complex I and complex III subunits and import proteins, and the partial disintegration of matrix complexes were observed. The presence of unassembled subunits of ATP synthase was accompanied by impairment in mitochondrial translation of its subunit. In cold and heat, the transcription profiles of mitochondrial genes were uncorrelated. The in-gel activities of respiratory complexes were particularly affected after stress recovery. Despite a general stability of respiratory chain complexes in heat, functional studies showed that their activity and the ATP synthesis yield were affected. Contrary to cold stress, heat stress resulted in a reduced efficiency of oxidative phosphorylation likely due to changes in alternative oxidase (AOX) activity. Stress and stress recovery differently modulated the protein level and activity of AOX. Heat stress induced an increase in AOX activity and protein level, and AOX1a and AOX1d transcript level, while heat recovery reversed the AOX protein and activity changes. Conversely, cold stress led to a decrease in AOX activity (and protein level), which was reversed after cold recovery. Thus, cauliflower AOX is only induced by heat stress. In heat, contrary to the AOX activity, the activity of rotenone-insensitive internal NADH dehydrogenase was diminished. The relevance of various steps of plant mitochondrial biogenesis to temperature stress response and recovery is discussed. PMID:25617518

  2. Mitochondrial quality control, promoted by PGC-1?, is dysregulated by Western diet-induced obesity and partially restored by moderate physical activity in mice

    PubMed Central

    Greene, Nicholas P; Lee, David E; Brown, Jacob L; Rosa, Megan E; Brown, Lemuel A; Perry, Richard A; Henry, Jordyn N; Washington, Tyrone A

    2015-01-01

    Skeletal muscle mitochondrial degeneration is a hallmark of insulin resistance/obesity marked by lost function, enhanced ROS emission, and altered morphology which may be ameliorated by physical activity (PA). However, no prior report has examined mitochondrial quality control regulation throughout biogenesis, fusion/fission dynamics, autophagy, and mitochondrial permeability transition pore (MPTP) in obesity. Therefore, we determined how each process is impacted by Western diet (WD)-induced obesity and whether voluntary PA may alleviate derangements in mitochondrial quality control mechanisms. Despite greater mitochondrial content following WD (COX-IV and Cytochrome C), induction of biogenesis controllers appears impaired (failed induction of PGC-1?). Mitochondrial fusion seems diminished (reduced MFN2, Opa1 proteins), with no significant changes in fission, suggesting a shift in balance of dynamics regulation favoring fission. Autophagy flux was promoted in WD (reduced p62, increased LC3II:I ratio); however, mitophagy marker BNIP3 is reduced in WD which may indicate reduced mitophagy despite enhanced total autophagy flux. MPTP regulator Ant mRNA is reduced by WD. Few processes were impacted by physical activity. Finally, mitochondrial quality control processes are partially promoted by PGC-1?, as PGC-1? transgenic mice display elevated mitochondrial biogenesis and autophagy flux. Additionally, these mice exhibit elevated Mfn1 and Opa1 mRNA, with no change in protein content suggesting these factors are transcriptionally promoted by PGC-1? overexpression. These data demonstrate dysfunctions across mitochondrial quality control in obesity and that PGC-1? is sufficient to promote multiple, but not necessarily all, aspects of mitochondrial quality control. Mitochondrial quality control may therefore be an opportune target to therapeutically treat metabolic disease. PMID:26177961

  3. Fly piRNA biogenesis: tap dancing with Tej.

    PubMed

    Yang, Zhaolin; Pillai, Ramesh S

    2014-01-01

    Piwi-interacting RNAs (piRNAs) protect animal germlines from the deleterious effects of transposon activity. Unlike other small RNA classes like microRNAs (miRNAs) and small interfering RNAs (siRNAs), an exceptionally large number of factors are implicated in the biogenesis of piRNAs. Kai et al. have now added another one to this growing list, which we discuss in the overall context of our current knowledge of the piRNA biogenesis pathway in the Drosophila ovarian germline. See research article: http://www.biomedcentral.com/1741-7007/12/61. PMID:25335561

  4. Dietary restriction, mitochondrial function and aging: from yeast to humans.

    PubMed

    Ruetenik, Andrea; Barrientos, Antoni

    2015-11-01

    Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on health-span and lifespan. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. PMID:25979234

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

    PubMed Central

    2010-01-01

    Background The purpose of this investigation was to determine the effects of a dietary supplement (Ambrotose AO®) on resting and exercise-induced blood antioxidant capacity and oxidative stress in exercise-trained and untrained men and women. Methods 25 individuals (7 trained and 5 untrained men; 7 trained and 6 untrained women) received Ambrotose AO® (4 capsules per day = 2 grams per day) or a placebo for 3 weeks in a random order, double blind cross-over design (with a 3 week washout period). Blood samples were collected at rest, and at 0 and 30 minutes following a graded exercise treadmill test (GXT) performed to exhaustion, both before and after each 3 week supplementation period. Samples were analyzed for Trolox Equivalent Antioxidant Capacity (TEAC), Oxygen Radical Absorbance Capacity (ORAC), malondialdehyde (MDA), hydrogen peroxide (H2O2), and nitrate/nitrite (NOx). Quality of life was assessed using the SF-12 form and exercise time to exhaustion was recorded. Resting blood samples were analyzed for complete blood count (CBC), metabolic panel, and lipid panel before and after each 3 week supplementation period. Dietary intake during the week before each exercise test was recorded. Results No condition effects were noted for SF-12 data, for GXT time to exhaustion, or for any variable within the CBC, metabolic panel, or lipid panel (p > 0.05). Treatment with Ambrotose AO® resulted in an increase in resting levels of TEAC (p = 0.02) and ORAC (p < 0.0001). No significant change was noted in resting levels of MDA, H2O2, or NOx (p > 0.05). Exercise resulted in an acute increase in TEAC, MDA, and H2O2 (p < 0.05), all which were higher at 0 minutes post exercise compared to pre exercise (p < 0.05). No condition effects were noted for exercise related data (p > 0.05), with the exception of ORAC (p = 0.0005) which was greater at 30 minutes post exercise for Ambrotose AO® compared to placebo. Conclusion Ambrotose AO® at a daily dosage of 4 capsules per day increases resting blood antioxidant capacity and may enhance post exercise antioxidant capacity. However, no statistically detected difference is observed in resting or exercise-induced oxidative stress biomarkers, in quality of life, or in GXT time to exhaustion. PMID:21040582

  6. Examination of mechanisms (E-MECHANIC) of exercise-induced weight compensation: study protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background Weight loss induced only by exercise is frequently less than expected, possibly because of compensatory changes in energy intake and/or energy expenditure. The purpose of the Examination of Mechanisms (E-MECHANIC) of Exercise-Induced Weight Compensation trial is to examine whether increased energy intake and/or reduced spontaneous activity or energy expenditure (outside of structured exercise) account for the less than expected, exercise-associated weight loss. Methods/Design E-MECHANIC is a three-arm, 6-month randomized (1:1:1) controlled trial. The two intervention arms are exercise doses that reflect current recommendations for (1) general health (8 kcal/kg body weight per week (8 KKW), about 900 kcal/wk) and (2) weight loss (20 KKW, about 2,250 kcal/wk). The third arm, a nonexercise control group, will receive health information only. The sample will include a combined total of 198sedentary, overweight or obese (body mass index: ?25 kg/m2 to ?45 kg/m2) men and women ages 18 to 65 years. The exercise dose will be supervised and tightly controlled in an exercise training laboratory. The primary outcome variables are energy intake, which will be measured using doubly labeled water (adjusted for change in energy stores) and laboratory-based food intake tests, and the discrepancy between expected weight loss and observed weight loss. Secondary outcomes include changes in resting metabolic rate (adjusted for change in body mass), activity levels (excluding structured exercise) and body composition. In an effort to guide the development of future interventions, the participants will be behaviorally phenotyped and defined as those who do compensate (that is, fail to lose the amount of weight expected) or do not compensate (that is, lose the amount of weight expected or more). Discussion In this study, we will attempt to identify underlying mechanisms to explain why exercise elicits less weight loss than expected. This information will guide the development of interventions to increase exercise-induced weight loss and maximize weight loss retention and related health benefits. Trial registration ClinicalTrials.gov ID: NCT01264406 (registration date: 20 December 2010). PMID:24906459

  7. Influence of pre-exercise muscle glycogen content on exercise-induced transcriptional regulation of metabolic genes

    PubMed Central

    Pilegaard, Henriette; Keller, Charlotte; Steensberg, Adam; Wulff Helge, Jørn; Klarlund Pedersen, Bente; Saltin, Bengt; Neufer, P Darrell

    2002-01-01

    Transcription of metabolic genes is transiently induced during recovery from exercise in skeletal muscle of humans. To determine whether pre-exercise muscle glycogen content influences the magnitude and/or duration of this adaptive response, six male subjects performed one-legged cycling exercise to lower muscle glycogen content in one leg and then, the following day, completed 2.5 h low intensity two-legged cycling exercise. Nuclei and mRNA were isolated from biopsies obtained from the vastus lateralis muscle of the control and reduced glycogen (pre-exercise glycogen = 609 ± 47 and 337 ± 33 mmol kg?1 dry weight, respectively) legs before and after 0, 2 and 5 h of recovery. Exercise induced a significant (P < 0.05) increase (2- to 3-fold) in transcription of the pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) genes in the reduced glycogen leg only. Although PDK4, lipoprotein lipase (LPL) and hexokinase II (HKII) mRNA were elevated in the reduced glycogen leg before exercise, no consistent difference was found between the two legs in response to exercise. In a second study, six subjects completed two trials (separated by 2 weeks) consisting of 3 h of two-legged knee extensor exercise with either control (398 ± 52 mmol kg?1 dry weight) or low (240 ± 38 mmol kg?1 dry weight) pre-exercise muscle glycogen. Exercise induced a significantly greater increase in PDK4 transcription in the low glycogen (> 6-fold) than in the control (< 3-fold) trial. Induction of PDK4 and UCP3 mRNA in response to exercise was also signficantly higher in the low glycogen (11.4- and 3.5-fold, respectively) than in the control (5.0- and 1.7-fold, respectively) trial. These data indicate that low muscle glycogen content enhances the transcriptional activation of some metabolic genes in response to exercise, raising the possibility that signalling mechanisms sensitive to glycogen content and/or FFA availability may be linked to the transcriptional control of exercise-responsive genes. PMID:12015434

  8. Exercise-induced changes in hippocampal brain-derived neurotrophic factor and neurotrophin-3: effects of rat strain.

    PubMed

    Johnson, Rebecca A; Mitchell, Gordon S

    2003-09-01

    We tested the hypothesis that exercise-induced changes in hippocampal brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) differ among rat strains exhibiting a range of voluntary wheel running activity. Four strains (Sprague-Dawley, Brown Norway, Dark Agouti and PVG) were given access to running wheels (1 or 7 nights). Over 7 nights, the average distance run per night was higher in PVG versus other strains, and higher in Brown Norway versus Sprague-Dawley rats. Hippocampal BDNF concentrations in sedentary rats were higher in PVG versus Sprague-Dawley rats. When data from all strains were combined, BDNF levels increased with 7 nights of wheel running and were positively correlated to the previous night distance run. Sedentary hippocampal NT-3 levels were not different between rat strains, but decreased with 7 nights of wheel access; NT-3 was negatively correlated with previous night distance run. There were no differences between strains in the correlation between distance run and BDNF or NT-3 levels. Although exercise decreases hippocampal NT-3, strain does not alter NT-3 levels. In contrast, BDNF levels increase with exercise and basal levels differ between strains, possibly due to strain differences in spontaneous activity. PMID:12914971

  9. Increased uptake of 18F-fluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina

    SciTech Connect

    Camici, P.; Araujo, L.I.; Spinks, T.; Lammertsma, A.A.; Kaski, J.C.; Shea, M.J.; Selwyn, A.P.; Jones, T.; Maseri, A.

    1986-07-01

    Regional myocardial perfusion and exogenous glucose uptake were assessed with rubidium-82 (82Rb) and 18F-2-fluoro-2-deoxyglucose (FDG) in 10 normal volunteers and 12 patients with coronary artery disease and stable angina pectoris by means of positron emission tomography. In patients at rest, the myocardial uptake of /sup 82/Rb and FDG did not differ significantly from that measured in normal subjects. The exercise test performed within the positron camera in eight patients produced typical chest pain and ischemic electrocardiographic changes in all. In each of the eight patients a region of reduced cation uptake was demonstrated in the /sup 82/Rb scan recorded at peak exercise, after which uptake of /sup 82/Rb returned to the control value 5 to 14 min after the end of the exercise. In these patients, FDG was injected in the recovery phase when all the variables that were altered during exercise, including regional myocardial /sup 82/Rb uptake, had returned to control values. In all but one patient, FDG accumulation in the regions of reduced /sup 82/Rb uptake during exercise was significantly higher than that in the nonischemic regions, i.e., the ones with a normal increment of /sup 82/Rb uptake on exercise. In the nonischemic areas, FDG uptake was not significantly different from that found in normal subjects after exercise. In conclusion, myocardial glucose transport and phosphorylation seem to be enhanced in the postischemic myocardium of patients with exercise-induced ischemia.

  10. 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

  11. Urinary myoglobin quantification by high-performance liquid chromatography: An alternative measurement for exercise-induced muscle damage.

    PubMed

    Lindsay, Angus; Carr, Sam; Draper, Nick; Gieseg, Steven P

    2015-12-15

    This study investigated a means of quantifying urinary myoglobin using a novel reverse-phase high-performance liquid chromatography (RP-HPLC) method that is an alternative measure of exercise-induced muscle damage. It also investigated the effect of storage and alkalization on urinary myoglobin stability issues. An RP-HPLC method was validated by precision and repeatability experiments. Myoglobin stability was determined through spiked urine samples stored at various temperatures over an 8-week period using alkalization and dilution in a pH 7.0 buffer. The method was validated with urine collected from mixed martial arts fighters during a competition and training session. The method produced linearity from 5 to 1000 ?g/ml (R(2) = 0.997), intra- and inter-assay coefficients of variation from 0.32 to 2.94%, and a lower detection limit of 0.2 ?g/ml in the final dilution and 2 ?g/ml in the original urine sample. Recovery ranged from 96.4 to 102.5%, myoglobin remained stable at 4 °C when diluted in a pH 7.0 buffer after 20 h, and a significant increase (P < 0.01) and an identifiable peak were observed following a mixed martial arts contest and training session. Storage length and conditions had significant effects (P < 0.05) on stability. The method's simplicity and noninvasive nature means it can be used as an alternative muscle damage assay following exercise and trauma. PMID:26363103

  12. Metallothionein induction in rat liver by dietary restriction or exercise and reduction of exercise-induced hepatic lipid peroxidation.

    PubMed

    Shinogi, M; Sakaridani, M; Yokoyama, I

    1999-02-01

    Metallothioneins (MTs) occur throughout the animal kingdom and they are induced in vivo by metals, hormones, cytotoxic agents, and some kind of stress. It is well known that various stresses such as starvation and immobilization can induce MT synthesis in animal tissues, but the influence of dietary restriction is unknown. The MT levels in the liver increased by food-deprivation and then decreased by refeeding, and a long period of starvation down-alters hepatic MT levels. When the stress is intensified, the induced quantity of hepatic MT is reduced. It became clear that hepatic MT concentrations are controlled within a two fold limit when stressed by dietary restriction. MT was also induced in rat liver at recovery stage following an exhaustive running exercise, and thionein was synthesized first and then zinc bound to the protein. The half-life of hepatic MT induced by exercise (which is a nonmetallic inducer) was estimated at 5.2 h. Preinduced MT markedly suppressed exercise-induced lipid peroxidation in rat liver. PMID:10077430

  13. Peroxisome Biogenesis Disorders: Biological, Clinical and Pathophysiological Perspectives

    ERIC Educational Resources Information Center

    Braverman, Nancy E.; D'Agostino, Maria Daniela; MacLean, Gillian E.

    2013-01-01

    The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 "PEX" genes;…

  14. Eicosapentaenoic acid but not docosahexaenoic acid restores skeletal muscle mitochondrial oxidative capacity in old mice

    PubMed Central

    Johnson, Matthew L; Lalia, Antigoni Z; Dasari, Surendra; Pallauf, Maximilian; Fitch, Mark; Hellerstein, Marc K; Lanza, Ian R

    2015-01-01

    Mitochondrial dysfunction is often observed in aging skeletal muscle and is implicated in age-related declines in physical function. Early evidence suggests that dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve mitochondrial function. Here, we show that 10 weeks of dietary eicosapentaenoic acid (EPA) supplementation partially attenuated the age-related decline in mitochondrial function in mice, but this effect was not observed with docosahexaenoic acid (DHA). The improvement in mitochondrial function with EPA occurred in the absence of any changes in mitochondrial abundance or biogenesis, which was evaluated from RNA sequencing, large-scale proteomics, and direct measurements of muscle mitochondrial protein synthesis rates. We find that EPA improves muscle protein quality, specifically by decreasing mitochondrial protein carbamylation, a post-translational modification that is driven by inflammation. These results demonstrate that EPA attenuated the age-related loss of mitochondrial function and improved mitochondrial protein quality through a mechanism that is likely linked with anti-inflammatory properties of n-3 PUFAs. Furthermore, we demonstrate that EPA and DHA exert some common biological effects (anticoagulation, anti-inflammatory, reduced FXR/RXR activation), but also exhibit many distinct biological effects, a finding that underscores the importance of evaluating the therapeutic potential of individual n-3 PUFAs. PMID:26010060

  15. Physical exercise-induced changes in the core body temperature of mice depend more on ambient temperature than on exercise protocol or intensity

    NASA Astrophysics Data System (ADS)

    Wanner, Samuel Penna; Costa, Kátia Anunciação; Soares, Anne Danieli Nascimento; Cardoso, Valbert Nascimento; Coimbra, Cândido Celso

    2014-08-01

    The mechanisms underlying physical exercise-induced hyperthermia may be species specific. Therefore, the present study aimed to investigate the effects of exercise intensity and ambient temperature on the core body temperature ( T core) of running mice, which provide an important experimental model for advancing the understanding of thermal physiology. We evaluated the influence of different protocols (constant- or incremental-speed exercises), treadmill speeds and ambient temperatures ( T a) on the magnitude of exercise-induced hyperthermia. To measure T core, a telemetric sensor was implanted in the abdominal cavity of male adult Swiss mice under anesthesia. After recovering from the surgery, the animals were familiarized to running on a treadmill and then subjected to the different running protocols and speeds at two T a: 24 °C or 34 °C. All of the experimental trials resulted in marked increases in T core. As expected, the higher-temperature environment increased the magnitude of running-induced hyperthermia. For example, during incremental exercise at 34 °C, the maximal T core achieved was increased by 1.2 °C relative to the value reached at 24 °C. However, at the same T a, neither treadmill speed nor exercise protocol altered the magnitude of exercise-induced hyperthermia. We conclude that T core of running mice is influenced greatly by T a, but not by the exercise protocols or intensities examined in the present report. These findings suggest that the magnitude of hyperthermia in running mice may be regulated centrally, independently of exercise intensity.

  16. Mitochondrial dysfunction and Parkinson disease: a Parkin-AMPK alliance in neuroprotection.

    PubMed

    Hang, Liting; Thundyil, John; Lim, Kah-Leong

    2015-09-01

    Although a subject of intense research, the etiology of Parkinson disease (PD) remains poorly understood. However, a wide range of studies conducted over the past few decades have collectively implicated aberrant mitochondrial homeostasis as a key contributor to the development of PD. Particularly strong support for this came from the recent demonstration that parkin, a familial PD-linked gene, is a critical regulator of mitochondrial quality control. Indeed, Parkin appears to be involved in all stages of the mitochondrial life cycle (i.e., from biogenesis to its exit from the cell (via mitophagy). Interestingly, the role of Parkin in the biogenesis and clearance of mitochondria is akin to that performed by the energy sensor AMP-activated protein kinase (AMPK), suggesting that the two proteins might act in a functionally converging manner to maintain the quality of cellular mitochondria. In this review, we discuss the contribution of mitochondrial dysfunction to PD pathogenesis and the role of Parkin and AMPK in preserving neuronal mitochondrial homeostasis. Alongside this, we will also articulate our thoughts on the potential alliance between Parkin and AMPK in offering neuroprotection through their ability to maintain energy balance in the brain. PMID:26121488

  17. Evolution and significance of the Lon gene family in Arabidopsis organelle biogenesis and energy metabolism.

    PubMed

    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

  18. 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

  19. Integrative Analysis of the Mitochondrial Proteome in Yeast

    SciTech Connect

    Prokisch, Holger; Scharfe, Curt M.; Camp, David G.; Xiao, Wenzhong; David, Lior; Andreoli, Christophe; Monroe, Matthew E.; Moore, Ronald J.; Gritsenko, Marina A.; Kozany, Christian; Hixson, Kim K.; Mottaz, Heather M.; Zischka, Hans; Ueffing, Marius; Herman, Zelek S.; Davis, Ronald W.; Meitinger, Thomas; Oefner, Peter; Smith, Richard D.; Steinmetz, Lars M.

    2004-06-30

    In this study yeast mitochondria were used as a model system to apply, evaluate, and integrate different genomic approaches to define the proteins of an organelle. Liquid chromatography mass spectrometry applied to purified mitochondria identified 546 proteins. By expression analysis and comparison to other proteome studies, we demonstrate that the proteomic approach identifies primarily highly abundant proteins. By expanding our evaluation to other types of genomic approaches, including systematic deletion phenotype screening, expression profiling, subcellular localization studies, protein interaction analyses, and computational predictions, we show that an integration of approaches moves beyond the limitations of any single approach. We report the success of each approach by benchmarking it against a reference set of known mitochondrial proteins, and predict approximately 700 proteins associated with the mitochondrial organelle from the integration of 22 datasets. We show that a combination of complementary approaches like deletion phenotype screening and mass spectrometry can identify over 75% of the known mitochondrial proteome. These findings have implications for choosing optimal genome-wide approaches for the study of other cellular systems, including organelles and pathways in various species. Furthermore, our systematic identification of genes involved in mitochondrial function and biogenesis in yeast expands the candidates genes available for mapping Mendelian and complex mitochondrial disorders in humans.

  20. Processing and Topology of the Yeast Mitochondrial Phosphatidylserine Decarboxylase 1*

    PubMed Central

    Horvath, Susanne E.; Böttinger, Lena; Vögtle, F.-Nora; Wiedemann, Nils; Meisinger, Chris; Becker, Thomas; Daum, Günther

    2012-01-01

    The inner mitochondrial membrane plays a crucial role in cellular lipid homeostasis through biosynthesis of the non-bilayer-forming lipids phosphatidylethanolamine and cardiolipin. In the yeast Saccharomyces cerevisiae, the majority of cellular phosphatidylethanolamine is synthesized by the mitochondrial phosphatidylserine decarboxylase 1 (Psd1). The biogenesis of Psd1 involves several processing steps. It was speculated that the Psd1 precursor is sorted into the inner membrane and is subsequently released into the intermembrane space by proteolytic removal of a hydrophobic sorting signal. However, components involved in the maturation of the Psd1 precursor have not been identified. We show that processing of Psd1 involves the action of the mitochondrial processing peptidase and Oct1 and an autocatalytic cleavage at a highly conserved LGST motif yielding the ?- and ?-subunit of the enzyme. The Psd1 ?-subunit (Psd1?) forms the membrane anchor, which binds the intermembrane space-localized ?-subunit (Psd1?). Deletion of a transmembrane segment in the ?-subunit results in mislocalization of Psd1 and reduced enzymatic activity. Surprisingly, autocatalytic cleavage does not depend on proper localization to the inner mitochondrial membrane. In summary, membrane integration of Psd1 is crucial for its functionality and for maintenance of mitochondrial lipid homeostasis. PMID:22984266

  1. 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

  2. Heart disease induced by AAS abuse, using experimental mice/rats models and the role of exercise-induced cardiotoxicity.

    PubMed

    Riezzo, I; De Carlo, D; Neri, M; Nieddu, A; Turillazzi, E; Fineschi, V

    2011-05-01

    The anabolic-androgenic steroids (AAS) are all synthetic derivates of testosterone and are commonly used as sport performance enhancers in athletes. The heart is one of the organs most frequently affected by administration of anabolic steroids. A direct myocardial injury caused by AAS is supposed to determine marked hypertrophy in myocardial cells, extensive regional fibrosis and necrosis. A number of excellent studies, using animal models, were performed to evaluate the cardiac effects of AAS. It is known that exogenous administration induced cardiac hypertrophy in vitro and in vivo, and when combined with exercise, anabolic steroid use has been shown to change exercise-induced physiological cardiac hypertrophy to pathophysiological cardiac hypertrophy. However the molecular mechanisms are still poorly understood. It's described that sudden cardiac death, myocardial infarct; ventricular remodelling and cardiomyopathy do to AAS is related to apoptosis and oxidative stress when associated with exercise. Mechanical stimuli and circulating humoral factors (TNF-?, HSP-70, IL-1?) released by the heart and peripheral organs are responsible. Testosterone and derivates can work through genomic (activation of specific androgen receptor, interaction with coactivators and co-repressors transcription factors, gene regulation) and non-genomic mechanism (membrane-receptor-second messenger cascades). Chronic AAS abuse results in different patterns of pathologic alterations, which depend on type, dose, frequency, and mode of use. The difficulty in interpreting experimental data on animals (mice and rats) lies in the diversity of experiments (the diversity of substances, which show different properties, different mice / rats by sex and age, duration of treatment with AAS, dosages used, type, scope and exercise duration). PMID:21443510

  3. 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

  4. Effects of rehydration fluid temperature and composition on body weight retention upon voluntary drinking following exercise-induced dehydration

    PubMed Central

    Bae, Yoon Jung; Lee, Yong Soo; Kim, Byeong Jo

    2012-01-01

    The purpose of this study was to determine the effects of beverage temperature and composition on weight retention and fluid balance upon voluntary drinking following exercise induced-dehydration. Eight men who were not acclimated to heat participated in four randomly ordered testing sessions. In each session, the subjects ran on a treadmill in a chamber maintained at 37? without being supplied fluids until 2% body weight reduction was reached. After termination of exercise, they recovered for 90 min under ambient air conditions and received one of the following four test beverages: 10? water (10W), 10? sports drink (10S), 26? water (26W), and 26? sports drink (26S). They consumed the beverages ad libitum. The volume of beverage consumed and body weight were measured at 30, 60, and 90 min post-recovery. Blood samples were taken before and immediately after exercise as well as at the end of recovery in order to measure plasma parameters and electrolyte concentrations. We found that mean body weight decreased by 1.8-2.0% following exercise. No differences in mean arterial pressure, plasma volume, plasma osmolality, and blood electrolytes were observed among the conditions. Total beverage volumes consumed were 1,164 ± 388, 1,505 ± 614, 948 ± 297, and 1,239 ± 401 ml for 10W, 10S, 26W, and 26S respectively (P > 0.05). Weight retention at the end of recovery from dehydration was highest in 10S (1.3 ± 0.7 kg) compared to 10W (0.4 ± 0.5 kg), 26W (0.4 ± 0.4 kg), and (0.6 ± 0.4 kg) (P < 0.005). Based on these results, carbohydrate/electrolyte-containing beverages at cool temperature were the most favorable for consumption and weight retention compared to plain water and moderate temperature beverages. PMID:22586501

  5. Long term dietary restriction ameliorates swimming exercise-induced oxidative stress in brain and lung of middle-aged rat.

    PubMed

    Aydin, Cenk; Sonat, Fusun; Sahin, Senay Koparan; Cangul, I Taci; Ozkaya, Guven

    2009-01-01

    Exhaustive exercise may generate oxidative stress in brain and reported findings are conflicting. Long term dietary restriction (DR) may be useful in the inhibiting of free oxygen radicals generated during exhaustive exercise in the brain of rat. Hence, in this study we evaluated beneficial effects of long term DR on the oxidative stress and antioxidant enzyme systems in brain cortex and lung in rats after different intensities of swimming exercise. Sprague-Dawley rats (60) were assigned as DR and ad libitum (AL) groups, and each group was further subdivided into three groups namely control (sedentery), submaximal exercise (endurance exercise) and maximal exercise (exhaustive swimming exercise) groups. Animals in the endurance exercise group swam 5 days/week for 8 weeks while exhaustive swimming group was subjected to an acute bout of exercise. With the increase in intensity of exercise, degree of lipid peroxidation (LP) and protein oxidation (PO) were also increased in DR and AL groups; however rate of increase was lower in DR group than AL group. Glutathione (GSH) and glutathione peroxidase (GSH-Px) activity were lower but glutathione reductase (GR) activity was higher in DR group compared to AL group in endurance and exhaustive swimming exercise. With increase in exercise intensity, GSH and GR enzyme activity decreased, whereas an increase was observed in GSH-Px enzyme activity. There was no difference in LP, PO, GSH and GR activity between DR and AL groups. GSH-Px activity in brain cortex was significantly lower in DR group than in AL group and sedentary rats. Results indicate that long term dietary restriction may protect against endurance and exhaustive swimming exercise-induced oxidative stress in rats by inhibiting oxidative stress. PMID:19317348

  6. Urinary excretion of 9?,11?-prostaglandin F2 and leukotriene E4 in patients with exercise-induced bronchoconstriction

    PubMed Central

    Shin, Tae-Rim; Kim, Joo-Hee; Kim, Cheol-Hong; Hyun, In-Gyu

    2015-01-01

    Background Increased levels of mast cell-derived eicosanoids, such as prostaglandin (PG) D2 and cysteinyl leukotrienes (CysLTs), have been reported in patients with exercise-induced bronchoconstriction (EIB), suggesting that mast cell activation is involved in the mechanism of EIB. However, it is still controversial since these results have not been reproduced in other studies. The aim of this study was to evaluate the role of PGD2 and LTE4 in adult asthma with EIB, as measuring urinary levels of their metabolites—9?,11?-PGF2 and LTE4 before and after an exercise challenge test. Methods Eight patients with asthma and EIB and five normal controls without EIB were enrolled. Exercise challenge tests comprised of 6 min of treadmill exercise or free running were performed in all study subjects, and urine samples before and 1 h after the challenge were collected. Urinary levels of 9?,11?-PGF2 and LTE4 were measured by enzyme immunoassay (EIA). Results No significant differences were observed in 9?,11?-PGF2 and LTE4 levels before/after the exercise challenge between patients with EIB and normal controls. No significant increases in urinary levels of 9?,11?-PGF2 or LTE4 were detected during the exercise challenge in patients with EIB and normal controls. No significant correlations were observed between the percent decrease in forced expiratory volume in 1 s (FEV1) or percent changes in 9?,11?-PGF2 and LTE4 levels after the exercise challenge. Conclusions Urinary 9?,11?-PGF2 and LTE4 levels did not increase after an exercise challenge in patients with EIB, suggesting that urinary excretion of 9?,11?-PGF2 and LTE4 may not be a good marker of mast cell activation in patients with EIB. PMID:26380736

  7. Overexpression of the Mitochondrial T3 Receptor p43 Induces a Shift in Skeletal Muscle Fiber Types

    PubMed Central

    Casas, François; Pessemesse, Laurence; Grandemange, Stéphanie; Seyer, Pascal; Gueguen, Naïg; Baris, Olivier; Lepourry, Laurence; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2008-01-01

    In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation.We have generated mice overexpressing p43 under control of the human ?-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8°C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1? and PPAR?, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1? and PPAR?. PMID:18575627

  8. Modulation of mitochondrial functions by the indirect antioxidant sulforaphane: a seemingly contradictory dual role and an integrative hypothesis.

    PubMed

    Negrette-Guzmán, Mario; Huerta-Yepez, Sara; Tapia, Edilia; Pedraza-Chaverri, José

    2013-12-01

    The chemotherapeutic isothiocyanate sulforaphane (SFN) was early linked to anticarcinogenic and antiproliferative activities. Soon after, this compound, derived from cruciferous vegetables, became an excellent and useful trial for anti-cancer research in experimental models including growth tumor, metastasis, and angiogenesis. Many subsequent reports showed modifications in mitochondrial signaling, functionality, and integrity induced by SFN. When cytoprotective effects were found in toxic and ischemic insult models, seemingly contradictory behaviors of SFN were discovered: SFN was inducing deleterious changes in cancer cell mitochondria that eventually would carry the cell to death via apoptosis and also was protecting noncancer cell mitochondria against oxidative challenge, which prevented cell death. In both cases, SFN exhibited effects on mitochondrial redox balance and phase II enzyme expression, mitochondrial membrane potential, expression of the family of B cell lymphoma 2 homologs, regulation of proapoptotic proteins released from mitochondria, activation/inactivation of caspases, mitochondrial respiratory complex activities, oxygen consumption and bioenergetics, mitochondrial permeability transition pore opening, and modulation of some kinase pathways. With the ultimate findings related to the induction of mitochondrial biogenesis by SFN, it could be considered that SFN has effects on mitochondrial dynamics that explain some divergent points. In this review, we list the reports involving effects on mitochondrial modulation by SFN in anti-cancer models as well as in cytoprotective models against oxidative damage. We also attempt to integrate the data into a mechanism explaining the various effects of SFN on mitochondrial function in only one concept, taking into account mitochondrial biogenesis and dynamics and making a comparison with the theory of reactive oxygen species threshold of cell death. Our interest is to achieve a complete view of cancer and protective therapies based on SFN that can be extended to other chemotherapeutic compounds with similar characteristics. The work needed to test this hypothesis is quite extensive. PMID:23999506

  9. Overexpression of tumor necrosis factor receptor-associated protein 1 (TRAP1), leads to mitochondrial aberrations in mouse fibroblast NIH/3T3 cells

    PubMed Central

    Im, Chang-Nim; Seo, Jeong-Sun

    2014-01-01

    Cancer cells undergo uncontrolled proliferation, and aberrant mitochondrial alterations. Tumor necrosis factor receptorassociated protein 1 (TRAP1) is a mitochondrial heat shock protein. TRAP1 mRNA is highly expressed in some cancer cell lines and tumor tissues. However, the effects of its overexpression on mitochondria are unclear. In this study, we assessed mitochondrial changes accompanying TRAP1 overexpression, in a mouse cell line, NIH/3T3. We found that overexpression of TRAP1 leads to a series of mitochondrial aberrations, including increase in basal ROS levels, and decrease in mitochondrial biogenesis, together with a decrease in peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?) mRNA levels. We also observed increased extracellular signal-regulated kinase (ERK) phosphorylation, and enhanced proliferation of TRAP1 overexpressing cells. This study suggests that overexpression of TRAP1 might be a critical link between mitochondrial disturbances and carcinogenesis. [BMB Reports 2014; 47(5): 280-285] PMID:24286320

  10. 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

  11. Regulation of mitochondrial morphology and function by stearoylation of TFR1.

    PubMed

    Senyilmaz, Deniz; Virtue, Sam; Xu, Xiaojun; Tan, Chong Yew; Griffin, Julian L; Miller, Aubry K; Vidal-Puig, Antonio; Teleman, Aurelio A

    2015-09-01

    Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. Although transcriptional mechanisms that regulate mitochondrial abundance are known, comparatively little is known about how mitochondrial function is regulated. Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. This leads to reduced ubiquitination of mitofusin via HUWE1, thereby promoting mitochondrial fusion and function. We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet. PMID:26214738

  12. 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...

  13. Regulation of chloroplast biogenesis: the immutans mutant of Arabidopsis

    SciTech Connect

    Rodermel, Steven

    2015-11-16

    The immutans (im) variegation mutant of Arabidopsis is an ideal model to gain insight into factors that control chloroplast biogenesis. im defines the gene for PTOX, a plastoquinol terminal oxidase that participates in control of thylakoid redox. Here, we report that the im defect can be suppressed during the late stages of plant development by gigantea (gi2), which defines the gene for GIGANTEA (GI), a central component of the circadian clock that plays a poorly-understood role in diverse plant developmental processes. imgi2 mutants are late-flowering and display other well-known phenotypes associated with gi2, such as starch accumulation and resistance to oxidative stress. We show that the restoration of chloroplast biogenesis in imgi2 is caused by a developmental-specific de-repression of cytokinin signaling that involves crosstalk with signaling pathways mediated by gibberellin (GA) and SPINDLY (SPY), a GA response inhibitor. Suppression of the plastid defect in imgi2 is likely caused by a relaxation of excitation pressures in developing plastids by factors contributed by gi2, including enhanced rates of photosynthesis and increased resistance to oxidative stress. Interestingly, the suppression phenotype of imgi can be mimicked by crossing im with the starch accumulation mutant, sex1, perhaps because sex1 utilizes pathways similar to gi. We conclude that our studies provide a direct genetic linkage between GIGANTEA and chloroplast biogenesis, and we construct a model of interactions between signaling pathways mediated by gi, GA, SPY, cytokinins, and sex1 that are required for chloroplast biogenesis.

  14. Activation of AMPK?2 Is Not Required for Mitochondrial FAT/CD36 Accumulation during Exercise

    PubMed Central

    Monaco, Cynthia; Whitfield, Jamie; Jain, Swati S.; Spriet, Lawrence L.; Bonen, Arend; Holloway, Graham P.

    2015-01-01

    Exercise has been shown to induce the translocation of fatty acid translocase (FAT/CD36), a fatty acid transport protein, to both plasma and mitochondrial membranes. While previous studies have examined signals involved in the induction of FAT/CD36 translocation to sarcolemmal membranes, to date the signaling events responsible for FAT/CD36 accumulation on mitochondrial membranes have not been investigated. In the current study muscle contraction rapidly increased FAT/CD36 on plasma membranes (7.5 minutes), while in contrast, FAT/CD36 only increased on mitochondrial membranes after 22.5 minutes of muscle contraction, a response that was exercise-intensity dependent. Considering that previous research has shown that AMP activated protein kinase (AMPK) ?2 is not required for FAT/CD36 translocation to the plasma membrane, we investigated whether AMPK ?2 signaling is necessary for mitochondrial FAT/CD36 accumulation. Administration of 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) induced AMPK phosphorylation, and resulted in FAT/CD36 accumulation on SS mitochondria, suggesting AMPK signaling may mediate this response. However, SS mitochondrial FAT/CD36 increased following acute treadmill running in both wild-type (WT) and AMPK? 2 kinase dead (KD) mice. These data suggest that AMPK signaling is not required for SS mitochondrial FAT/CD36 accumulation. The current data also implicates alternative signaling pathways that are exercise-intensity dependent, as IMF mitochondrial FAT/CD36 content only occurred at a higher power output. Taken altogether the current data suggests that activation of AMPK signaling is sufficient but not required for exercise-induced accumulation in mitochondrial FAT/CD36. PMID:25965390

  15. Bmi1 promotes erythroid development through regulating ribosome biogenesis

    PubMed Central

    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

    2015-01-01

    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 down-regulation of 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 (HSPCs) 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

  16. Microprocessor activity controls differential miRNA biogenesis In Vivo.

    PubMed

    Conrad, Thomas; Marsico, Annalisa; Gehre, Maja; Orom, Ulf Andersson

    2014-10-23

    In miRNA biogenesis, pri-miRNA transcripts are converted into pre-miRNA hairpins. The in vivo properties of this process remain enigmatic. Here, we determine in vivo transcriptome-wide pri-miRNA processing using next-generation sequencing of chromatin-associated pri-miRNAs. We identify a distinctive Microprocessor signature in the transcriptome profile from which efficiency of the endogenous processing event can be accurately quantified. This analysis reveals differential susceptibility to Microprocessor cleavage as a key regulatory step in miRNA biogenesis. Processing is highly variable among pri-miRNAs and a better predictor of miRNA abundance than primary transcription itself. Processing is also largely stable across three cell lines, suggesting a major contribution of sequence determinants. On the basis of differential processing efficiencies, we define functionality for short sequence features adjacent to the pre-miRNA hairpin. In conclusion, we identify Microprocessor as the main hub for diversified miRNA output and suggest a role for uncoupling miRNA biogenesis from host gene expression. PMID:25310978

  17. Exercise-Induced Asthma

    MedlinePLUS

    ... to recover. And extremes of temperature, especially cold weather, can make it even worse. Diagnosing EIA A ... basketball) may be more challenging, as can cold-weather endurance sports like cross-country skiing or ice ...

  18. Mitochondrial heat shock protein (Hsp) 70 and Hsp10 cooperate in the formation of Hsp60 complexes.

    PubMed

    Böttinger, Lena; Oeljeklaus, Silke; Guiard, Bernard; Rospert, Sabine; Warscheid, Bettina; Becker, Thomas

    2015-05-01

    Mitochondrial Hsp70 (mtHsp70) mediates essential functions for mitochondrial biogenesis, like import and folding of proteins. In these processes, the chaperone cooperates with cochaperones, the presequence translocase, and other chaperone systems. The chaperonin Hsp60, together with its cofactor Hsp10, catalyzes folding of a subset of mtHsp70 client proteins. Hsp60 forms heptameric ring structures that provide a cavity for protein folding. How the Hsp60 rings are assembled is poorly understood. In a comprehensive interaction study, we found that mtHsp70 associates with Hsp60 and Hsp10. Surprisingly, mtHsp70 interacts with Hsp10 independently of Hsp60. The mtHsp70-Hsp10 complex binds to the unassembled Hsp60 precursor to promote its assembly into mature Hsp60 complexes. We conclude that coupling to Hsp10 recruits mtHsp70 to mediate the biogenesis of the heptameric Hsp60 rings. PMID:25792736

  19. Translation and Assembly of Radiolabeled Mitochondrial DNA-Encoded Protein Subunits from Cultured Cells and Isolated Mitochondria.

    PubMed

    Formosa, Luke E; Hofer, Annette; Tischner, Christin; Wenz, Tina; Ryan, Michael T

    2016-01-01

    In higher eukaryotes, the mitochondrial electron transport chain consists of five multi-subunit membrane complexes responsible for the generation of cellular ATP. Of these, four complexes are under dual genetic control as they contain subunits encoded by both the mitochondrial and nuclear genomes, thereby adding another layer of complexity to the puzzle of respiratory complex biogenesis. These subunits must be synthesized and assembled in a coordinated manner in order to ensure correct biogenesis of different respiratory complexes. Here, we describe techniques to (1) specifically radiolabel proteins encoded by mtDNA to monitor the rate of synthesis using pulse labeling methods, and (2) analyze the stability, assembly, and turnover of subunits using pulse-chase methods in cultured cells and isolated mitochondria. PMID:26530678

  20. Enhanced renal Na+ reabsorption by carbohydrate in beverages during restitution from thermal and exercise-induced dehydration in men.

    PubMed

    Kamijo, Yoshi-Ichiro; Ikegawa, Shigeki; Okada, Yoshiyuki; Masuki, Shizue; Okazaki, Kazunobu; Uchida, Koji; Sakurai, Masao; Nose, Hiroshi

    2012-10-15

    We examined whether carbohydrate in beverages accelerated fluid retention during recovery from thermal and exercise-induced dehydration and whether it was caused in part by an enhanced renal Na+ reabsorption rate due to insulin secretion. After dehydrating by ?2.3% body weight by exercise in a hot environment, seven young men underwent high-carbohydrate, low-carbohydrate, or control rehydration trials by drinking one of three beverages with 3.4 g glucose + 3.1 g fructose, 1.7 g glucose + 1.6 g fructose, or 0.0 g glucose + 0.0 g fructose per deciliter, respectively, in a common composition of electrolyte solution: 21 meq/l [Na+], 5 meq/l [K+], 16.5 meq/l [Cl-], 10 meq/l [citrate(-3)]. They drank the same amount of beverage as total body weight loss within 30 min. During the 60 min before the start of drinking and the following 180 min, we measured plasma volume (PV), plasma glucose ([Glc]p), serum insulin ([Ins]s), plasma Na+ concentrations, and the renal clearances of inulin, lithium, and Na+ with plasma vasopressin ([AVP]p) and aldosterone concentrations ([Ald]p) every 30 min. After dehydration, PV decreased by ?5% and plasma osmolality increased by ?6 mosmol/kg H2O in all trials with no significant differences among them. We found in the high-carbohydrate trial that 1) PV increased faster than in the control trial and remained at the higher level than other trials for the last 60 min (P < 0.05); 2) accumulated urine volume was smallest after 90 min (P < 0.05); 3) the renal Na+ reabsorption rate was greatest for the first 120 min (P < 0.05); 4) during which period [AVP]p and [Ald](p) were not significantly different from other trials (both, P > 0.9); and 5) [Glc](p) and [Ins]s were highest from 45 to 105 min (P < 0.05) during rehydration. Thus carbohydrate in beverages enhances renal Na+ reabsorption, and insulin is possibly involved in this enhancement. PMID:22874424

  1. Effect of arginine aspartate on the exercise-induced hyperammoniemia in humans: a two periods cross-over trial.

    PubMed

    Denis, C; Dormois, D; Linossier, M T; Eychenne, J L; Hauseux, P; Lacour, J R

    1991-02-01

    To investigate the effect of the ingestion of arginine aspartate (AA) in the decrease of the exercise-induced accumulation of ammonia in plasma, 11 voluntary subjects took part in a cross-over study where AA effect was tested against placebo. Both treatments were randomly administered in a double-blind procedure. To ensure the subjects would be able to present reproducible exercise-testing results during repetitive sessions, they were involved before the experiment in a cycle ergometer training program during 8 weeks. This training determined a significant 14% increase (P less than 0.001) in maximal oxygen uptake (VO2 max). The treatments were administered during 10 days and the two treatments were separated by a 10 day-wash-out period. A 45 min-cycle ergometer test was performed at 80% VO2 max during the 10th day of each treatment to measure plasma ammonia (p[NH4+]) and total blood lactate (b[lact]) concentrations at rest and at the 15th, 30th and 45th min of exercise (determinations of changes from rest; delta p[NH4+] and delta b[lact]). Both concentrations were unchanged between AA and placebo at rest but a significant lesser delta p[NH4+] was found under AA at the 15th min of exercise only (P less than 0.05). On the other hand, an order effect was found for delta p[NH4+] between the two periods of randomized treatment that was interpreted as a remaining training effect. This effect was highly significant at the 30th and 45th min of exercise (P less than 0.001). It was concluded that AA effect was minor with regard to the training effect. As it was not located at the same time of exercise, AA effect would not consequently have the same functional origin (postulated increase in the peripheral clearance of ammonia) than those of training (decrease in muscle production of ammonia). PMID:1713484

  2. Effect of electrical stimulation-induced resistance exercise on mitochondrial fission and fusion proteins in rat skeletal muscle.

    PubMed

    Kitaoka, Yu; Ogasawara, Riki; Tamura, Yuki; Fujita, Satoshi; Hatta, Hideo

    2015-11-01

    It is well known that resistance exercise increases muscle protein synthesis and muscle strength. However, little is known about the effect of resistance exercise on mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria exist as dynamic networks that are continuously remodeling through fusion and fission. The purpose of this study was to investigate the effect of acute and chronic resistance exercise, which induces muscle hypertrophy, on the expression of proteins related to mitochondrial dynamics in rat skeletal muscle. Resistance exercise consisted of maximum isometric contraction, which was induced by percutaneous electrical stimulation of the gastrocnemius muscle. Our results revealed no change in levels of proteins that regulate mitochondrial fission (Fis1 and Drp1) or fusion (Opa1, Mfn1, and Mfn2) over the 24-h period following acute resistance exercise. Phosphorylation of Drp1 at Ser616 was increased immediately after exercise (P < 0.01). Four weeks of resistance training (3 times/week) increased Mfn1 (P < 0.01), Mfn2 (P < 0.05), and Opa1 (P < 0.01) protein levels without altering mitochondrial oxidative phosphorylation proteins. These observations suggest that resistance exercise has little effect on mitochondrial biogenesis but alters the expression of proteins involved in mitochondrial fusion and fission, which may contribute to mitochondrial quality control and improved mitochondrial function. PMID:26513006

  3. Beneficial effects of astragaloside IV against angiotensin II-induced mitochondrial dysfunction in rat vascular smooth muscle cells

    PubMed Central

    LU, YAO; LI, SU; WU, HENGFANG; BIAN, ZHIPING; XU, JINDAN; GU, CHUNRONG; CHEN, XIANGJIAN; YANG, DI

    2015-01-01

    Angiotensin II (Ang II)-induced mitochondrial dysfunction is a prominent characteristic of the majority of cardiovascular diseases. Astragaloside IV (As-IV), the major active ingredient of Astragalus membranaceus (Fisch.) Bge. (a traditional Chinese herbal medicine), possesses antioxidant properties. The present study was carried out to examine whether As-IV can reverse Ang II-induced mitochondrial dysfunction in vascular smooth muscle cells (VSMCs) and to elucidate the underlying molecular mechanisms. Cultured rat aortic VSMCs treated with Ang II (1 µM) for 24 h exhibited mitochondrial dysfunction, including a decrease in mitochondrial oxygen consumption rates (OCRs), adenosine triphosphate (ATP) production and mitochondrial DNA (mtDNA) levels, as well as the disruption of mitochondrial structural integrity. Following treatment with Ang II, As-IV (50 µg/ml) was added to the culture medium followed by incubation for a further 24 h. The administration of As-IV significantly increased the mitochondrial OCRs, ATP production and the mtDNA levels, and reversed the mitochondrial morphological changes which occurred in the VSMCs. Treatment with As-IV also reversed the Ang II-induced increase in the production of reactive oxygen species (ROS), the increase in NADPH oxidase and xanthine oxidase activity, as well as the decrease in mitochondrial membrane potential (??m) and manganese superoxide dismutase (Mn-SOD) activity. Furthermore, treatment with As-IV led to an increase in the mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1? (PGC-1?) and mitochondrial transcription factor A (Tfam), and in the protein expression of PGC-1?, parkin and dynamin 1-like protein 1 (Drp1) in the VSMCs. These results indicate that As-IV exerts beneficial effects on Ang II-induced mitochondrial dysfunction in rat VSMCs and that these effects are mediated through the inhibition of ROS overproduction, as well as the promotion of mitochondrial autophagy and mitochondrial biogenesis. These data demonstrate the antioxidant properties of As-IV. PMID:26398547

  4. Mitochondrial Transcription Factor A (TFAM) Binds to RNA Containing 4-Way Junctions and Mitochondrial tRNA

    PubMed Central

    Brown, Timothy A.; Tkachuk, Ariana N.; Clayton, David A.

    2015-01-01

    Mitochondrial DNA (mtDNA) is maintained within nucleoprotein complexes known as nucleoids. These structures are highly condensed by the DNA packaging protein, mitochondrial Transcription Factor A (TFAM). Nucleoids also include RNA, RNA:DNA hybrids, and are associated with proteins involved with RNA processing and mitochondrial ribosome biogenesis. Here we characterize the ability of TFAM to bind various RNA containing substrates in order to determine their role in TFAM distribution and function within the nucleoid. We find that TFAM binds to RNA-containing 4-way junctions but does not bind appreciably to RNA hairpins, internal loops, or linear RNA:DNA hybrids. Therefore the RNA within nucleoids largely excludes TFAM, and its distribution is not grossly altered with removal of RNA. Within the cell, TFAM binds to mitochondrial tRNAs, consistent with our RNA 4-way junction data. Kinetic binding assays and RNase-insensitive TFAM distribution indicate that DNA remains the preferred substrate within the nucleoid. However, TFAM binds to tRNA with nanomolar affinity and these complexes are not rare. TFAM-immunoprecipitated tRNAs have processed ends, suggesting that binding is not specific to RNA precursors. The amount of each immunoprecipitated tRNA is not well correlated with tRNA celluar abundance, indicating unequal TFAM binding preferences. TFAM-mt-tRNA interaction suggests potentially new functions for this protein. PMID:26545237

  5. Post-Transcriptional Regulators of microRNA Biogenesis Regulate Pathogenesis - Pavel Sumazin, TCGA Scientific Symposium 2011

    Cancer.gov

    Home News and Events Multimedia Library Videos Post-Transcriptional Regulators of microRNA Biogenesis Regulate Pathogenesis - Pavel Sumazin Post-Transcriptional Regulators of microRNA Biogenesis Regulate Pathogenesis - Pavel Sumazin, TCGA Scientific

  6. Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients.

    PubMed

    Alcocer-Gómez, Elísabet; Garrido-Maraver, Juan; Bullón, Pedro; Marín-Aguilar, Fabiola; Cotán, David; Carrión, Angel M; Alvarez-Suarez, José Miguel; Giampieri, Francesca; Sánchez-Alcazar, José Antonio; Battino, Maurizio; Cordero, Mario D

    2015-07-01

    Impaired AMPK is associated with a wide spectrum of clinical and pathological conditions, ranging from obesity, altered responses to exercise or metabolic syndrome, to inflammation, disturbed mitochondrial biogenesis and defective response to energy stress. Fibromyalgia (FM) is a world-wide diffused musculoskeletal chronic pain condition that affects up to 5% of the general population and comprises all the above mentioned pathophysiological states. Here, we tested the involvement of AMPK activation in fibroblasts derived from FM patients. AMPK was not phosphorylated in fibroblasts from FM patients and was associated with decreased mitochondrial biogenesis, reduced oxygen consumption, decreased antioxidant enzymes expression levels and mitochondrial dysfunction. However, mtDNA sequencing analysis did not show any important alterations which could justify the mitochondrial defects. AMPK activation in FM fibroblast was impaired in response to moderate oxidative stress. In contrast, AMPK activation by metformin or incubation with serum from caloric restricted mice improved the response to moderate oxidative stress and mitochondrial metabolism in FM fibroblasts. These results suggest that AMPK plays an essential role in FM pathophysiology and could represent the basis for a valuable new therapeutic target/strategy. Furthermore, both metformin and caloric restriction could be an interesting therapeutic approach in FM. PMID:25779083

  7. Exercise-induced myofibrillar disruption with sarcolemmal integrity prior to simulated diving has no effect on vascular bubble formation in rats.

    PubMed

    Jørgensen, Arve; Foster, Philip P; Eftedal, Ingrid; Wisløff, Ulrik; Paulsen, Gøran; Havnes, Marianne B; Brubakk, Alf O

    2013-05-01

    Decompression sickness is initiated by gas bubbles formed during decompression, and it has been generally accepted that exercise before decompression causes increased bubble formation. There are indications that exercise-induced muscle injury seems to be involved. Trauma-induced skeletal muscle injury and vigorous exercise that could theoretically injure muscle tissues before decompression have each been shown to result in profuse bubble formation. Based on these findings, we hypothesized that exercise-induced skeletal muscle injury prior to decompression from diving would cause increase of vascular bubbles and lower survival rates after decompression. In this study, we examined muscle injury caused by eccentric exercise in rats prior to simulated diving and we observed the resulting bubble formation. Female Sprague-Dawley rats (n = 42) ran downhill (-16º) for 100 min on a treadmill followed by 90 min rest before a 50-min simulated saturation dive (709 kPa) in a pressure chamber. Muscle injury was evaluated by immunohistochemistry and qPCR, and vascular bubbles after diving were detected by ultrasonic imaging. The exercise protocol resulted in increased mRNA expression of markers of muscle injury; ?B-crystallin, NF-?B, and TNF-?, and myofibrillar disruption with preserved sarcolemmal integrity. Despite evident myofibrillar disruption after eccentric exercise, no differences in bubble amounts or survival rates were observed in the exercised animals as compared to non-exercised animals after diving, a novel finding that may be applicable to humans. PMID:23129090

  8. Adipose tissue ABCA1 contributes to HDL biogenesis in vivo

    PubMed Central

    Chung, Soonkyu; Sawyer, Janet K.; Gebre, Abraham K.; Maeda, Nobuyo; Parks, John S.

    2011-01-01

    Background Adipose tissue (AT) is the body’s largest free cholesterol (FC) reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), a key cholesterol transporter for HDL biogenesis. However, the extent to which AT ABCA1 expression contributes to HDL biogenesis in vivo is unknown. Methods and Results Adipocyte-specific ABCA1 knockout mice (ABCA1?A/?A) were generated by crossing ABCA1floxed mice with aP2 cre transgenic mice. AT from ABCA1?A/?A mice had <10% of wild type (WT) ABCA1 protein expression, but normal hepatic and intestinal expression. Deletion of adipocyte ABCA1 resulted in a significant decrease in plasma HDL cholesterol (~15%) and apoA-I (~13%) concentrations. AT from ABCA1?A/?A mice had a two-fold increase in FC content, compared to WT mice, and failed to efflux cholesterol to apoA-I. However, cholesterol efflux from AT to plasma HDL was similar for both genotypes of mice. Incubation of WT AT explants with apoA-I resulted in formation of multiple discrete-sized nascent HDL particles ranging in diameter from 7.1–12 nm; similar incubations with ABCA1?A/?A AT explants resulted in nascent HDL <8 nm. Plasma decay and tissue uptake of WT 125I-HDL tracer was similar in both genotypes of recipient mice, suggesting that adipocyte ABCA1 deficiency reduces plasma HDL concentrations solely by reducing nascent HDL particle formation. Conclusions We provide in vivo evidence that AT ABCA1-dependent cholesterol efflux and nascent HDL particle formation contribute to systemic HDL biogenesis and that AT ABCA1 expression plays an important role in adipocyte cholesterol homeostasis. PMID:21931081

  9. The mitochondrial ADP/ATP carrier associates with the inner membrane presequence translocase in a stoichiometric manner.

    PubMed

    Mehnert, Carola S; Rampelt, Heike; Gebert, Michael; Oeljeklaus, Silke; Schrempp, Sandra G; Kochbeck, Lioba; Guiard, Bernard; Warscheid, Bettina; van der Laan, Martin

    2014-09-26

    The majority of mitochondrial proteins are synthesized with amino-terminal signal sequences. The presequence translocase of the inner membrane (TIM23 complex) mediates the import of these preproteins. The essential TIM23 core complex closely cooperates with partner protein complexes like the presequence translocase-associated import motor and the respiratory chain. The inner mitochondrial membrane also contains a large number of metabolite carriers, but their association with preprotein translocases has been controversial. We performed a comprehensive analysis of the TIM23 interactome based on stable isotope labeling with amino acids in cell culture. Subsequent biochemical studies on identified partner proteins showed that the mitochondrial ADP/ATP carrier associates with the membrane-embedded core of the TIM23 complex in a stoichiometric manner, revealing an unexpected connection of mitochondrial protein biogenesis to metabolite transport. Our data indicate that direct TIM23-AAC coupling may support preprotein import into mitochondria when respiratory activity is low. PMID:25124039

  10. MITOCHONDRIAL FRAGMENTATION IN NEURODEGENERATION

    PubMed Central

    Knott, Andrew B.; Perkins, Guy; Schwarzenbacher, Robert; Bossy-Wetzel, Ella

    2008-01-01

    PREFACE Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA (mtDNA) 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 mitochondrial fusion GTPases (mitofusin-2 and optic atrophy-1), neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired bioenergetics and mitochondrial migration and can trigger neurodegeneration. These findings suggest potential new treatment avenues for neurodegenerative diseases. PMID:18568013

  11. 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

  12. Targeting Mitochondrial Metabolism by Inhibiting Autophagy in Braf-driven Cancers

    PubMed Central

    Strohecker, Anne M.; White, Eileen

    2014-01-01

    Metabolomic analyses of human tumors and mouse models of cancer have identified key roles for autophagy in supporting mitochondrial metabolism and homeostasis. In this review, we highlight data suggesting that autophagy inhibition may be particularly effective in Braf-driven malignancies. Catalytic BRAF inhibitors have profound efficacy in tumors carrying activating mutations in Braf but are limited by the rapid emergence of resistance due in part to increased mitochondrial biogenesis and heightened rates of oxidative phosphorylation. We suggest that combined inhibition of autophagy and BRAF may overcome this limitation. Significance BrafV600E-driven tumors require autophagy and likely autophagy-provided substrates to maintain mitochondrial metabolism and to promote tumor growth, suggesting that autophagy ablation may improve cancer therapy. PMID:24860158

  13. 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

  14. Disrupted Renal Mitochondrial Homeostasis after Liver Transplantation in Rats

    PubMed Central

    Liu, Qinlong; Krishnasamy, Yasodha; Rehman, Hasibur; Lemasters, John J.; Schnellmann, Rick G.; Zhong, Zhi

    2015-01-01

    Background Suppressed mitochondrial biogenesis (MB) contributes to acute kidney injury (AKI) after many insults. AKI occurs frequently after liver transplantation (LT) and increases mortality. This study investigated whether disrupted mitochondrial homeostasis plays a role in AKI after LT. Methods Livers were explanted from Lewis rats and implanted after 18 h cold storage. Kidney and blood were collected 18 h after LT. Results In the kidney, oxidative phosphorylation (OXPHOS) proteins ATP synthase-? and NADH dehydrogenase-3 decreased 44% and 81%, respectively, with marked reduction in associated mRNAs. Renal PGC-1?, the major regulator of MB, decreased 57% with lower mRNA and increased acetylation, indicating inhibited synthesis and suppressed activation. Mitochondrial transcription factor-A, which controls mtDNA replication and transcription, protein and mRNA decreased 66% and 68%, respectively, which was associated with 64% decreases in mtDNA. Mitochondrial fission proteins Drp-1 and Fis-1 and mitochondrial fusion protein mitofusin-1 all decreased markedly. In contrast, PTEN-induced putative kinase 1 and microtubule-associated protein 1A/1B-light chain 3 increased markedly after LT, indicating enhanced mitophagy. Concurrently, 18- and 13-fold increases in neutrophil gelatinase-associated lipocalin and cleaved caspase-3 occurred in renal tissue. Both serum creatinine and blood urea nitrogen increased >2 fold. Mild to moderate histological changes were observed in the kidney, including loss of brush border, vacuolization of tubular cells in the cortex, cast formation and necrosis in some proximal tubular cells. Finally, myeloperoxidase and ED-1 also increased, indicating inflammation. Conclusion Suppression of MB, inhibition of mitochondrial fission/fusion and enhancement of mitophagy occur in the kidneys of recipients of liver grafts after long cold storage, which may contribute to the occurrence of AKI and increased mortality after LT. PMID:26480480

  15. GTP-dependent Formation of a Ribonucleoprotein Subcomplex Required for Ribosome Biogenesis

    E-print Network

    Doudna, Jennifer A.

    GTP-dependent Formation of a Ribonucleoprotein Subcomplex Required for Ribosome Biogenesis Katrin at Berkeley, Berkeley CA 94720-3206, USA Ribosome biogenesis in eukaryotic organisms involves the coordinated assembly of 78 ribosomal proteins onto the four ribosomal RNAs, mediated by a host of trans-acting factors

  16. Available online at www.sciencedirect.com Growth control and ribosome biogenesis

    E-print Network

    Halazonetis, Thanos

    Available online at www.sciencedirect.com Growth control and ribosome biogenesis Harri Lempia¨ inen and David Shore Ribosomes provide the basis for protein production and this drives cell growth. Recent the elaborate control of ribosome biogenesis, which requires coordinate regulation of all three RNA polymerases

  17. Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19.

    PubMed

    Saha, Prasenjit Prasad; Srivastava, Shubhi; Kumar S K, Praveen; Sinha, Devanjan; D'Silva, Patrick

    2015-10-23

    Biogenesis of the iron-sulfur (Fe-S) cluster is an indispensable process in living cells. In mammalian mitochondria, the initial step of the Fe-S cluster assembly process is assisted by the NFS1-ISD11 complex, which delivers sulfur to scaffold protein ISCU during Fe-S cluster synthesis. Although ISD11 is an essential protein, its cellular role in Fe-S cluster biogenesis is still not defined. Our study maps the important ISD11 amino acid residues belonging to putative helix 1 (Phe-40), helix 3 (Leu-63, Arg-68, Gln-69, Ile-72, Tyr-76), and C-terminal segment (Leu-81, Glu-84) are critical for in vivo Fe-S cluster biogenesis. Importantly, mutation of these conserved ISD11 residues into alanine leads to its compromised interaction with NFS1, resulting in reduced stability and enhanced aggregation of NFS1 in the mitochondria. Due to altered interaction with ISD11 mutants, the levels of NFS1 and Isu1 were significantly depleted, which affects Fe-S cluster biosynthesis, leading to reduced electron transport chain complex (ETC) activity and mitochondrial respiration. In humans, a clinically relevant ISD11 mutation (R68L) has been associated in the development of a mitochondrial genetic disorder, COXPD19. Our findings highlight that the ISD11 R68A/R68L mutation display reduced affinity to form a stable subcomplex with NFS1, and thereby fails to prevent NFS1 aggregation resulting in impairment of the Fe-S cluster biogenesis. The prime affected machinery is the ETC complex, which showed compromised redox properties, causing diminished mitochondrial respiration. Furthermore, the R68L ISD11 mutant displayed accumulation of mitochondrial iron and reactive oxygen species, leading to mitochondrial dysfunction, which correlates with the phenotype observed in COXPD19 patients. PMID:26342079

  18. Tissue- and Cell-Specific Mitochondrial Defect in Parkin-Deficient Mice

    PubMed Central

    Bulteau, Anne-Laure; Ferrando-Miguel, Rosa; Gouarne, Caroline; Paoli, Marc Giraudon; Pruss, Rebecca; Auchère, Françoise; L'Hermitte-Stead, Caroline; Bouillaud, Frédéric; Brice, Alexis; Corti, Olga; Lombès, Anne

    2014-01-01

    Loss of Parkin, encoded by PARK2 gene, is a major cause of autosomal recessive Parkinson's disease. In Drosophila and mammalian cell models Parkin has been shown in to play a role in various processes essential to maintenance of mitochondrial quality, including mitochondrial dynamics, biogenesis and degradation. However, the relevance of altered mitochondrial quality control mechanisms to neuronal survival in vivo is still under debate. We addressed this issue in the brain of PARK2?/? mice using an integrated mitochondrial evaluation, including analysis of respiration by polarography or by fluorescence, respiratory complexes activity by spectrophotometric assays, mitochondrial membrane potential by rhodamine 123 fluorescence, mitochondrial DNA content by real time PCR, and oxidative stress by total glutathione measurement, proteasome activity, SOD2 expression and proteins oxidative damage. Respiration rates were lowered in PARK2?/? brain with high resolution but not standard respirometry. This defect was specific to the striatum, where it was prominent in neurons but less severe in astrocytes. It was present in primary embryonic cells and did not worsen in vivo from 9 to 24 months of age. It was not associated with any respiratory complex defect, including complex I. Mitochondrial inner membrane potential in PARK2?/? mice was similar to that of wild-type mice but showed increased sensitivity to uncoupling with ageing in striatum. The presence of oxidative stress was suggested in the striatum by increased mitochondrial glutathione content and oxidative adducts but normal proteasome activity showed efficient compensation. SOD2 expression was increased only in the striatum of PARK2?/? mice at 24 months of age. Altogether our results show a tissue-specific mitochondrial defect, present early in life of PARK2?/? mice, mildly affecting respiration, without prominent impact on mitochondrial membrane potential, whose underlying mechanisms remain to be elucidated, as complex I defect and prominent oxidative damage were ruled out. PMID:24959870

  19. ?(1)-pyrroline-5-carboxylate/glutamate biogenesis is required for fungal virulence and sporulation.

    PubMed

    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

  20. Outer membrane lipoprotein biogenesis: Lol is not the end.

    PubMed

    Konovalova, Anna; Silhavy, Thomas J

    2015-10-01

    Bacterial lipoproteins are lipid-anchored proteins that contain acyl groups covalently attached to the N-terminal cysteine residue of the mature protein. Lipoproteins are synthesized in precursor form with an N-terminal signal sequence (SS) that targets translocation across the cytoplasmic or inner membrane (IM). Lipid modification and SS processing take place at the periplasmic face of the IM. Outer membrane (OM) lipoproteins take the localization of lipoproteins (Lol) export pathway, which ends with the insertion of the N-terminal lipid moiety into the inner leaflet of the OM. For many lipoproteins, the biogenesis pathway ends here. We provide examples of lipoproteins that adopt complex topologies in the OM that include transmembrane and surface-exposed domains. Biogenesis of such lipoproteins requires additional steps beyond the Lol pathway. In at least one case, lipoprotein sequences reach the cell surface by being threaded through the lumen of a beta-barrel protein in an assembly reaction that requires the heteropentomeric Bam complex. The inability to predict surface exposure reinforces the importance of experimental verification of lipoprotein topology and we will discuss some of the methods used to study OM protein topology. PMID:26370942

  1. Outer membrane protein biogenesis in Gram-negative bacteria.

    PubMed

    Rollauer, Sarah E; Sooreshjani, Moloud A; Noinaj, Nicholas; Buchanan, Susan K

    2015-10-01

    Gram-negative bacteria contain a double membrane which serves for both protection and for providing nutrients for viability. The outermost of these membranes is called the outer membrane (OM), and it contains a host of fully integrated membrane proteins which serve essential functions for the cell, including nutrient uptake, cell adhesion, cell signalling and waste export. For pathogenic strains, many of these outer membrane proteins (OMPs) also serve as virulence factors for nutrient scavenging and evasion of host defence mechanisms. OMPs are unique membrane proteins in that they have a ?-barrel fold and can range in size from 8 to 26 strands, yet can still serve many different functions for the cell. Despite their essential roles in cell survival and virulence, the exact mechanism for the biogenesis of these OMPs into the OM has remained largely unknown. However, the past decade has witnessed significant progress towards unravelling the pathways and mechanisms necessary for moulding a nascent polypeptide into a functional OMP within the OM. Here, we will review some of these recent discoveries that have advanced our understanding of the biogenesis of OMPs in Gram-negative bacteria, starting with synthesis in the cytoplasm to folding and insertion into the OM. PMID:26370935

  2. Microalgal lipid droplets: composition, diversity, biogenesis and functions.

    PubMed

    Goold, Hugh; Beisson, Fred; Peltier, Gilles; Li-Beisson, Yonghua

    2015-04-01

    Lipid droplet is the major site of neutral lipid storage in eukaryotic cells, and increasing evidence show its involvement in numerous cellular processes such as lipid homeostasis, signaling, trafficking and inter-organelle communications. Although the biogenesis, structure, and functions of lipid droplets have been well documented for seeds of vascular plants, mammalian adipose tissues, insects and yeasts, relative little is known about lipid droplets in microalgae. Over the past 5 years, the growing interest of microalgae as a platform for biofuel, green chemicals or value-added polyunsaturated fatty acid production has brought algal lipid droplets into spotlight. Studies conducted on the green microalga Chlamydomonas reinhardtii and other model microalgae such as Haematococcus and Nannochloropsis species have led to the identification of proteins associated with lipid droplets, which include putative structural proteins different from plant oleosins and animal perilipins, as well as candidate proteins for lipid biosynthesis, mobilization, trafficking and homeostasis. Biochemical and microscopy studies have also started to shed light on the role of chloroplasts in the biogenesis of lipid droplets in Chlamydomonas. PMID:25433857

  3. Dynamic evolution and biogenesis of small RNAs during sex reversal

    PubMed Central

    Liu, Jie; Luo, Majing; Sheng, Yue; Hong, Qiang; Cheng, Hanhua; Zhou, Rongjia

    2015-01-01

    Understanding origin, evolution and functions of small RNA (sRNA) genes has been a great challenge in the past decade. Molecular mechanisms underlying sexual reversal in vertebrates, particularly sRNAs involved in this process, are largely unknown. By deep-sequencing of small RNA transcriptomes in combination with genomic analysis, we identified a large amount of piRNAs and miRNAs including over 1,000 novel miRNAs, which were differentially expressed during gonad reversal from ovary to testis via ovotesis. Biogenesis and expressions of miRNAs were dynamically changed during the reversal. Notably, phylogenetic analysis revealed dynamic expansions of miRNAs in vertebrates and an evolutionary trajectory of conserved miR-17-92 cluster in the Eukarya. We showed that the miR-17-92 cluster in vertebrates was generated through multiple duplications from ancestor miR-92 in invertebrates Tetranychus urticae and Daphnia pulex from the Chelicerata around 580 Mya. Moreover, we identified the sexual regulator Dmrt1 as a direct target of the members miR-19a and -19b in the cluster. These data suggested dynamic biogenesis and expressions of small RNAs during sex reversal and revealed multiple expansions and evolutionary trajectory of miRNAs from invertebrates to vertebrates, which implicate small RNAs in sexual reversal and provide new insight into evolutionary and molecular mechanisms underlying sexual reversal. PMID:25944477

  4. Syntenin and syndecan in the biogenesis of exosomes.

    PubMed

    Friand, Véronique; David, Guido; Zimmermann, Pascale

    2015-10-01

    Cells communicate with their environment in various ways, including by secreting vesicles. Secreted vesicles are loaded with proteins, lipids and RNAs that compose 'a signature' of the cell of origin and potentially can reprogram recipient cells. Secreted vesicles recently gained in interest for medicine. They represent potential sources of biomarkers that can be collected from body fluids and, by disseminating pathogenic proteins, might also participate in systemic diseases like cancer, atherosclerosis and neurodegeneration. The mechanisms controlling the biogenesis and the uptake of secreted vesicles are poorly understood. Some of these vesicles originate from endosomes and are called 'exosomes'. In this review, we recapitulate recent insight on the role of the syndecan (SDC) heparan sulphate proteoglycans, the small intracellular adaptor syntenin and associated regulators in the biogenesis and loading of exosomes with cargo. SDC-syntenin-associated regulators include the endosomal sorting complex required for transport accessory component ALG-2-interacting protein X, the small GTPase adenosine 5'-diphosphate-ribosylation factor 6, the lipid-modifying enzyme phospholipase D2 and the endoglycosidase heparanase. All these molecules appear to support the budding of SDC-syntenin and associated cargo into the lumen of endosomes. This highlights a major mechanism for the formation of intraluminal vesicles that will be released as exosomes. PMID:26032692

  5. Preliminary X-ray crystallographic studies of yeast mitochondrial protein Tom70p

    SciTech Connect

    Wu, Yunkun; McCombs, Debbie; Nagy, Lisa; DeLucas, Lawrence; Sha, Bingdong

    2006-03-01

    Tom70p is an important translocase of the outer membrane complex member and a major surface receptor of the protein-translocation machinery in the outer mitochondrial membrane. To investigate the mechanism by which Tom70p functions to deliver the mitochondrial protein precursors, the cytosolic fragment of yeast Tom70p (cTom70p) has been crystallized. Protein translocations across mitochondrial membranes play critical roles in mitochondrion biogenesis. Protein transport from the cell cytosol to the mitochondrial matrix is carried out by the translocase of the outer membrane (TOM) complex and the translocase of the inner membrane (TIM) complexes. Tom70p is an important TOM-complex member and a major surface receptor of the protein-translocation machinery in the outer mitochondrial membrane. To investigate the mechanism by which Tom70p functions to deliver the mitochondrial protein precursors, the cytosolic fragment of yeast Tom70p (cTom70p) was crystallized. The crystals diffract to 3.2 Å using a synchrotron X-ray source and belong to space group P2{sub 1}, with unit-cell parameters a = 44.89, b = 168.78, c = 83.41 Å, ? = 90.00, ? = 102.74, ? = 90.00°. There are two Tom70p molecules in one asymmetric unit, which corresponds to a solvent content of approximately 51%. Structure determination by MAD methods is under way.

  6. Preliminary crystallographic studies of yeast mitochondrial peripheral membrane protein Tim44p

    SciTech Connect

    Josyula, Ratnakar; Jin, Zhongmin; McCombs, Deborah; DeLucas, Lawrence; Sha, Bingdong

    2006-02-01

    Tim44p is an essential mitochondrial peripheral membrane protein. To investigate the mechanism by which Tim44p functions in the TIM23 translocon to deliver the mitochondrial protein precursors, the yeast Tim44p has been crystallized. Protein translocations across mitochondrial membranes play critical roles in mitochondrion biogenesis. Protein transport from the cell cytosol to the mitochondrial matrix is carried out by the translocase of the outer membrane (TOM) complex and the translocase of the inner membrane (TIM) complexes. Tim44p is an essential mitochondrial peripheral membrane protein and a major component of the TIM23 translocon. To investigate the mechanism by which Tim44p functions in the TIM23 translocon to deliver the mitochondrial protein precursors, the yeast Tim44p was crystallized. The crystals diffract to 3.2 Å using a synchrotron X-ray source and belong to space group P6{sub 3}22, with unit-cell parameters a = 124.25, c = 77.83 Å. There is one Tim44p molecule in one asymmetric unit, which corresponds to a solvent content of approximately 43%. Structure determination by MAD methods is under way.

  7. Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-?.

    PubMed

    Distelmaier, Felix; Valsecchi, Federica; Liemburg-Apers, Dania C; Lebiedzinska, Magdalena; Rodenburg, Richard J; Heil, Sandra; Keijer, Jaap; Fransen, Jack; Imamura, Hiromi; Danhauser, Katharina; Seibt, Annette; Viollet, Benoit; Gellerich, Frank N; Smeitink, Jan A M; Wieckowski, Mariusz R; Willems, Peter H G M; Koopman, Werner J H

    2015-03-01

    Dysfunction of complex I (CI) of the mitochondrial electron transport chain (ETC) features prominently in human pathology. Cell models of ETC dysfunction display adaptive survival responses that still are poorly understood but of relevance for therapy development. Here we comprehensively examined how primary human skin fibroblasts adapt to chronic CI inhibition. CI inhibition triggered transient and sustained changes in metabolism, redox homeostasis and mitochondrial (ultra)structure but no cell senescence/death. CI-inhibited cells consumed no oxygen and displayed minor mitochondrial depolarization, reverse-mode action of complex V, a slower proliferation rate and futile mitochondrial biogenesis. Adaptation was neither prevented by antioxidants nor associated with increased PGC1-?/SIRT1/mTOR levels. Survival of CI-inhibited cells was strictly glucose-dependent and accompanied by increased AMPK-? phosphorylation, which occurred without changes in ATP or cytosolic calcium levels. Conversely, cells devoid of AMPK-? died upon CI inhibition. Chronic CI inhibition did not increase mitochondrial superoxide levels or cellular lipid peroxidation and was paralleled by a specific increase in SOD2/GR, whereas SOD1/CAT/Gpx1/Gpx2/Gpx5 levels remained unchanged. Upon hormone stimulation, fully adapted cells displayed aberrant cytosolic and ER calcium handling due to hampered ATP fueling of ER calcium pumps. It is concluded that CI dysfunction triggers an adaptive program that depends on extracellular glucose and AMPK-?. This response avoids cell death by suppressing energy crisis, oxidative stress induction and substantial mitochondrial depolarization. PMID:25536029

  8. Centella asiatica attenuates ?-amyloid-induced oxidative stress and mitochondrial dysfunction

    PubMed Central

    Gray, Nora E.; Sampath, Harini; Zweig, Jonathan A.; Quinn, Joseph F.; Soumyanath, Amala

    2015-01-01

    Background We previously showed that a water extract of the medicinal plant Centella asiatica (CAW) attenuates ?-amyloid (A?)-induced cognitive deficits in vivo, and prevents A?-induced cytotoxicity in vitro. Yet the neuroprotective mechanism of CAW is unknown. Objective The goal of this study was to identify biochemical pathways altered by CAW using in vitro models of A? toxicity. Methods The effects of CAW on aberrations in antioxidant response, calcium homeostasis and mitochondrial function induced by A? were evaluated in MC65 and SH-SY5Y neuroblastoma cells. Results CAW decreased intracellular ROS and calcium levels elevated in response to A?, and induced the expression of antioxidant response genes in both cell lines. In SH-SY5Y cells, CAW increased basal and maximal oxygen consumption without altering spare capacity, and attenuated A?-induced decreases in mitochondrial respiration. CAW also prevented A? –induced decreases in ATP and induced the expression of mitochondrial genes and proteins in both cell types. Caffeoylquinic acids from CAW were shown to have a similar effect on antioxidant and mitochondrial gene expression in neuroblastoma cells. Primary rat hippocampal neurons treated with CAW also showed an increase in mitochondrial and antioxidant gene expression. Conclusions These data suggest an effect of CAW on mitochondrial biogenesis, which in conjunction with activation of antioxidant response genes and normalizing calcium homeostasis, likely contributes to its neuroprotective action against A? toxicity. PMID:25633675

  9. Mitochondrial mass, a new metabolic biomarker for stem-like cancer cells: Understanding WNT/FGF-driven anabolic signaling.

    PubMed

    Lamb, Rebecca; Bonuccelli, Gloria; Ozsvári, Béla; Peiris-Pagès, Maria; Fiorillo, Marco; Smith, Duncan L; Bevilacqua, Generoso; Mazzanti, Chiara Maria; McDonnell, Liam A; Naccarato, Antonio Giuseppe; Chiu, Maybo; Wynne, Luke; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2015-10-13

    Here, we developed an isogenic cell model of "stemness" to facilitate protein biomarker discovery in breast cancer. For this purpose, we used knowledge gained previously from the study of the mouse mammary tumor virus (MMTV). MMTV initiates mammary tumorigenesis in mice by promoter insertion adjacent to two main integration sites, namely Int-1 (Wnt1) and Int-2 (Fgf3), which ultimately activates Wnt/?-catenin signaling, driving the propagation of mammary cancer stem cells (CSCs). Thus, to develop a humanized model of MMTV signaling, we over-expressed WNT1 and FGF3 in MCF7 cells, an ER(+) human breast cancer cell line. We then validated that MCF7 cells over-expressing both WNT1 and FGF3 show a 3.5-fold increase in mammosphere formation, and that conditioned media from these cells is also sufficient to promote stem cell activity in untransfected parental MCF7 and T47D cells, as WNT1 and FGF3 are secreted factors. Proteomic analysis of this model system revealed the induction of i) EMT markers, ii) mitochondrial proteins, iii) glycolytic enzymes and iv) protein synthesis machinery, consistent with an anabolic CSC phenotype. MitoTracker staining validated the expected WNT1/FGF3-induced increase in mitochondrial mass and activity, which presumably reflects increased mitochondrial biogenesis. Importantly, many of the proteins that were up-regulated by WNT/FGF-signaling in MCF7 cells, were also transcriptionally over-expressed in human breast cancer cells in vivo, based on the bioinformatic analysis of public gene expression datasets of laser-captured patient samples. As such, this isogenic cell model should accelerate the discovery of new biomarkers to predict clinical outcome in breast cancer, facilitating the development of personalized medicine.Finally, we used mitochondrial mass as a surrogate marker for increased mitochondrial biogenesis in untransfected MCF7 cells. As predicted, metabolic fractionation of parental MCF7 cells, via MitoTracker staining, indicated that high mitochondrial mass is a new metabolic biomarker for the enrichment of anabolic CSCs, as functionally assessed by mammosphere-forming activity. This observation has broad implications for understanding the role of mitochondrial biogenesis in the propagation of stem-like cancer cells. Technically, this general metabolic approach could be applied to any cancer type, to identify and target the mitochondrial-rich CSC population.The implications of our work for understanding the role of mitochondrial metabolism in viral oncogenesis driven by random promoter insertions are also discussed, in the context of MMTV and ALV infections. PMID:26421711

  10. 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

  11. Mitochondrial threshold effects.

    PubMed Central

    Rossignol, Rodrigue; Faustin, Benjamin; Rocher, Christophe; Malgat, Monique; Mazat, Jean-Pierre; Letellier, Thierry

    2003-01-01

    The study of mitochondrial diseases has revealed dramatic variability in the phenotypic presentation of mitochondrial genetic defects. To attempt to understand this variability, different authors have studied energy metabolism in transmitochondrial cell lines carrying different proportions of various pathogenic mutations in their mitochondrial DNA. The same kinds of experiments have been performed on isolated mitochondria and on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, phenotypic manifestation of the genetic defect occurs only when a threshold level is exceeded, and this phenomenon has been named the 'phenotypic threshold effect'. Subsequently, several authors showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the 'biochemical threshold effect'. More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a 'translational threshold effect'. In this review these different mitochondrial threshold effects are discussed, along with their molecular bases and the roles that they play in the presentation of mitochondrial diseases. PMID:12467494

  12. High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation.

    PubMed

    Larsen, Filip J; Schiffer, Tomas A; Ørtenblad, Niels; Zinner, Christoph; Morales-Alamo, David; Willis, Sarah J; Calbet, Jose A; Holmberg, Hans-Christer; Boushel, Robert

    2016-01-01

    Intense exercise training is a powerful stimulus that activates mitochondrial biogenesis pathways and thus increases mitochondrial density and oxidative capacity. Moderate levels of reactive oxygen species (ROS) during exercise are considered vital in the adaptive response, but high ROS production is a serious threat to cellular homeostasis. Although biochemical markers of the transition from adaptive to maladaptive ROS stress are lacking, it is likely mediated by redox sensitive enzymes involved in oxidative metabolism. One potential enzyme mediating such redox sensitivity is the citric acid cycle enzyme aconitase. In this study, we examined biopsy specimens of vastus lateralis and triceps brachii in healthy volunteers, together with primary human myotubes. An intense exercise regimen inactivated aconitase by 55-72%, resulting in inhibition of mitochondrial respiration by 50-65%. In the vastus, the mitochondrial dysfunction was compensated for by a 15-72% increase in mitochondrial proteins, whereas H2O2 emission was unchanged. In parallel with the inactivation of aconitase, the intermediary metabolite citrate accumulated and played an integral part in cellular protection against oxidative stress. In contrast, the triceps failed to increase mitochondrial density, and citrate did not accumulate. Instead, mitochondrial H2O2 emission was decreased to 40% of the pretraining levels, together with a 6-fold increase in protein abundance of catalase. In this study, a novel mitochondrial stress response was highlighted where accumulation of citrate acted to preserve the redox status of the cell during periods of intense exercise.-Larsen, F. J., Schiffer, T. A., Ørtenblad, N., Zinner, C., Morales-Alamo, D., Willis, S. J., Calbet, J. A., Holmberg, H.-C., Boushel, R. High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation. PMID:26452378

  13. 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

  14. Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans.

    PubMed

    Schiavi, Alfonso; Maglioni, Silvia; Palikaras, Konstantinos; Shaik, Anjumara; Strappazzon, Flavie; Brinkmann, Vanessa; Torgovnick, Alessandro; Castelein, Natascha; De Henau, Sasha; Braeckman, Bart P; Cecconi, Francesco; Tavernarakis, Nektarios; Ventura, Natascia

    2015-07-20

    Frataxin is a nuclear-encoded mitochondrial protein involved in the biogenesis of Fe-S-cluster-containing proteins and consequently in the functionality of the mitochondrial respiratory chain. Similar to other proteins that regulate mitochondrial respiration, severe frataxin deficiency leads to pathology in humans--Friedreich's ataxia, a life-threatening neurodegenerative disorder--and to developmental arrest in the nematode C. elegans. Interestingly, partial frataxin depletion extends C. elegans lifespan, and a similar anti-aging effect is prompted by reduced expression of other mitochondrial regulatory proteins from yeast to mammals. The beneficial adaptive responses to mild mitochondrial stress are still largely unknown and, if characterized, may suggest novel potential targets for the treatment of human mitochondria-associated, age-related disorders. Here we identify mitochondrial autophagy as an evolutionarily conserved response to frataxin silencing, and show for the first time that, similar to mammals, mitophagy is activated in C. elegans in response to mitochondrial stress in a pdr-1/Parkin-, pink-1/Pink-, and dct-1/Bnip3-dependent manner. The induction of mitophagy is part of a hypoxia-like, iron starvation response triggered upon frataxin depletion and causally involved in animal lifespan extension. We also identify non-overlapping hif-1 upstream (HIF-1-prolyl-hydroxylase) and downstream (globins) regulatory genes mediating lifespan extension upon frataxin and iron depletion. Our findings indicate that mitophagy induction is part of an adaptive iron starvation response induced as a protective mechanism against mitochondrial stress, thus suggesting novel potential therapeutic strategies for the treatment of mitochondrial-associated, age-related disorders. PMID:26144971

  15. 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

  16. AMPK? is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle.

    PubMed

    Fentz, Joachim; Kjøbsted, Rasmus; Kristensen, Caroline Maag; Hingst, Janne Rasmus; Birk, Jesper Bratz; Gudiksen, Anders; Foretz, Marc; Schjerling, Peter; Viollet, Benoit; Pilegaard, Henriette; Wojtaszewski, Jørgen F P

    2015-12-01

    Exercise training increases skeletal muscle expression of metabolic proteins improving the oxidative capacity. Adaptations in skeletal muscle by pharmacologically induced activation of 5'-AMP-activated protein kinase (AMPK) are dependent on the AMPK?2 subunit. We hypothesized that exercise training-induced increases in exercise capacity and expression of metabolic proteins, as well as acute exercise-induced gene regulation, would be compromised in muscle-specific AMPK?1 and -?2 double-knockout (mdKO) mice. An acute bout of exercise increased skeletal muscle mRNA content of cytochrome c oxidase subunit I, glucose transporter 4, and VEGF in an AMPK-dependent manner, whereas cluster of differentiation 36 and fatty acid transport protein 1 mRNA content increased similarly in AMPK? wild-type (WT) and mdKO mice. During 4 wk of voluntary running wheel exercise training, the AMPK? mdKO mice ran less than WT. Maximal running speed was lower in AMPK? mdKO than in WT mice but increased similarly in both genotypes with exercise training. Exercise training increased quadriceps protein content of ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), cytochrome c, hexokinase II, plasma membrane fatty acid-binding protein, and citrate synthase activity more in AMPK? WT than in mdKO muscle. However, analysis of a subgroup of mice matched for running distance revealed that only UQCRC1 protein content increased more in WT than in mdKO mice with exercise training. Thus, AMPK?1 and -?2 subunits are important for acute exercise-induced mRNA responses of some genes and may be involved in regulating basal metabolic protein expression but seem to be less important in exercise training-induced adaptations in metabolic proteins. PMID:26419588

  17. 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

  18. The emerging role of Nrf2 in mitochondrial function.

    PubMed

    Dinkova-Kostova, Albena T; Abramov, Andrey Y

    2015-11-01

    The transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) allows adaptation and survival under conditions of stress by regulating the gene expression of diverse networks of cytoprotective proteins, including antioxidant, anti-inflammatory, and detoxification enzymes as well as proteins that assist in the repair or removal of damaged macromolecules. Nrf2 has a crucial role in the maintenance of cellular redox homeostasis by regulating the biosynthesis, utilization, and regeneration of glutathione, thioredoxin, and NADPH and by controlling the production of reactive oxygen species by mitochondria and NADPH oxidase. Under homeostatic conditions, Nrf2 affects the mitochondrial membrane potential, fatty acid oxidation, availability of substrates (NADH and FADH2/succinate) for respiration, and ATP synthesis. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria via transcriptional upregulation of uncoupling protein 3 and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor ? coactivator 1?, as well as by promoting purine nucleotide biosynthesis. Pharmacological Nrf2 activators, such as the naturally occurring isothiocyanate sulforaphane, inhibit oxidant-mediated opening of the mitochondrial permeability transition pore and mitochondrial swelling. Curiously, a synthetic 1,4-diphenyl-1,2,3-triazole compound, originally designed as an Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis. Thus, Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress. PMID:25975984

  19. Long mRNAs coding for yeast mitochondrial proteins of prokaryotic origin preferentially localize to the vicinity of mitochondria

    PubMed Central

    Sylvestre, Julien; Vialette, Stéphane; Corral Debrinski, Marisol; Jacq, Claude

    2003-01-01

    Background Subcellular messenger RNA localization is important in most eukaryotic cells, even in unicellular organisms like yeast for which this process has been underestimated. Microarrays are rarely used to study subcellular mRNA localization at whole-genome level, but can be adapted to that purpose. This work focuses on studying the repartition of yeast nuclear transcripts encoding mitochondrial proteins between free cytosolic polysomes and polysomes bound to the mitochondrial outer membrane. Results Combining biochemical fractionations with oligonucleotide array analyses permits clustering of genes on the basis of the subcellular sites of their mRNA translation. A large fraction of yeast nuclear transcripts known to encode mitochondrial proteins is found in mitochondrial outer-membrane-bound fractions. These results confirm and extend a previous analysis conducted with partial genomic microarrays. Interesting statistical relations among mRNA localization, gene origin and mRNA lengths were found: longer and older mRNAs are more prone to be localized to the vicinity of mitochondria. These observations are included in a refined model of mitochondrial protein import. Conclusions Mitochondrial biogenesis requires concerted expression of the many genes whose products make up the organelle. In the absence of any clear transcriptional program, coordinated mRNA localization could be an important element of the time-course of organelle construction. We have built a 'MitoChip' localization database from our results which allows us to identify interesting genes whose mRNA localization might be essential for mitochondrial biogenesis in most eukaryotic cells. Moreover, many components of the experimental and data-analysis strategy implemented here are of general relevance in global transcription studies. PMID:12844360

  20. New tricks for an old dog: ribosome biogenesis contributes to stem cell homeostasis.

    PubMed

    Brombin, Alessandro; Joly, Jean-Stéphane; Jamen, Françoise

    2015-10-01

    Although considered a 'house-keeping' function, ribosome biogenesis is regulated differently between cells and can be modulated in a cell-type-specific manner. These differences are required to generate specialized ribosomes that contribute to the translational control of gene expression by selecting mRNA subsets to be translated. Thus, differences in ribosome biogenesis between stem and differentiated cells indirectly contribute to determine cell identity. The concept of the existence of stem cell-specific mechanisms of ribosome biogenesis has progressed from an attractive theory to a useful working model with important implications for basic and medical research. PMID:26343009

  1. Changes in ribosome biogenesis may induce cancer by down-regulating the cell tumor suppressor potential.

    PubMed

    Montanaro, Lorenzo; Treré, Davide; Derenzini, Massimo

    2012-01-01

    Many human pathological conditions, not linked to genetic alterations of oncogenes or tumor suppressors, are nevertheless associated with an increased risk of developing cancer, and some of them are characterized by quantitative and/or qualitative changes in ribosome biogenesis. Indeed, there is evidence that both an up-regulation of ribosome biogenesis, such as that occurring during the abnormal stimulation of cell growth, and intrinsic dysfunctions of ribosomes, such as those characterizing a series of inherited disorders, show an increased incidence of tumor onset. Here we discuss some recent insights into the mechanisms by which these alterations in ribosome biogenesis may facilitate tumorigenesis. PMID:22079382

  2. Flexibility in targeting and insertion during bacterial membrane protein biogenesis

    SciTech Connect

    Bloois, Edwin van; Hagen-Jongman, Corinne M. ten; Luirink, Joen

    2007-10-26

    The biogenesis of Escherichia coli inner membrane proteins (IMPs) is assisted by targeting and insertion factors such as the signal recognition particle (SRP), the Sec-translocon and YidC with translocation of (large) periplasmic domains energized by SecA and the proton motive force (pmf). The use of these factors and forces is probably primarily determined by specific structural features of an IMP. To analyze these features we have engineered a set of model IMPs based on endogenous E. coli IMPs known to follow distinct targeting and insertion pathways. The modified model IMPs were analyzed for altered routing using an in vivo protease mapping approach. The data suggest a facultative use of different combinations of factors.

  3. The Virus-Host Interplay: Biogenesis of +RNA Replication Complexes

    PubMed Central

    Reid, Colleen R.; Airo, Adriana M.; Hobman, Tom C.

    2015-01-01

    Positive-strand RNA (+RNA) viruses are an important group of human and animal pathogens that have significant global health and economic impacts. Notable members include West Nile virus, Dengue virus, Chikungunya, Severe acute respiratory syndrome (SARS) Coronavirus and enteroviruses of the Picornaviridae family.Unfortunately, prophylactic and therapeutic treatments against these pathogens are limited. +RNA viruses have limited coding capacity and thus rely extensively on host factors for successful infection and propagation. A common feature among these viruses is their ability to dramatically modify cellular membranes to serve as platforms for genome replication and assembly of new virions. These viral replication complexes (VRCs) serve two main functions: To increase replication efficiency by concentrating critical factors and to protect the viral genome from host anti-viral systems. This review summarizes current knowledge of critical host factors recruited to or demonstrated to be involved in the biogenesis and stabilization of +RNA virus VRCs. PMID:26287230

  4. Getting ready for building: signaling and autophagosome biogenesis

    PubMed Central

    Abada, Adi; Elazar, Zvulun

    2014-01-01

    Autophagy is the main cellular catabolic process responsible for degrading organelles and large protein aggregates. It is initiated by the formation of a unique membrane structure, the phagophore, which engulfs part of the cytoplasm and forms a double-membrane vesicle termed the autophagosome. Fusion of the outer autophagosomal membrane with the lysosome and degradation of the inner membrane contents complete the process. The extent of autophagy must be tightly regulated to avoid destruction of proteins and organelles essential for cell survival. Autophagic activity is thus regulated by external and internal cues, which initiate the formation of well-defined autophagy-related protein complexes that mediate autophagosome formation and selective cargo recruitment into these organelles. Autophagosome formation and the signaling pathways that regulate it have recently attracted substantial attention. In this review, we analyze the different signaling pathways that regulate autophagy and discuss recent progress in our understanding of autophagosome biogenesis. PMID:25027988

  5. Myristoylated CIL-7 regulates ciliary extracellular vesicle biogenesis

    PubMed Central

    Maguire, Julie E.; Silva, Malan; Nguyen, Ken C.Q.; Hellen, Elizabeth; Kern, Andrew D.; Hall, David H.; Barr, Maureen M.

    2015-01-01

    The cilium both releases and binds to extracellular vesicles (EVs). EVs may be used by cells as a form of intercellular communication and mediate a broad range of physiological and pathological processes. The mammalian polycystins (PCs) localize to cilia, as well as to urinary EVs released from renal epithelial cells. PC ciliary trafficking defects may be an underlying cause of autosomal dominant polycystic kidney disease (PKD), and ciliary–EV interactions have been proposed to play a central role in the biology of PKD. In Caenorhabditis elegans and mammals, PC1 and PC2 act in the same genetic pathway, act in a sensory capacity, localize to cilia, and are contained in secreted EVs, suggesting ancient conservation. However, the relationship between cilia and EVs and the mechanisms generating PC-containing EVs remain an enigma. In a forward genetic screen for regulators of C. elegans PKD-2 ciliary localization, we identified CIL-7, a myristoylated protein that regulates EV biogenesis. Loss of CIL-7 results in male mating behavioral defects, excessive accumulation of EVs in the lumen of the cephalic sensory organ, and failure to release PKD-2::GFP-containing EVs to the environment. Fatty acylation, such as myristoylation and palmitoylation, targets proteins to cilia and flagella. The CIL-7 myristoylation motif is essential for CIL-7 function and for targeting CIL-7 to EVs. C. elegans is a powerful model with which to study ciliary EV biogenesis in vivo and identify cis-targeting motifs such as myristoylation that are necessary for EV–cargo association and function. PMID:26041936

  6. Exosome Biogenesis, Regulation, and Function in Viral Infection.

    PubMed

    Alenquer, Marta; Amorim, Maria João

    2015-09-01

    Exosomes are extracellular vesicles released upon fusion of multivesicular bodies(MVBs) with the cellular plasma membrane. They originate as intraluminal vesicles (ILVs) during the process of MVB formation. Exosomes were shown to contain selectively sorted functional proteins, lipids, and RNAs, mediating cell-to-cell communications and hence playing a role in the physiology of the healthy and diseased organism. Challenges in the field include the identification of mechanisms sustaining packaging of membrane-bound and soluble material to these vesicles and the understanding of the underlying processes directing MVBs for degradation or fusion with the plasma membrane. The investigation into the formation and roles of exosomes in viral infection is in its early years. Although still controversial, exosomes can, in principle, incorporate any functional factor, provided they have an appropriate sorting signal, and thus are prone to viral exploitation.This review initially focuses on the composition and biogenesis of exosomes. It then explores the regulatory mechanisms underlying their biogenesis. Exosomes are part of the endocytic system,which is tightly regulated and able to respond to several stimuli that lead to alterations in the composition of its sub-compartments. We discuss the current knowledge of how these changes affect exosomal release. We then summarize how different viruses exploit specific proteins of endocytic sub-compartments and speculate that it could interfere with exosome function, although no direct link between viral usage of the endocytic system and exosome release has yet been reported. Many recent reports have ascribed functions to exosomes released from cells infected with a variety of animal viruses, including viral spread, host immunity, and manipulation of the microenvironment, which are discussed. Given the ever-growing roles and importance of exosomes in viral infections, understanding what regulates their composition and levels, and defining their functions will ultimately provide additional insights into the virulence and persistence of infections. PMID:26393640

  7. Exosome Biogenesis, Regulation, and Function in Viral Infection

    PubMed Central

    Alenquer, Marta; Amorim, Maria João

    2015-01-01

    Exosomes are extracellular vesicles released upon fusion of multivesicular bodies (MVBs) with the cellular plasma membrane. They originate as intraluminal vesicles (ILVs) during the process of MVB formation. Exosomes were shown to contain selectively sorted functional proteins, lipids, and RNAs, mediating cell-to-cell communications and hence playing a role in the physiology of the healthy and diseased organism. Challenges in the field include the identification of mechanisms sustaining packaging of membrane-bound and soluble material to these vesicles and the understanding of the underlying processes directing MVBs for degradation or fusion with the plasma membrane. The investigation into the formation and roles of exosomes in viral infection is in its early years. Although still controversial, exosomes can, in principle, incorporate any functional factor, provided they have an appropriate sorting signal, and thus are prone to viral exploitation. This review initially focuses on the composition and biogenesis of exosomes. It then explores the regulatory mechanisms underlying their biogenesis. Exosomes are part of the endocytic system, which is tightly regulated and able to respond to several stimuli that lead to alterations in the composition of its sub-compartments. We discuss the current knowledge of how these changes affect exosomal release. We then summarize how different viruses exploit specific proteins of endocytic sub-compartments and speculate that it could interfere with exosome function, although no direct link between viral usage of the endocytic system and exosome release has yet been reported. Many recent reports have ascribed functions to exosomes released from cells infected with a variety of animal viruses, including viral spread, host immunity, and manipulation of the microenvironment, which are discussed. Given the ever-growing roles and importance of exosomes in viral infections, understanding what regulates their composition and levels, and defining their functions will ultimately provide additional insights into the virulence and persistence of infections. PMID:26393640

  8. Myristoylated CIL-7 regulates ciliary extracellular vesicle biogenesis.

    PubMed

    Maguire, Julie E; Silva, Malan; Nguyen, Ken C Q; Hellen, Elizabeth; Kern, Andrew D; Hall, David H; Barr, Maureen M

    2015-08-01

    The cilium both releases and binds to extracellular vesicles (EVs). EVs may be used by cells as a form of intercellular communication and mediate a broad range of physiological and pathological processes. The mammalian polycystins (PCs) localize to cilia, as well as to urinary EVs released from renal epithelial cells. PC ciliary trafficking defects may be an underlying cause of autosomal dominant polycystic kidney disease (PKD), and ciliary-EV interactions have been proposed to play a central role in the biology of PKD. In Caenorhabditis elegans and mammals, PC1 and PC2 act in the same genetic pathway, act in a sensory capacity, localize to cilia, and are contained in secreted EVs, suggesting ancient conservation. However, the relationship between cilia and EVs and the mechanisms generating PC-containing EVs remain an enigma. In a forward genetic screen for regulators of C. elegans PKD-2 ciliary localization, we identified CIL-7, a myristoylated protein that regulates EV biogenesis. Loss of CIL-7 results in male mating behavioral defects, excessive accumulation of EVs in the lumen of the cephalic sensory organ, and failure to release PKD-2::GFP-containing EVs to the environment. Fatty acylation, such as myristoylation and palmitoylation, targets proteins to cilia and flagella. The CIL-7 myristoylation motif is essential for CIL-7 function and for targeting CIL-7 to EVs. C. elegans is a powerful model with which to study ciliary EV biogenesis in vivo and identify cis-targeting motifs such as myristoylation that are necessary for EV-cargo association and function. PMID:26041936

  9. Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis.

    PubMed

    Russell, Aaron P; Wada, Shogo; Vergani, Lodovica; Hock, M Benjamin; Lamon, Séverine; Léger, Bertrand; Ushida, Takashi; Cartoni, Romain; Wadley, Glenn D; Hespel, Peter; Kralli, Anastasia; Soraru, Gianni; Angelini, Corrado; Akimoto, Takayuki

    2013-01-01

    Skeletal muscle mitochondrial dysfunction is believed to play a role in the progression and severity of amyotrophic lateral sclerosis (ALS). The regulation of transcriptional co-activators involved in mitochondrial biogenesis and function in ALS is not well known. When compared with healthy control subjects, patients with ALS, but not neurogenic disease (ND), had lower levels of skeletal muscle peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) mRNA and protein and estrogen-related receptor-? (ERR?) and mitofusin-2 (Mfn2) mRNA. PGC-1?, nuclear respiratory factor-1 (NRF-1) and Mfn1 mRNA as well as cytochrome C oxidase subunit IV (COXIV) mRNA and protein were lower in patients with ALS and ND. Both patient groups had reductions in citrate synthase and cytochrome c oxidase activity. Similar observations were made in skeletal muscle from transgenic ALS G93A transgenic mice. In vitro, PGC-1? and PGC-1? regulated Mfn1 and Mfn2 in an ERR?-dependent manner. Compared to healthy controls, miRNA 23a, 29b, 206 and 455 were increased in skeletal muscle of ALS patients. miR-23a repressed PGC-1? translation in a 3' UTR dependent manner. Transgenic mice over expressing miR-23a had a reduction in PGC-1?, cytochome-b and COXIV protein levels. These results show that skeletal muscle mitochondrial dysfunction in ALS patients is associated with a reduction in PGC-1? signalling networks involved in mitochondrial biogenesis and function, as well as increases in several miRNAs potentially implicated in skeletal muscle and neuromuscular junction regeneration. As miR-23a negatively regulates PGC-1? signalling, therapeutic inhibition of miR-23a may be a strategy to rescue PGC-1? activity and ameliorate skeletal muscle mitochondrial function in ALS. PMID:22975021

  10. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi's Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

    PubMed Central

    Szalárdy, Levente; Zádori, Dénes; Klivényi, Péter; Toldi, József; Vécsei, László

    2015-01-01

    Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson's and Huntington's diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson's and Huntington's disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1?), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes. PMID:26301042

  11. Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

    PubMed

    Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

    2015-11-01

    Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. PMID:26348137

  12. Mitochondrial ER contacts are crucial for mitophagy in yeast.

    PubMed

    Böckler, Stefan; Westermann, Benedikt

    2014-02-24

    Damaged and superfluous mitochondria are removed from the cell by selective autophagy, a process termed mitophagy. This serves to maintain the proper quantity and quality of the organelle. Mitophagy is executed by an evolutionarily conserved pathway, many components of which were first discovered and characterized in yeast. In a systematic screen of a yeast deletion collection, we identified ERMES, a complex connecting mitochondria and the endoplasmic reticulum (ER), as an important factor contributing to the selective degradation of mitochondria. We show that efficient mitophagy depends on mitochondrial ER tethering. ERMES colocalizes with sites of mitophagosome biogenesis and affects the formation of the isolation membrane that engulfs the organelles destined for degradation. These results provide insights into the cellular mechanisms that govern organelle homeostasis. PMID:24530295

  13. Mitochondrial inheritance in yeast.

    PubMed

    Westermann, Benedikt

    2014-07-01

    Mitochondria are the site of oxidative phosphorylation, play a key role in cellular energy metabolism, and are critical for cell survival and proliferation. The propagation of mitochondria during cell division depends on replication and partitioning of mitochondrial DNA, cytoskeleton-dependent mitochondrial transport, intracellular positioning of the organelle, and activities coordinating these processes. Budding yeast Saccharomyces cerevisiae has proven to be a valuable model organism to study the mechanisms that drive segregation of the mitochondrial genome and determine mitochondrial partitioning and behavior in an asymmetrically dividing cell. Here, I review past and recent advances that identified key components and cellular pathways contributing to mitochondrial inheritance in yeast. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. Guest Editors: Manuela Pereira and Miguel Teixeira. PMID:24183694

  14. The biogenesis and assembly of photosynthetic proteins in thylakoid Francis-Andre Wollman aY

    E-print Network

    . . . . . . . . . . . . . . . . . . . . . . . . . 61 9. The chloroplast ATP synthase; accepted 22 February 1999 Keywords: Chloroplast; Thylakoid membrane; Protein biogenesis; Protein assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.1. Site of translation of the cyanobacterial and chloroplast-encoded PP subunits

  15. Impulse Conduction Increases Mitochondrial Transport in Adult Mammalian Peripheral Nerves In Vivo

    PubMed Central

    Sajic, Marija; Mastrolia, Vincenzo; Lee, Chao Yu; Trigo, Diogo; Sadeghian, Mona; Mosley, Angelina J.; Gregson, Norman A.; Duchen, Michael R.; Smith, Kenneth J.

    2013-01-01

    Matching energy supply and demand is critical in the bioenergetic homeostasis of all cells. This is a special problem in neurons where high levels of energy expenditure may occur at sites remote from the cell body, given the remarkable length of axons and enormous variability of impulse activity over time. Positioning mitochondria at areas with high energy requirements is an essential solution to this problem, but it is not known how this is related to impulse conduction in vivo. Therefore, to study mitochondrial trafficking along resting and electrically active adult axons in vivo, confocal imaging of saphenous nerves in anaesthetised mice was combined with electrical and pharmacological stimulation of myelinated and unmyelinated axons, respectively. We show that low frequency activity induced by electrical stimulation significantly increases anterograde and retrograde mitochondrial traffic in comparison with silent axons. Higher frequency conduction within a physiological range (50 Hz) dramatically further increased anterograde, but not retrograde, mitochondrial traffic, by rapidly increasing the number of mobile mitochondria and gradually increasing their velocity. Similarly, topical application of capsaicin to skin innervated by the saphenous nerve increased mitochondrial traffic in both myelinated and unmyelinated axons. In addition, stationary mitochondria in axons conducting at higher frequency become shorter, thus supplying additional mitochondria to the trafficking population, presumably through enhanced fission. Mitochondria recruited to the mobile population do not accumulate near Nodes of Ranvier, but continue to travel anterogradely. This pattern of mitochondrial redistribution suggests that the peripheral terminals of sensory axons represent sites of particularly high metabolic demand during physiological high frequency conduction. As the majority of mitochondrial biogenesis occurs at the cell body, increased anterograde mitochondrial traffic may represent a mechanism that ensures a uniform increase in mitochondrial density along the length of axons during high impulse load, supporting the increased metabolic demand imposed by sustained conduction. PMID:24391474

  16. Dysregulation of Mitochondrial Quality Control Processes Contribute to Sarcopenia in a Mouse Model of Premature Aging

    PubMed Central

    Wawrzyniak, Nicholas R.; Wohlgemuth, Stephanie E.; Picca, Anna; Kujoth, Gregory C.; Prolla, Tomas A.; Leeuwenburgh, Christiaan

    2013-01-01

    Mitochondrial DNA (mtDNA) mutations lead to decrements in mitochondrial function and accelerated rates of these mutations has been linked to skeletal muscle loss (sarcopenia). The purpose of this study was to investigate the effect of mtDNA mutations on mitochondrial quality control processes in skeletal muscle from animals (young; 3–6 months and older; 8–15 months) expressing a proofreading-deficient version of mtDNA polymerase gamma (PolG). This progeroid aging model exhibits elevated mtDNA mutation rates, mitochondrial dysfunction, and a premature aging phenotype that includes sarcopenia. We found increased expression of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?) and its target proteins, nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (Tfam) in PolG animals compared to wild-type (WT) (P<0.05). Muscle from older PolG animals displayed higher mitochondrial fission protein 1 (Fis1) concurrent with greater induction of autophagy, as indicated by changes in Atg5 and p62 protein content (P<0.05). Additionally, levels of the Tom22 import protein were higher in PolG animals when compared to WT (P<0.05). In contrast, muscle from normally-aged animals exhibited a distinctly different expression profile compared to PolG animals. Older WT animals appeared to have higher fusion (greater Mfn1/Mfn2, and lower Fis1) and lower autophagy (Beclin-1 and p62) compared to young WT suggesting that autophagy is impaired in aging muscle. In conclusion, muscle from mtDNA mutator mice display higher mitochondrial fission and autophagy levels that likely contribute to the sarcopenic phenotype observed in premature aging and this differs from the response observed in normally-aged muscle. PMID:23935986

  17. ABCD1 deletion-induced mitochondrial dysfunction is corrected by SAHA: implication for adrenoleukodystrophy.

    PubMed

    Baarine, Mauhamad; Beeson, Craig; Singh, Avtar; Singh, Inderjit

    2015-05-01

    X-linked Adrenoleukodystrophy (X-ALD), an inherited peroxisomal metabolic neurodegenerative disorder, is caused by mutations/deletions in the ATP-binding cassette transporter (ABCD1) gene encoding peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Metabolic dysfunction in X-ALD is characterized by the accumulation of very long chain fatty acids ? C22:0) in the tissues and plasma of patients. Here, we investigated the mitochondrial status following deletion of ABCD1 in B12 oligodendrocytes and U87 astrocytes. This study provides evidence that silencing of peroxisomal protein ABCD1 produces structural and functional perturbations in mitochondria. Activities of electron transport chain-related enzymes and of citric acid cycle (TCA cycle) were reduced; mitochondrial redox status was dysregulated and the mitochondrial membrane potential was disrupted following ABCD1 silencing. A greater reduction in ATP levels and citrate synthase activities was observed in oligodendrocytes as compared to astrocytes. Furthermore, most of the mitochondrial perturbations induced by ABCD1 silencing were corrected by treating cells with suberoylanilide hydroxamic acid, an Histone deacetylase inhibitor. These observations indicate a novel relationship between peroxisomes and mitochondria in cellular homeostasis and the importance of intact peroxisomes in relation to mitochondrial integrity and function in the cell types that participate in the pathobiology of X-ALD. These observations suggest suberoylanilide hydroxamic acid as a potential therapy for X-ALD. Schematic description of the effects of loss of peroxisomal ATP-binding cassette transporter D1 (ABCD1) gene on cellular Redox and mitochondrial activities and their correction by suberoylanilide hydroxamic acid (SAHA) treatment. Pathogenomic accumulation of very long chain fatty acids (VLCFA) as a result of loss of ABCD1 leads to dysfunctions of mitochondrial biogenesis and its activities. Treatment with SAHA corrects mitochondrial dysfunctions. These studies describe unique cooperation between mitochondria and peroxisome for cellular activities. PMID:25393703

  18. Treatment of Mitochondrial Disorders

    PubMed Central

    Avula, Sreenivas; Parikh, Sumit; Demarest, Scott; Kurz, Jonathan; Gropman, Andrea

    2014-01-01

    Opinion statement While numerous treatments for mitochondrial disorders have been suggested, relatively few have undergone controlled clinical trials. Treatment of these disorders is challenging, as only symptomatic therapy is available. In this review we will focus on newer drugs and treatment trials in mitochondrial diseases, with a special focus on medications to avoid in treating epilepsy and ICU patient with mitochondrial disease, which has not been included in such a review. Readers are also referred to the opinion statement in A Modern Approach to the Treatment of Mitochondrial Disease published in Current Treatment Options in Neurology 2009. Many of the supplements used for treatment were reviewed in the previous abstract, and dosing guidelines were provided. The focus of this review is on items not previously covered in depth, and our discussion includes more recently studied compounds as well as any relevant updates on older compounds. We review a variety of vitamins and xenobiotics, including dichloroacetate (DCA), arginine, coenzyme Q10, idebenone, EPI-743, and exercise training. Treatment of epilepsy, which is a common feature in many mitochondrial phenotypes, warrants special consideration due to the added toxicity of certain medications, and we provide a discussion of these unique treatment challenges. Interesting, however, with only a few exceptions, the treatment strategies for epilepsy in mitochondrial cytopathies are the same as for epilepsy without mitochondrial dysfunction. We also discuss intensive care management, building upon similar reviews, adding new dimensions, and demonstrating the complexity of overall care of these patients. PMID:24700433

  19. Coexpression within Integrated Mitochondrial Pathways Reveals Different Networks in Normal and Chemically Treated Transcriptomes.

    PubMed

    Chen, Cong; Hyun, Tae Kyung; Han, Xiao; Feng, Zhihui; Li, Yuan; Liu, Xiaolong; Liu, Jiankang

    2014-01-01

    As energy producers, mitochondria play a pivotal role in multiple cellular processes. Although several lines of evidence suggest that differential expression of mitochondrial respiratory complexes (MRCs) has a significant impact on mitochondrial function, the role of integrated MRCs in the whole coexpression network has yet to be revealed. In this study, we construct coexpression networks based on microarray datasets from different tissues and chemical treatments to explore the role of integrated MRCs in the coexpression network and the effects of different chemicals on the mitochondrial network. By grouping MRCs as one seed target, the hypergeometric distribution allowed us to identify genes that are significantly coexpress with whole MRCs. Coexpression among 46 MRC genes (approximately 78% of MRC genes tested) was significant in the normal tissue transcriptome dataset. These MRC genes are coexpressed with genes involved in the categories "muscle system process," "metabolic process," and "neurodegenerative disease pathways," whereas, in the chemically treated tissues, coexpression of these genes mostly disappeared. These results indicate that chemical stimuli alter the normal coexpression network of MRC genes. Taken together, the datasets obtained from the different coexpression networks are informative about mitochondrial biogenesis and should contribute to understanding the side effects of drugs on mitochondrial function. PMID:25089262

  20. Coexpression within Integrated Mitochondrial Pathways Reveals Different Networks in Normal and Chemically Treated Transcriptomes

    PubMed Central

    Chen, Cong; Hyun, Tae Kyung; Han, Xiao; Feng, Zhihui; Li, Yuan; Liu, Xiaolong; Liu, Jiankang

    2014-01-01

    As energy producers, mitochondria play a pivotal role in multiple cellular processes. Although several lines of evidence suggest that differential expression of mitochondrial respiratory complexes (MRCs) has a significant impact on mitochondrial function, the role of integrated MRCs in the whole coexpression network has yet to be revealed. In this study, we construct coexpression networks based on microarray datasets from different tissues and chemical treatments to explore the role of integrated MRCs in the coexpression network and the effects of different chemicals on the mitochondrial network. By grouping MRCs as one seed target, the hypergeometric distribution allowed us to identify genes that are significantly coexpress with whole MRCs. Coexpression among 46 MRC genes (approximately 78% of MRC genes tested) was significant in the normal tissue transcriptome dataset. These MRC genes are coexpressed with genes involved in the categories “muscle system process,” “metabolic process,” and “neurodegenerative disease pathways,” whereas, in the chemically treated tissues, coexpression of these genes mostly disappeared. These results indicate that chemical stimuli alter the normal coexpression network of MRC genes. Taken together, the datasets obtained from the different coexpression networks are informative about mitochondrial biogenesis and should contribute to understanding the side effects of drugs on mitochondrial function. PMID:25089262

  1. Mitochondrial Dysfunction during Brain Aging: Role of Oxidative Stress and Modulation by Antioxidant Supplementation

    PubMed Central

    Chakrabarti, Sasanka; Munshi, Soumyabrata; Banerjee, Kalpita; Thakurta, Ishita Guha; Sinha, Maitrayee; Bagh, Maria Bindu

    2011-01-01

    Mitochondrial dysfunction and oxidative stress are two interdependent and reinforcing damage mechanisms that play a central role in brain aging. Oxidative stress initiated and propagated by active oxyradicals and various other free radicals in the presence of catalytic metal ions not only can damage the phospholipid, protein and DNA molecules within the cell but can also modulate cell signalling pathways and gene expression pattern and all these processes may be of critical importance in the aging of brain. The present article describes the mechanism of formation of reactive oxyradicals within mitochondria and then explains how these can initiate mitochondrial biogenesis program and activate various transcriptional factors in the cytosol to boost up the antioxidative capacity of the mitochondria and the cell. However, a high level of oxidative stress finally inflicts critical damage to the oxidative phosphorylation machinery and mitochondrial DNA (mtDNA). The latter part of the article is a catalogue showing the accumulating evidence in favour of oxidative inactivation of mitochondrial functions in aged brain and the detailed reports of various studies with antioxidant supplementation claiming variable success in preventing the age-related brain mitochondrial decay and cognitive decline. The antioxidant supplementation approach may be of potential help in the management of neurodegenerative diseases like Alzheimer’s disease. The newly developed mitochondria-targeted antioxidants have brought a new direction to experimental studies related to oxidative damage and they may provide potential drugs in near future for a variety of diseases or degenerative conditions including brain aging and neurodegenerative disorders. PMID:22396876

  2. Desmin common mutation is associated with multi-systemic disease manifestations and depletion of mitochondria and mitochondrial DNA

    PubMed Central

    McCormick, Elizabeth M.; Kenyon, Lawrence; Falk, Marni J.

    2015-01-01

    Desmin (DES) is a major muscle scaffolding protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children's Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and mood disorders. Muscle biopsy at age 45 was remarkable for cytoplasmic bodies, as well as ragged red fibers and SDH positive/COX negative fibers that were suggestive of a mitochondrial myopathy. Muscle also showed significant reductions in mitochondrial content (16% of control mean for citrate synthase activity) and mitochondrial DNA (35% of control mean). His family history was significant for cardiac conduction defects and myopathy in multiple maternal relatives. Multiple single gene and panel-based sequencing studies were unrevealing. Whole exome sequencing identified a known pathogenic p.S13F mutation in DES that had previously been associated with desmin-related myopathy. Desmin-related myopathy is an autosomal dominant disorder characterized by right ventricular hypertrophic cardiomyopathy, myopathy, and arrhythmias. However, neuropathy, gastrointestinal dysfunction, and depletion of both mitochondria and mitochondrial DNA have not previously been widely recognized in this disorder. Recognition that mitochondrial dysfunction occurs in desmin-related myopathy clarifies the basis for the multi-systemic manifestations, as are typical of primary mitochondrial disorders. Understanding the mitochondrial pathophysiology of desmin-related myopathy highlights the possibility of new therapies for this otherwise untreatable and often fatal class of disease. We postulate that drug treatments aimed at improving mitochondrial biogenesis or reducing oxidative stress may be effective therapies to ameliorate the effects of desmin-related disease. PMID:26097489

  3. Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells.

    PubMed

    Váraljai, Renáta; Islam, Abul B M M K; Beshiri, Michael L; Rehman, Jalees; Lopez-Bigas, Nuria; Benevolenskaya, Elizaveta V

    2015-09-01

    The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1? (peroxisome proliferator-activated receptor ?-coactivator 1?; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1?, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype. PMID:26314709

  4. The effects of acute oral glutamine supplementation on exercise-induced gastrointestinal permeability and heat shock protein expression in peripheral blood mononuclear cells.

    PubMed

    Zuhl, Micah; Dokladny, Karol; Mermier, Christine; Schneider, Suzanne; Salgado, Roy; Moseley, Pope

    2015-01-01

    Chronic glutamine supplementation reduces exercise-induced intestinal permeability and inhibits the NF-?B pro-inflammatory pathway in human peripheral blood mononuclear cells. These effects were correlated with activation of HSP70. The purpose of this paper is to test if an acute dose of oral glutamine prior to exercise reduces intestinal permeability along with activation of the heat shock response leading to inhibition of pro-inflammatory markers. Physically active subjects (N?=?7) completed baseline and exercise intestinal permeability tests, determined by the percent ratio of urinary lactulose (5 g) to rhamnose (2 g). Exercise included two 60-min treadmill runs at 70 % of VO2max at 30 °C after ingestion of glutamine (Gln) or placebo (Pla). Plasma levels of endotoxin and TNF-?, along with peripheral blood mononuclear cell (PBMC) protein expression of HSP70 and I?B?, were measured pre- and post-exercise and 2 and 4 h post-exercise. Permeability increased in the Pla trial compared to that at rest (0.06?±?0.01 vs. 0.02?±?0.018) and did not increase in the Gln trial. Plasma endotoxin was lower at the 4-h time point in the Gln vs. 4 h in the Pla (6.715?±?0.046 pg/ml vs. 7.952?±?1.11 pg/ml). TNF-? was lower 4 h post-exercise in the Gln vs. Pla (1.64?±?0.09 pg/ml vs. 1.87?±?0.12 pg/ml). PBMC expression of IkB? was higher 4 h post-exercise in the Gln vs. 4 h in the Pla (1.29?±?0.43 vs. 0.8892?±?0.040). HSP70 was higher pre-exercise and 2 h post-exercise in the Gln vs. Pla (1.35?±?0.21 vs. 1.000?±?0.000 and 1.65?±?0.21 vs. 1.27?±?0.40). Acute oral glutamine supplementation prevents an exercise-induced rise in intestinal permeability and suppresses NF-?B activation in peripheral blood mononuclear cells. PMID:25062931

  5. Low molecular weight guluronate prevents TNF-?-induced oxidative damage and mitochondrial dysfunction in C2C12 skeletal muscle cells.

    PubMed

    Dun, Yun-lou; Zhou, Xiao-lin; Guan, Hua-shi; Yu, Guang-li; Li, Chun-xia; Hu, Ting; Zhao, Xia; Cheng, Xiao-lei; He, Xiao-xi; Hao, Jie-jie

    2015-09-01

    Muscle wasting is associated with a variety of chronic or inflammatory disorders. Evidence suggests that inflammatory cytokines play a vital role in muscle inflammatory pathology and this may result in oxidative damage and mitochondrial dysfunction in skeletal muscle. In our study, we used microwave degradation to prepare a water-soluble low molecular weight guluronate (LMG) of 3000 Da from Fucus vesiculosus obtained from Canada, the Atlantic Ocean. We demonstrated the structural characteristics, using HPLC, FTIR and NMR of LMG and investigated its effects on oxidative damage and mitochondrial dysfunction in C2C12 skeletal muscle cells induced by tumor necrosis factor alpha (TNF-?), a cell inflammatory cytokine. The results indicated that LMG could alleviate mitochondrial reactive oxygen species (ROS) production, increase the activities of antioxidant enzymes (GSH and SOD), promote mitochondrial membrane potential (MMP) and upregulate the expression of mitochondrial respiratory chain protein in TNF-?-induced C2C12 cells. LMG supplement also increased the mitochondrial DNA copy number and mitochondrial biogenesis related genes in TNF-?-induced C2C12 cells. LMG may exert these protective effects through the nuclear factor kappa B (NF-?B) signaling pathway. These suggest that LMG is capable of protecting TNF-?-induced C2C12 cells against oxidative damage and mitochondrial dysfunction. PMID:26205038

  6. Peroxisome proliferator activated receptor-? agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiation.

    PubMed

    De Nuccio, C; Bernardo, A; Cruciani, C; De Simone, R; Visentin, S; Minghetti, L

    2015-09-01

    The activation of the nuclear receptor peroxisome proliferator-activated receptor-? (PPAR-?) is known to exert anti-inflammatory and neuroprotective effects and PPAR-? agonists are considered potential therapeutic agents in brain diseases including those affecting myelin. In demyelinating diseases such as multiple sclerosis (MS), inflammation is one of the causes of myelin and axonal damage. Oligodendrocyte (OL) differentiation is highly dependent on mitochondria, which are major targets of inflammatory insult. Here we show that PPAR-? agonists protect OL progenitors against the maturational arrest induced by the inflammatory cytokine TNF-? by affecting mitochondrial functions. We demonstrate that the inhibition of OL differentiation by TNF-? is associated with i) increased mitochondrial superoxide production; ii) decreased mitochondrial membrane potential (mMP); and iii) decreased ADP-induced Ca(2+) oscillations, which we previously showed to be dependent on efficient mitochondria. The TNF-? effects were comparable to those of the mitochondrial toxin rotenone, further suggesting that TNF-? damage is mediated by mitochondrial function impairment. PPAR-? agonists protected OL progenitors against the inhibitory activities of both TNF-? and rotenone on mMP, mitochondrial ROS production, Ca(2+) oscillations and OL differentiation. Finally, the PPAR-? agonist pioglitazone increased the expression of PGC-1? (a mitochondrial biogenesis master regulator), UCP2 (a mitochondrial protein known to reduce ROS production), and cytochrome oxidase subunit COX1. These findings confirm the central role of mitochondria in OL differentiation and point to mitochondria as major targets of PPAR-? agonist protection against TNF-? damage. PMID:26210873

  7. Recent advances in septum biogenesis in Neurospora crassa.

    PubMed

    Mouriño-Pérez, Rosa Reyna; Riquelme, Meritxell

    2013-01-01

    Hyphae of the Ascomycota are tubular cells compartmentalized by perforated septa, whose central pore allows the flow of organelles and cytoplasm. While in plants and yeast septation leads to cell separation, in filamentous fungi the formation of crosswalls appears to have an architectural role, limits the extent of mechanical damage thus maintaining hyphal integrity, and also is of fundamental importance as part of cell differentiation. The increasing number of available fungal genome sequences, knockout mutants, versatile tools for protein tagging, and the continuous improvement of fluorescence microscopes have allowed scientists to analyze living cells and reveal the molecular and cellular basis of septation with unprecedented detail. This review summarizes the recent advances in septum ontogenesis in Neurospora crassa. A "septal actomyosin tangle" is the first indication of impending septation. It assembles prior to any visible evidence of plasma membrane inward growth, which occurs concomitantly with the formation and constriction of a contractile actomyosin ring and synthesis of the septum wall. One of the key questions in septum biogenesis is how the septation machinery is assembled to construct a centripetally growing crosswall. Most of the machinery utilized in apical cell wall growth can be expected at septation sites to ensure an organized arrival and supply of vesicles leading to the formation of a septum. Yet, the intrinsically different architecture of the septum may require a different organization and regulation of the wall-synthesizing machinery. PMID:23890213

  8. Extracellular Streptomyces lividans vesicles: composition, biogenesis and antimicrobial activity

    PubMed Central

    Schrempf, Hildgund; Merling, Philipp

    2015-01-01

    We selected Streptomyces lividans to elucidate firstly the biogenesis and antimicrobial activities of extracellular vesicles that a filamentous and highly differentiated Gram-positive bacterium produces. Vesicle types range in diameter from 110 to 230?nm and 20 to 60?nm, respectively; they assemble to clusters, and contain lipids and phospholipids allowing their in situ imaging by specific fluorescent dyes. The presence of the identified secondary metabolite undecylprodigiosin provokes red fluorescence of a portion of the heterogeneous vesicle populations facilitating in vivo monitoring. Protuberances containing vesicles generate at tips, and alongside of substrate hyphae, and enumerate during late vegetative growth to droplet-like exudates. Owing to in situ imaging in the presence and absence of a green fluorescent vancomycin derivative, we conclude that protuberances comprising vesicles arise at sites with enhanced levels of peptidoglycan subunits [pentapeptide of lipid II (C55)-linked disaccharides], and reduced levels of polymerized and cross-linked peptidoglycan within hyphae. These sites correlate with enhanced levels of anionic phospholipids and lipids. Vesicles provoke pronounced damages of Aspergillus proliferans, Verticillium dahliae and induced clumping and distortion of Escherichia coli. These harmful effects are likely attributable to the action of the identified vesicular compounds including different enzyme types, components of signal transduction cascades and undecylprodigiosin. Based on our pioneering findings, we highlight novel clues with environmental implications and application potential. PMID:25851532

  9. Signaling Pathways in Exosomes Biogenesis, Secretion and Fate

    PubMed Central

    Urbanelli, Lorena; Magini, Alessandro; Buratta, Sandra; Brozzi, Alessandro; Sagini, Krizia; Polchi, Alice; Tancini, Brunella; Emiliani, Carla

    2013-01-01

    Exosomes are small extracellular vesicles (30–100 nm) derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated. PMID:24705158

  10. Lipid partitioning at the nuclear envelope controls membrane biogenesis.

    PubMed

    Barbosa, Antonio Daniel; Sembongi, Hiroshi; Su, Wen-Min; Abreu, Susana; Reggiori, Fulvio; Carman, George M; Siniossoglou, Symeon

    2015-10-15

    Partitioning of lipid precursors between membranes and storage is crucial for cell growth, and its disruption underlies pathologies such as cancer, obesity, and type 2 diabetes. However, the mechanisms and signals that regulate this process are largely unknown. In yeast, lipid precursors are mainly used for phospholipid synthesis in nutrient-rich conditions in order to sustain rapid proliferation but are redirected to triacylglycerol (TAG) stored in lipid droplets during starvation. Here we investigate how cells reprogram lipid metabolism in the endoplasmic reticulum. We show that the conserved phosphatidate (PA) phosphatase Pah1, which generates diacylglycerol from PA, targets a nuclear membrane subdomain that is in contact with growing lipid droplets and mediates TAG synthesis. We find that cytosol acidification activates the master regulator of Pah1, the Nem1-Spo7 complex, thus linking Pah1 activity to cellular metabolic status. In the absence of TAG storage capacity, Pah1 still binds the nuclear membrane, but lipid precursors are redirected toward phospholipids, resulting in nuclear deformation and a proliferation of endoplasmic reticulum membrane. We propose that, in response to growth signals, activation of Pah1 at the nuclear envelope acts as a switch to control the balance between membrane biogenesis and lipid storage. PMID:26269581

  11. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives.

    PubMed

    Braverman, Nancy E; D'Agostino, Maria Daniela; Maclean, Gillian E

    2013-01-01

    The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment. PMID:23798008

  12. Lipid partitioning at the nuclear envelope controls membrane biogenesis

    PubMed Central

    Barbosa, Antonio Daniel; Sembongi, Hiroshi; Su, Wen-Min; Abreu, Susana; Reggiori, Fulvio; Carman, George M.; Siniossoglou, Symeon

    2015-01-01

    Partitioning of lipid precursors between membranes and storage is crucial for cell growth, and its disruption underlies pathologies such as cancer, obesity, and type 2 diabetes. However, the mechanisms and signals that regulate this process are largely unknown. In yeast, lipid precursors are mainly used for phospholipid synthesis in nutrient-rich conditions in order to sustain rapid proliferation but are redirected to triacylglycerol (TAG) stored in lipid droplets during starvation. Here we investigate how cells reprogram lipid metabolism in the endoplasmic reticulum. We show that the conserved phosphatidate (PA) phosphatase Pah1, which generates diacylglycerol from PA, targets a nuclear membrane subdomain that is in contact with growing lipid droplets and mediates TAG synthesis. We find that cytosol acidification activates the master regulator of Pah1, the Nem1-Spo7 complex, thus linking Pah1 activity to cellular metabolic status. In the absence of TAG storage capacity, Pah1 still binds the nuclear membrane, but lipid precursors are redirected toward phospholipids, resulting in nuclear deformation and a proliferation of endoplasmic reticulum membrane. We propose that, in response to growth signals, activation of Pah1 at the nuclear envelope acts as a switch to control the balance between membrane biogenesis and lipid storage. PMID:26269581

  13. Mitochondrial Toxicity of Cadmium Telluride Quantum Dot Nanoparticles in Mammalian Hepatocytes

    PubMed Central

    Nguyen, Kathy C.; Rippstein, Peter; Tayabali, Azam F.; Willmore, William G.

    2015-01-01

    There are an increasing number of studies indicating that mitochondria are relevant targets in nanomaterial-induced toxicity. However, the underlying mechanisms by which nanoparticles (NPs) interact with these organelles and affect their functions are unknown. The aim of this study was to investigate the effects of cadmium telluride quantum dot (CdTe-QD) NPs on mitochondria in human hepatocellular carcinoma HepG2 cells. CdTe-QD treatment resulted in the enlargement of mitochondria as examined with transmission electron microscopy and confocal microscopy. CdTe-QDs appeared to associate with the isolated mitochondria as detected by their inherent fluorescence. Further analyses revealed that CdTe-QD caused disruption of mitochondrial membrane potential, increased intracellular calcium levels, impaired cellular respiration, and decreased adenosine triphosphate synthesis. The effects of CdTe-QDs on mitochondrial oxidative phosphorylation were evidenced by changes in levels and activities of the enzymes of the electron transport chain. Elevation of peroxisome proliferator-activated receptor-? coactivator levels after CdTe-QD treatment suggested the effects of CdTe-QDs on mitochondrial biogenesis. Our results also showed that the effects of CdTe-QDs were similar or greater to those of cadmium chloride at equivalent concentrations of cadmium, suggesting that the toxic effects of CdTe-QDs were not solely due to cadmium released from the NPs. Overall, the study demonstrated that CdTe-QDs induced multifarious toxicity by causing changes in mitochondrial morphology and structure, as well as impairing their function and stimulating their biogenesis. PMID:25809595

  14. Mitochondrial approaches for neuroprotection

    PubMed Central

    Chaturvedi, Rajnish K.; Beal, M. Flint

    2008-01-01

    A large body of evidence from post-mortem brain tissue and genetic analysis in man and biochemical and pathological studies in animal models (transgenic and toxin) of neurodegeneration suggest that mitochondrial dysfunction is a common pathological mechanism. Mitochondrial dysfunction due to oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology and interaction of pathogenic proteins with mitochondria leads to neuronal demise. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. This review discusses the potential therapeutic efficacy of creatine, coenzyme Q10, idebenone, synthetic triterpenoids, and mitochondrial targeted antioxidants (MitoQ) and peptides (SS-31) in in vitro studies and in animal models of Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's disease (AD). We have also reviewed the current status of clinical trials of creatine, coenzyme Q10, idebenone and MitoQ in neurodegenerative disorders. Further, we discuss newly identified therapeutic targets including PGC-1? and Sirtuins, which provide promise for future therapeutic developments in neurodegenerative disorders. PMID:19076459

  15. Exercise induced changes in lymphocyte beta adrenergic receptors correlate with peak exercise heart rates in healthy trained and sedentary human subjects

    SciTech Connect

    Eisinger, M.; Engelmeier, R.; Glisson, S.; Scanlon, P.

    1986-03-05

    Lymphocyte beta adrenergic receptors (lymph BAR) increase after maximal multistage treadmill exercise (TME) presumably by externalization from intracellular vesicles. Nine healthy subjects underwent symptom limited TME by the Bruce protocol. Heart rate was measured at the end of each 3 minute stage. Plasma norepinephrine (NE), plasma epinephrine (EPI) and lymph BAR were measured at rest and at peak exercise. Catecholamines were determined by high performance liquid chromatography. Lymph BAR were measured by separating cells from 25cc of whole blood across a Ficoll-Hypaque density gradient and incubating membrane preparations with 7 dilutions of I/sup 125/ cyanopindolol in the presence or absence of 1..mu..M(-) propranolol in a total assay volume of 450 ..mu..l. BAR was standardized to Lowry-Peterson protein at rest and exercise. The relationship of maximum heart rate versus peak plasma NE, EPI and lymph BAR was analyzed by linear regression. The following conclusions were reached: (1) there is a significant correlation between exercise induced changes in lymph BAR and peak heart rate; (2) this relationship does not exist between peak plasma NE or EPI and peak heart rate.

  16. Rapid Exercise-Induced Mobilization of Dendritic Cells Is Potentially Mediated by a Flt3L- and MMP-9-Dependent Process in Multiple Sclerosis

    PubMed Central

    Deckx, Nathalie; Wens, Inez; Nuyts, Amber H.; Lee, Wai-Ping; Hens, Niel; Koppen, Gudrun; Goossens, Herman; Van Damme, Pierre; Berneman, Zwi N.; Eijnde, Bert O.; Cools, Nathalie

    2015-01-01

    In healthy individuals, one exercise bout induces a substantial increase in the number of circulating leukocytes, while their function is transiently suppressed. The effect of one exercise bout in multiple sclerosis (MS) is less studied. Since recent evidence suggests a role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of one combined endurance/resistance exercise bout on the number and function of DC in M