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Farrar 2015 US Patent + (A nucleic acid sequence encoding the yeast … A nucleic acid sequence encoding the yeast NDI1 protein of SEQ ID NO: 542 or a functional variant thereof having at least 90% sequence identity with SEQ ID NO: 2 is described. The nucleic acid sequence comprises at least 50 codons which are codon optimised compared with the sequence of yeast NDI1 gene of SEQ ID NO: 1. An immune optimised functional variant of the yeast NDI1 protein of SEQ ID NO: 542 having at least 90% sequence identity with SEQ ID NO: 542 is also described, and includes at least one amino acid change selected from the group consisting of L194F, K283E, K9R, S142N, L501M, L402I, A386S, S85K, F89H, L93M, K195E, L18M, K213E, K372E, L258F, K510E, L158M, R478Q, L482M. K372E, L258F, K510E, L158M, R478Q, L482M.)
Bentinger 2007 Mitochondrion + (A number of functions for coenzyme Q (CoQ) … A number of functions for coenzyme Q (CoQ) have been established during the years but its role as an effective antioxidant of the cellular membranes remains of dominating interest. This compound is our only endogenously synthesized lipid soluble antioxidant, present in all membranes and exceeding both in amount and efficiency that of other antioxidants. The protective effect is extended to lipids, proteins and DNA mainly because of its close localization to the oxidative events and the effective regeneration by continuous reduction at all locations. Its biosynthesis is influenced by nuclear receptors which may give the possibility, in the future, by using agonists or antagonists, of reestablishing the normal level in deficiencies caused by genetic mutations, aging or cardiomyopathy. An increase in CoQ concentration in specific cellular compartments in the presence of various types of oxidative stress appears to be of considerable interest.ss appears to be of considerable interest.)
Bastow 2016 J Cell Sci + (A number of genes have been linked to fami … A number of genes have been linked to familial forms of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Over 150 mutations within the gene encoding superoxide dismutase 1 (SOD1) have been implicated in ALS, but why such mutations lead to ALS-associated cellular dysfunction is unclear. In this study, we identify how ALS-linked SOD1 mutations lead to changes in the cellular health of the yeast ''Saccharomyces cerevisiae''. We find that it is not the accumulation of aggregates but the loss of Sod1 protein stability that drives cellular dysfunction. The toxic effect of Sod1 instability does not correlate with a loss of mitochondrial function or increased production of reactive oxygen species, but instead prevents acidification of the vacuole, perturbs metabolic regulation and promotes senescence. Central to the toxic gain-of-function seen with the SOD1 mutants examined was an inability to regulate amino acid biosynthesis. We also report that leucine supplementation results in an improvement in motor function in a ''Caenorhabditis elegans'' model of ALS. Our data suggest that metabolic dysfunction plays an important role in Sod1-mediated toxicity in both the yeast and worm models of ALS.© 2016. Published by The Company of Biologists Ltd.ublished by The Company of Biologists Ltd.)
Ruiz-Pesini 2004 Science + (A phylogenetic analysis of 1125 global hum … A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.variants are influencing our health today.)
Berg 2016 Science + (A preprint is a complete scientific manusc … A preprint is a complete scientific manuscript (often one also being submitted to a peer-reviewed journal) that is uploaded by the authors to a public server without formal review. After a brief inspection to ensure that the work is scientific in nature, the posted scientific manuscript can be viewed without charge on the Web.Conclusions: Preprints could play important roles in accelerating scientific progress; they could serve the needs and foster the careers of scientists; and, in cooperation with existing journals, they could enhance the current system for communicating results and ideas in the life sciences. However, preprints are relatively new to biology, and many questions remain unanswered. Will funding agencies encourage the use of preprint servers? Will all journals accept manuscripts for publication after they have been disseminated as preprints? Will the life sciences community find ways to make biology preprints easily discoverable? And will researchers themselves decide to submit, cite, and evaluate work presented in preprint form? The cooperative spirit displayed by the attendees at ASAPbio gives hope that these complex issues, as well as others that limit the communication of scientific ideas and results, can be addressed in a productive and thoughtful manner.sed in a productive and thoughtful manner.)
Committee 2018 COPE Discussion Document + (A preprint is a scholarly manuscript poste … A preprint is a scholarly manuscript posted by the author(s) in an openly accessible platform, usually before or in parallel with the peer review process. While the sharing of manuscripts via preprint platforms has been common in some disciplines (such as physics and mathematics) for many years, uptake in other disciplines traditionally had been low, possibly influenced by differences in research culture and strong opposition by some journal publishers [1]. The landscape has evolved rapidly in other fields in recent years, however, thanks to the launch of additional, discipline-specific preprint platforms and increased support by funders and initiatives such as ASAPBio[2, 3].ers and initiatives such as ASAPBio[2, 3].)
Gnaiger 1991 Soc Exp Biol Seminar Series + (A previous critique of the term facultative invertebrate anaerobiosis focused on the duration of anoxia. An addition, important, yet much neglected aspect is dicussed here, namely the extent and quantification of the 'anaerobic' condition.)
Podrabsky 2000 Am J Physiol Regul Integr Comp Physiol + (A previous phylogenetic analysis among 15 … A previous phylogenetic analysis among 15 taxa of the teleost fish ''Fundulus'' suggested that there should be thermal-adaptive differences in heart metabolism among populations. To test this hypothesis, the rate of oxygen consumption and the activities of all 11 glycolytic enzymes were measured in isolated heart ventricle from two populations of ''Fundulus heteroclitus''. Heart ventricular metabolism is greater in a northern population versus a southern population of these fish. Analysis of the amount of glycolytic enzymes indicates that 87% of the variation in cardiac metabolism within and between populations is explained by the variation in three enzymes (pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase, and lactate dehydrogenase). These enzymes are the same three enzymes that were predicted to be important based on previously determined phylogenetic patterns of expression. Our data indicate that near-equilibrium enzymes, as well as classically defined rate-limiting enzymes, can also influence metabolism.ng enzymes, can also influence metabolism.)
Gurakan 1990 Thermochim Acta + (A procedure has been developed for the pre … A procedure has been developed for the preparation of microbial biomass of standard, defined quality suitable for the determination of elemental composition and enthalpy of combustion. Furthermore methods for the determination of residual moisture and ash content of biomass samples have been established. The results indicate that samples should be prepared in a freeze-dried (lyophilized) state and that residual moisture content should be determined immediately prior to sample preparation for combustion calorimetry and elemental analysis. Results from such analysis should then be related to material which is first freeze- dried and subsequently oven dried (100 °C for 24 hours) as reference state. The method outlined here for microbial biomass should prove suitable for biological samples from a wide variety of sources including both pure proteins, fats etc. as well as cells and tissues.s, fats etc. as well as cells and tissues.)
Bradford 1976 Anal Biochem + (A protein determination method which invol … A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls. eliminated by the use of proper controls.)
Lam 1967 Arch Biochem Biophys + (A protein factor, designated as Factor B, … A protein factor, designated as Factor B, was extracted from lyophilized acetone-washed bovine heart mitochondria and purified by ammonium sulfate fractionation, and ion-exchange chromatography on DEAE-cellulose and CM-cellulose. Centrifugation in a sucrose density gradient showed that the activity of the purified factor was closely associated with a symmetrical protein peak comprising approximately 70% of the protein. Its molecular weight was estimated to be 32,000, using hemoglobin and cytochrome c as markers. Factor B produces several-fold stimulation of ATP-driven NAD reduction, and of net phosphorylation coupled to NADH or succinate oxidation in ammonia particles. The stimulation of ATP-driven NAD reduction activity exceeds that given by an optimal amount of oligomycin, and in the presence of a saturation level of Factor B, oligomycin stimulation disappears. Also, Factor B stimulation is evident in urea-depleted particles which have been supplemented by Factor A. These particles show no stimulation by oligomycin. The results suggest that Factor B may participate in the energy transfer reactions between the respiratory chain and the terminal step resulting in ATP synthesis. terminal step resulting in ATP synthesis.)
Wijermars 2016 Am J Transplant + (A recent seminal paper implicated ischemia … A recent seminal paper implicated ischemia-related succinate accumulation followed by succinate driven-reactive oxygen species formation as key driver of ischemia reperfusion injury. Although the data show that the mechanism is universal for all organs tested (kidney, liver, heart and brain), a remaining question is to what extend these observations for mouse translate to man. We here show that succinate accumulation is not a universal event during ischemia, and does not occur during renal graft procurement, in fact tissue succinate content progressively decreases with advancing graft ischemia time (p<0.007). Contrasting responses were also found with respect to mitochondrial susceptibility towards ischemia and reperfusion, with rodent mitochondria robustly resistant towards warm ischemia, but human and pig mitochondria being highly susceptible to warm ischemia (p<0.05). These observations suggest that succinate-driven reactive oxygen formation does not occur in the context of kidney transplantation. In fact absent allantoin release from the reperfused grafts suggests minimal oxidative stress during clinical reperfusion.This article is protected by copyright. All rights reserved. is protected by copyright. All rights reserved.)
Tomporowski 2003 Acta Psychol (Amst) + (A review was conducted of studies that ass … A review was conducted of studies that assessed the effects of acute bouts of physical activity on adults' cognitive performance. Three groups of studies were constituted on the basis of the type of exercise protocol employed. Each group was then evaluated in terms of information-processing theory. It was concluded that submaximal aerobic exercise performed for periods up to 60 min facilitate specific aspects of information processing; however, extended exercise that leads to dehydration compromises both information processing and memory functions. The selective effects of exercise on cognitive performance are explained in terms of Sanders' [Acta Psychol. 53 (1983) 61] cognitive-energetic model.. 53 (1983) 61] cognitive-energetic model.)
Meunier 1995 Biochemistry + (A screen has been performed of possible in … A screen has been performed of possible inhibitors of the quinol oxidation sites of the two terminal oxidases of ''Escherichia coli'', cytochromes bo and bd. Aurachin C and its analogues were found to be particularly effective inhibitors of both enzymes, whereas aurachin D and its analogues displayed a selectivity for inhibition of cytochrome bd. In addition, a tridecyl derivative of stigmatellin was found to inhibit cytochrome bo at concentrations which were without significant effect on cytochrome bd. Titration of membrane-bound cytochromes bo and bd with aurachin C gave an observed dissociation constant in the range of 10-8 M. A similar observed dissociation constant was determined for aurachin D inhibition of cytochrome bd. For both enzymes, their kinetic behavior during a series of substrate pulses indicates that it is reduction of the enzyme by quinol, and not reaction with oxygen, which is inhibited. It is concluded that the aurachins are powerful inhibitors of the quinol oxidation sites of bacterial cytochromes bo and bd. The effects of aurachin C on cytochrome bo were investigated in more detail. The number of inhibitor binding sites on the purified enzyme was determined by titration to be 0.6 per enzyme. At an inhibitorloxidase ratio of 1.0, electron donation into the enzyme from added quinol is extremely slow, making it very unlikely that there is more than one quinone-reactive site. Aurachin C caused a potent inhibition of electron donation from a pulse of quinol. In contrast, it was without effect on cyanide or carbon monoxide binding to the reduced enzyme, on cyanide binding to the oxidized enzyme, on the optical spectra of the heme groups, or on the kinetics of oxygen reduction after photolysis of carbon monoxide from the reduced enzyme. We conclude that binding of aurachin C specifically inhibits the quinol oxidation site and does not directly affect the properties of the binuclear center.irectly affect the properties of the binuclear center.)
Bers 1982 Am J Physiol + (A simple method for the accurate determina … A simple method for the accurate determination of free [Ca] in ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (EGTA)-buffered Ca solutions is described. This method is useful for calibration of Ca macro- and microelectrodes to low free [Ca] and should improve the reliability of calculated free [Ca] in more complex solutions. Briefly, free [Ca] in Ca-EGTA solutions is measured with a Ca electrode, bound Ca is calculated, and Scatchard and double-reciprocal plots are resolved for the total [EGTA] and the apparent Ca-EGTA association constant (K'Ca) in the solutions used. The free [Ca] is then recalculated using the determined parameters, giving a more accurate knowledge of the free [Ca] in these solutions and providing an accurate calibration curve for the Ca electrode. These solutions can then be used to calibrate other Ca electrodes (e.g., Ca microelectrodes) or the calibrated Ca electrode can be used to measure free [Ca] in solutions containing multiple metal ligands. This method allows determination of free [Ca], K'Ca, and total [EGTA] in the actual solutions used regardless of pH, temperature, or ionic strength. It does not require accurate knowledge of K'Ca or EGTA purity and circumvents many potential errors due to assumption of binding parameters. K'Ca was found to be 2.45 +/- 0.04 X 10(6) M-1 in 100 mM KCl, 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, and 1 mM EGTA at pH 7.00 and 23 degrees C. Total [EGTA] varied with supplier but was always less than quoted. supplier but was always less than quoted.)
Stokich 2014 Cryobiology + (A simple method to cryogenically preserve … A simple method to cryogenically preserve hepatocyte monolayers is currently not available but such a technique would facilitate numerous applications in the field of biomedical engineering, cell line development, and drug screening. We investigated the effect of trehalose and dimethyl sulfoxide (Me2SO) in cryopreservation of human hepatocellular carcinoma (HepG2) cells in suspension and monolayer formats. HepG2 cell monolayers were incubated for 24 h at varying concentrations of trehalose (50-150 mM) prior to cryopreservation to identify the optimum concentration for such preincubation. When trehalose alone was used as the cryoprotective agent (CPA), cells in monolayer format did not survive freezing while cells in suspension demonstrated 14% viability 24 h after thawing. Only 6-13% of cells in monolayers survived freezing in cell culture medium supplemented with 10% Me2SO, but 42% of cells were recovered successfully if monolayers were preincubated with 100 mM trehalose prior to freezing in the Me2SO supplemented medium. Interestingly, for cells frozen in suspension in presence of 10% Me2SO, metabolic activity immediately following thawing did not change appreciably compared to unfrozen control cells. Finally, Raman spectroscopy techniques were employed to evaluate ice crystallization in the presence and absence of trehalose in freezing solutions without cells because crystallization may alter the extent of injury observed in cell monolayers. We speculate that biomimetic approaches of using protective sugars to preserve cells in monolayer format will facilitate the development of techniques for long-term preservation of human tissues and organs in the future.of human tissues and organs in the future.)
Small 1985 Biochem J + (A simple spectrophotometric assay was deve … A simple spectrophotometric assay was developed for peroxisomal fatty [[acyl-CoA oxidase]] activity. The assay, based on the H2O2-dependent oxidation of leuco-dichlorofluorescein catalysed by exogenous [[peroxidase]], is more sensitive than methods previously described. By using mouse liver samples, cofactor requirements were assessed and a linear relationship was demonstrated between dye oxidation and enzyme concentration. By using this assay on subcellular fractions, palmitoyl-CoA oxidase activity was localized for the first time in microperoxisomes of rat intestine. The assay was also adapted to measure D-amino acid oxidase activity, demonstrating the versatility of this method for measuring activity of other H2O2-producing oxidases.g activity of other H2O2-producing oxidases.)
Petrova 2014 Proc Chem + (A simple, accurate and rapid voltammetric … A simple, accurate and rapid voltammetric method has been developed for the quantitative determination of coenzyme Q10. Studies with direct current voltammetry were carried out using a glassy carbon electrode (GCE) in a phosphate buffer solution (pH 6.86). A well-defined oxidation peak of CoQ10 was obtained at -0.600 V vs Ag/AgCl. The magnitude of the oxidation peak current has been found to be related to the concentration of the coenzyme over the range of (2·10-5 to 2·10-4 M) (''r'' = 0.991). Antioxidant activity of CoQ10 was investigated.) (''r'' = 0.991). Antioxidant activity of CoQ10 was investigated.)
Lin 2012 FASEB J + (A single high-fat meal acutely increases s … A single high-fat meal acutely increases skeletal muscle mitochondrial H2O2 emitting potential (mEH2O2), shifts the intracellular redox environment to a more oxidized state, and increases circulating markers of oxidative stress. Bioenergetically, this implies an acute lipid load may elevate the reducing pressure/membrane potential ({Delta}{Psi}m) within mitochondria and, conversely, that even a mild increase in energy expenditure may be sufficient to prevent these effects. To test this hypothesis, male Sprague-Dawley rats received an oral lipid gavage (20% intralipid, 45 Kcal/kg lean body mass) or water followed either by 2h of rest or 1h of rest plus 1h of low intensity treadmill exercise (15 m/min, 0% grade). Permeabilized fiber bundles were prepared from red gastrocnemius muscle for testing mitochondrial function. In rats receiving lipid, {Delta}{Psi}m and mEH2O2 were higher (P<0.05) and calcium retention capacity (mCa2+RC, an index of resistance to mitochondrial permeability transition) was lower under state IV and/or "clamped" ADP-stimulated state III conditions. All three effects were prevented when lipid gavage was followed by low-intensity exercise. Respiratory capacity was unaffected by any of the interventions. These findings provide evidence that mitochondrial {Delta}{Psi}m, mEH2O2, and mCa2+RC are acutely affected by nutritional overload in skeletal muscle, but can be prevented by low intensity exercise. NIH DK073488ented by low intensity exercise. NIH DK073488)
Ortega 2017 Biol Reprod + (A single missense mutation at position 159 … A single missense mutation at position 159 of coenzyme Q9 (COQ9) (G→A; rs109301586) has been associated with genetic variation in fertility in Holstein cattle, with the A allele associated with higher fertility. COQ9 is involved in the synthesis of coenzyme COQ10, a component of the electron transport system of the mitochondria. Here we tested whether reproductive phenotype is associated with the mutation and evaluated functional consequences for cellular oxygen metabolism, body weight changes, and ovarian function. The mutation in COQ9 modifies predicted tertiary protein structure and affected mitochondrial respiration of peripheral blood mononuclear cells. The A allele was associated with low resting oxygen consumption and high electron transport system capacity. Phenotypic measurements for fertility were evaluated for up to five lactations in a population of 2273 Holstein cows. There were additive effects of the mutation (P < 0.05) in favor of the A allele for pregnancy rate, interval from calving to conception, and services per conception. There was no association of genotype with milk production or body weight changes ''postpartum''. The mutation in COQ9 affected ovarian function; the A allele was associated with increased mitochondrial DNA copy number in oocytes, and there were overdominance effects for COQ9 expression in oocytes, follicle number, and antimullerian hormone concentrations. Overall, results show how a gene involved in mitochondrial function is associated with overall fertility, possibly in part by affecting oocyte quality.possibly in part by affecting oocyte quality.)
Du 1998 Free Radic Biol Med + (A small portion of the oxygen consumed by … A small portion of the oxygen consumed by aerobic cells is converted to superoxide anion at the level of the mitochondrial respiratory chain. If produced in excess, this harmful radical is considered to impair cellular structures and functions. Damage at the level of mitochondria have been reported after ischemia and reperfusion of organs. However, the complexity of the ''in vivo'' system prevents from understanding and describing precise mechanisms and locations of mitochondrial impairment. An ''in vitro'' model of isolated-mitochondria anoxia-reoxygenation is used to investigate superoxide anion generation together with specific damage at the level of mitochondrial oxidative phosphorylation. Superoxide anion is detected by electron paramagnetic resonance spin trapping with POBN-ethanol. Mitochondrial respiratory parameters are calculated from oxygen consumption traces recorded with a Clark electrode. Respiring mitochondria produce superoxide anion in unstressed conditions, however, the production is raised during postanoxic reoxygenation. Several respiratory parameters are impaired after reoxygenation, as shown by decreases of phosphorylating and uncoupled respiration rates and of ADP/O ratio and by increase of resting respiration. Partial protection of mitochondrial function by POBN suggests that functional damage is related and secondary to superoxide anion production by the mitochondria ''in vitro''.oduction by the mitochondria ''in vitro''.)
Hellgren 2016 Abstract Proceedings of The Physiological Society + (A suboptimal prenatal environment can affe … A suboptimal prenatal environment can affect organogenesis and the natural development of an individual by epigenetic modifications of the genome. While these changes are permanent, it is common not to see any pathological effects until adulthood. The impact of nutritional insults during development has been well-studied in a wide variation of physiological systems. Less studied however, are the effects of hypoxic developmental insults. To this end, our aim is to investigate the long-term effects of prenatal hypoxia on cardiovascular metabolism of adult offspring. We have utilised spectrophotometry to investigate mitochondrial enzyme activity combined with high resolution respirometry to investigate ''in vivo'' mitochondrial efficiency and production of reactive oxygen species. With these methods we aim to identify changes in myocardial mitochondrial energy production, taking a step towards understanding the effect of intrauterine hypoxia on cardiac energetics. Pregnant mice were placed in hypoxic chambers with 14% O2 from gestational day 3-19 and reared in normoxia until six months of age. Heart tissue was harvested and enzymatic activity of citrate synthase and mitochondrial Electron Transport Chain Complexes I-IV was measured using spectrophotometry. High-resolution respirometry lets us further investigate the status of the mitochondria, with emphasis on oxygen consumption and ROS production. Preliminary data show promising differences between treatment and control groups, as well as sexual dimorphism regarding response and effect. We hope to be able to identify possible mechanistic changes, on a cellular level, that underlie the pathological cardiovascular phenotype associated with intrauterine hypoxia.scular phenotype associated with intrauterine hypoxia.)
Petrus 2015 Can J Physiol Pharmacol + (A substantial body of evidence indicates t … A substantial body of evidence indicates that pharmacological activation of mitochondrial ATP-sensitive potassium channels (mKATP) in the heart is protective in conditions associated with ischemia/reperfusion injury. Several mechanisms have been postulated to be responsible for cardioprotection, including the modulation of mitochondrial respiratory function. The aim of the present study was to characterize the dose-dependent effects of novel synthetic benzopyran analogues, derived from a BMS-191095, a selective mKATP opener, on mitochondrial respiration and reactive oxygen species (ROS) production in isolated rat heart mitochondria. Mitochondrial respiratory function was assessed by high-resolution respirometry, and H2O2 production was measured by the Amplex Red fluorescence assay. Four compounds, namely KL-1487, KL-1492, KL-1495, and KL-1507, applied in increasing concentrations (50, 75, 100, and 150 μmol/L, respectively) were investigated. When added in the last two concentrations, all compounds significantly increased State 2 and 4 respiratory rates, an effect that was not abolished by 5-hydroxydecanoate (5-HD, 100 μmol/L), the classic mKATP inhibitor. The highest concentration also elicited an important decrease of the oxidative phosphorylation in a K(+) independent manner. Both concentrations of 100 and 150 μmol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 μmol/L for KL-1507, respectively, mitigated the mitochondrial H2O2 release. In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner.ylation and decrease the generation of reactive oxygen species in a dose-dependent manner.)
Gnaiger 2011 Abstract-Berlin + (A tight relationship is described between … A tight relationship is described between mitochondrial respiratory capacity of human skeletal muscle and physical fitness, which quantifies the decline of respiratory function as the result of a sedentary life style in the progression towards obesity [1]. Tissue-OXPHOS capacity is the capacity of oxidative phosphorylation in skeletal muscle, which is the product of mitochondrial density and respiratory intensity (structure times function; i.e. mitochondrial marker per tissue mass times OXPHOS capacity per mitochondrial marker). Tissue-OXPHOS capacity per unit wet weight [pmol O2∙s-1∙mg-1] is measured directly in permeabilized muscle fibres, and high-resolution respirometry provides a routine approach under physiological conditions (37 °C; Complex I+II substrate combination) with minimal amounts of tissue biopsy (1 to 3 mg wet weight per assay) [2].In healthy subjects varying from athletic to sedentary life styles, tissue-OXPHOS capacity of vastus lateralis increases linearly with maximum aerobic ergometric performance (''V''O2max) and declines steeply with body mass index (BMI=body mass per body height squared [kg/m2]) in the range of 180 to 60 pmol O2∙s-1∙mg-1. The tissue-OXPHOS/BMI relationship spans from endurance athletes and physically active subjects (normal BMI 20-25), overweight individuals (BMI 25-30) with predominantly sedentary life style, to obese patients who are qualified as healthy controls in studies of type 2 diabetes (BMI >30). Total muscle tissue is unchanged or increases rather than decreases with higher BMI, whereas over-proportionally reduced mitochondrial density per muscle mass explains the loss of aerobic ergometric performance in the sedentary life style and development of obesity. Mitochondrial quality (OXPHOS capacity per mitochondrial marker) is largely maintained, but fatty acid oxidation capacity and coupling control decline as a result of diminishing exercise [2]. Specific mitochondrial injuries accumulate as a consequence of reduced mitochondrial density and correspondingly low mitochondrial turnover. Based on the tissue-OXPHOS/BMI relationship and integrating known mechanisms responsible for dysregulation of mitochondrial biosynthesis under conditions of chronic low-grade inflammation, low mitochondrial density is a primary risk factor related to a wide range of degenerative diseases, including type 2 diabetes. The health benefits are emphasized of maintaining muscle mitochondrial density high, particularly with progressive age, as achieved by a physically active and nutritionally normal life style. The diagnostic perspective gained from analysis of mitochondrial competence after exercise training2 challenges the definition of the control group [3]: Are sedentary subjects healthy? Contribution to K-Regio ''[[MitoCom_O2k-Fluorometer|MitoCom Tyrol]]''.1. [[Gnaiger 2009 Int J Biochem Cell Biol|Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int. J. Biochem. Cell Biol. 41: 1837–1845.]]2. [[Pesta_2011_AJP|Pesta D, Hoppel F, Macek C, Messner H, Faulhaber M, Kobel C, Parson W, Burtscher M, Schocke M, Gnaiger E (2011) Similar qualitative and quantitative changes of mitochondrial respiration following strength and endurance training in normoxia and hypoxia in sedentary humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. doi: 10.1152/ajpregu.00285.2011]]3. Martin B, Ji S, Maudsley S, Mattson MP (2010) "Control" laboratory rodents are metabolically morbid: why it matters. Proc. Natl. Acad. Sci. USA 107: 6127-6133.ttson MP (2010) "Control" laboratory rodents are metabolically morbid: why it matters. Proc. Natl. Acad. Sci. USA 107: 6127-6133.)
Gnaiger 2016 Abstract Mito Xmas Meeting Innsbruck + (A variety of lifestyles developed in human … A variety of lifestyles developed in human populations to cope with the environmental and socioeconomic conditions in the inhabited areas of our world. Extremes at high altitude and latitude impose stress conditions which require adjustments in physiological performance or limit permanent settlements. Modern strength and endurance training regimes may be closely linked to a variety of traditional life styles. Diversity is nature’s treasure and the subject of comparative physiology [1].The Polar Inuit of Thule and Qaarnaak in Greenland are among the northernmost populations. This human heritage of a culture and physiological type is endangered not only by a historical politically forced limitation of their territory, but by the current effects of global environmental pollution and climate change, causing social destabilization and a shift towards an unhealthy sedentary in contrast to the traditional active life style of Inuit hunters. The uncoupling hypothesis for mitochondrial haplogroups of arctic populations suggests that lower coupling of mitochondrial respiration to ATP production was selected for in favour of higher heat dissipation as an adaptation to cold climates through a higher mitochondrial proton leak [2]. Our studies show that mitochondrial coupling control in skeletal muscle of Inuit haplogroups is identical to Danes from western Europe haplogroups, such that biochemical coupling efficiency was preserved across variations in muscle fibre type and lifestyle [3]. Unexpectedly, total capacity of oxidative phosphorylation (OXPHOS) in the leg of the Inuit hunters was lower compared to untrained Danes. In line with this apparent ‘mitochondrial paradox’, total OXPHOS capacity decreased in the Danes during 42 days of active skiing on the sea ice in northern Greenland. The Inuit had a higher capacity to oxidize fat substrate in skeletal muscle which increased in Danes approaching the level of the Inuit. A common pattern emerges of mitochondrial acclimatization and evolutionary adaptation in humans at high latitude and high altitude [3-4]: In these environments, economy of locomotion is optimized by preservation of biochemical coupling efficiency at modest mitochondrial density, when ''V''O2max and sustained submaximum performance are not dependent on peripherally increased capacities of oxidative phosphorylation.lly increased capacities of oxidative phosphorylation.)

(A variety of lifestyles developed in human populations to cope with the)

Maddalena 2017 Biochim Biophys Acta + (A variety of mitochondria-targeted small m … A variety of mitochondria-targeted small molecules have been invented to manipulate mitochondrial redox activities and improve function in certain disease states. 3-Hydroxypropyl-triphenylphosphonium-conjugated imidazole-substituted oleic acid (TPP-IOA) was developed as a specific inhibitor of cytochrome c peroxidase activity that inhibits apoptosis by preventing cardiolipin oxidation and cytochrome c release to the cytosol. Here we evaluate the effects of TPP-IOA on oxidative phosphorylation in isolated mitochondria and on mitochondrial function in live cells. We demonstrate that, at concentrations similar to those required to achieve inhibition of cytochrome c peroxidase activity, TPP-IOA perturbs oxidative phosphorylation in isolated mitochondria. In live SH-SY5Y cells, TPP-IOA partially collapsed mitochondrial membrane potential, caused extensive fragmentation of the mitochondrial network, and decreased apparent mitochondrial abundance within 3h of exposure. Many cultured cell lines rely primarily on aerobic glycolysis, potentially making them less sensitive to small molecules disrupting oxidative phosphorylation. We therefore determined the anti-apoptotic efficacy of TPP-IOA in SH-SY5Y cells growing in glucose or in galactose, the latter of which increases reliance on oxidative phosphorylation for ATP supply. The anti-apoptotic activity of TPP-IOA that was observed in glucose media was not seen in galactose media. It therefore appears that, at concentrations required to inhibit cytochrome c peroxidase activity, TPP-IOA perturbs oxidative phosphorylation. In light of these data it is predicted that potential future therapeutic applications of TPP-IOA will be restricted to highly glycolytic cell types with limited reliance on oxidative phosphorylation.Copyright © 2016 Elsevier B.V. All rights reserved. © 2016 Elsevier B.V. All rights reserved.)
Mould 2023 Front Physiol + (A wide variety of studies have reported so … A wide variety of studies have reported some form of non-chemical or non-aqueous communication between physically isolated organisms, eliciting changes in cellular proliferation, morphology, and/or metabolism. The sources and mechanisms of such signalling pathways are still unknown, but have been postulated to involve vibration, volatile transmission, or light through the phenomenon of ultraweak photon emission. Here, we report non-chemical communication between isolated mitochondria from MCF7 (cancer) and MCF10A (non-cancer) cell lines. We found that mitochondria in one cuvette stressed by an electron transport chain inhibitor, antimycin, alters the respiration of mitochondria in an adjacent, but chemically and physically separate cuvette, significantly decreasing the rate of oxygen consumption compared to a control (p = <0.0001 in MCF7 and MCF10A mitochondria). Moreover, the changes in O2-consumption were dependent on the origin of mitochondria (cancer vs. non-cancer) as well as the presence of "ambient" light. Our results support the existence of non-chemical signalling between isolated mitochondria. The experimental design suggests that the non-chemical communication is light-based, although further work is needed to fully elucidate its nature.work is needed to fully elucidate its nature.)
Li 2020 G3 (Bethesda) + (A yeast deletion mutation in the nuclear-e … A yeast deletion mutation in the nuclear-encoded gene, AFO1, which codes for a mitochondrial ribosomal protein, led to slow growth on glucose, the inability to grow on glycerol or ethanol, and loss of mitochondrial DNA and respiration. We noticed that afo1- yeast readily obtains secondary mutations that suppress aspects of this phenotype, including its growth defect. We characterized and identified a dominant missense suppressor mutation in the ATP3 gene. Comparing isogenic slowly growing rho-zero and rapidly growing suppressed afo1- strains under carefully controlled fermentation conditions showed that energy charge was not significantly different between strains and was not causal for the observed growth properties. Surprisingly, in a wild-type background, the dominant suppressor allele of ATP3 still allowed respiratory growth but increased the petite frequency. Similarly, a slow-growing respiratory deficient afo1- strain displayed an about twofold increase in spontaneous frequency of point mutations (comparable to the rho-zero strain) while the suppressed strain showed mutation frequency comparable to the repiratory-competent WT strain. We conclude, that phenotypes that result from afo1- are mostly explained by rapidly emerging mutations that compensate for the slow growth that typically follows respiratory deficiency.tations that compensate for the slow growth that typically follows respiratory deficiency.)
Papadimitriou 2018 Thesis + (ACTN3 has been labelled as the ‘gene for s … ACTN3 has been labelled as the ‘gene for speed’ due to the increased frequency of the R allele encoding the α-actinin-3 protein in elite sprint athletes compared to the general population. The results of the first study of this thesis demonstrate that elite athletes who express α-actinin-3 (ACTN3 RR genotype) have faster sprint times compared to those who do not express α-actinin-3 (ACTN3 XX genotype). Further analysis indicates that the ACTN3 genotype accounts for 0.92% in sprint speed amongst elite 200-m athletes. In study two, the same quantitative genetic epidemiological design applied to elite endurance athletes, showed no evidence that a trade-off existed. The endurance athletes with the ACTN3 XX genotype were no faster than those who express the α-actinin-3 protein. These results added to literature that it is unlikely the ACTN3 XX genotype to offer an advantage for endurance performance. While ACTN3 genotype does not appear to influence endurance performance in athletes, studies in mice that completely lack the α-actinin-3 protein suggest the ACTN3 genotype influences the adaptive response to endurance exercise. Based on these findings, the aim of study 3 was to investigate if ACTN3 genotype influences exercise-induced changes in the content of genes and proteins associated with mitochondrial biogenesis. At baseline, there was a compensatory greater α-actinin-2 protein content in ACTN3 XX vs ACTN3 RR participants (p=0.018) but there were no differences in the endurance-related phenotypes measured. There was a main effect of genotype (p=0.006), without a significant interaction effect, for RCAN1-4 or significant exercise-induced expression of genes associated with mitochondrial biogenesis. Together, these results suggest that ACTN3 genotype has a small but significant influence on sprint speed amongst elite sprint athletes. However, loss of α-actinin-3 protein is not associated with higher values for endurance-related phenotypes, endurance performance, or a greater adaptive response to a single session of high-intensity endurance exercise.sion of high-intensity endurance exercise.)
Kotiadis 2012 J Cell Sci + (ADF/cofilin family proteins are essential … ADF/cofilin family proteins are essential regulators of actin cytoskeletal dynamics. Recent evidence also implicates cofilin in the regulation of mitochondrial function. Here, we identify new functional surfaces of cofilin that are linked with mitochondrial function and stress responses in the budding yeast ''S. cerevisiae''. Our data links surfaces of cofilin that are involved in separable activities of actin filament disassembly or stabilisation, to the regulation of mitochondrial morphology and the activation status of Ras respectively. Importantly, charge alterations to conserved surfaces of cofilin that do not interfere with its actin regulatory activity leads to a dramatic increase in respiratory function that triggers a retrograde signal to up-regulate a battery of ABC transporters and concurrent metabolic changes that support multi-drug resistance. We hypothesise that cofilin functions within a novel bio-sensing system that connects the cytoskeleton and mitochondrial function to environmental challenge.drial function to environmental challenge.)
Scheibye-Knudsen 2009 Eur J Appl Physiol + (ADP is generally accepted as a key regulat … ADP is generally accepted as a key regulator of oxygen consumption both in isolated mitochondria and in permeabilized fibers from skeletal muscle. The present study explored inorganic phosphate in a similar regulatory role. Saponin permeabilized fibers and isolated mitochondria from type-I and type-II muscle from male Wistar rats were prepared. Respiration was measured while the medium Pi concentration was gradually increased. The apparent Km values for Pi were 607 ± 17 µM and 405 ± 15 μM (P < 0.0001) for type-I and type-II fibers, respectively. For isolated mitochondria the values were significantly lower than type-1 permeabilized fibers, 338 ± 130 μM and 235 ± 30 μM (P < 0.05), but not different with respect to fiber type. The reason for this difference in Km values in the permeabilized muscle is unknown, but a similar pattern has been observed for K m of ADP. Our data indicate that phosphate may play a role in regulation of oxygen consumption ''in vitro'' and ''in vivo''.oxygen consumption ''in vitro'' and ''in vivo''.)
Ara 2011 Int J Obes + (AIM/HYPOTHESIS: The aim of this study was … AIM/HYPOTHESIS: The aim of this study was to investigate mitochondrial function, fibre-type distribution and substrate oxidation during exercise in arm and leg muscles in male postobese (PO), obese (O) and age- and body mass index (BMI)-matched control (C) subjects. The hypothesis of the study was that fat oxidation during exercise might be differentially preserved in leg and arm muscles after weight loss.METHODS: Indirect calorimetry was used to calculate fat and carbohydrate oxidation during both progressive arm-cranking and leg-cycling exercises. Muscle biopsy samples were obtained from musculus deltoideus (m. deltoideus) and m. vastus lateralis muscles. Fibre-type composition, enzyme activity and O2 flux capacity of saponin-permeabilized muscle fibres were measured, the latter by high-resolution respirometry.RESULTS: During the graded exercise tests, peak fat oxidation during leg cycling and the relative workload at which it occurred (FatMax) were higher in PO and O than in C. During arm cranking, peak fat oxidation was higher in O than in C, and FatMax was higher in O than in PO and C. Similar fibre-type composition was found between groups. Plasma adiponectin was higher in PO than in C and O, and plasma leptin was higher in O than in PO and C.CONCLUSIONS: In O subjects, maximal fat oxidation during exercise and the eliciting relative exercise intensity are increased. This is associated with higher intramuscular triglyceride levels and higher resting non esterified fatty acid (NEFA) concentrations, but not with differences in fibre-type composition, mitochondrial function or muscle enzyme levels compared with Cs. In PO subjects, the changes in fat oxidation are preserved during leg, but not during arm, exercise. during leg, but not during arm, exercise.)
Nakhostin-Roohi 2008 J Sports Med Phys Fitness + (AIM: Low levels of physical activity and c … AIM:Low levels of physical activity and cardio respiratory fitness are both associated with higher risk of all-cause and disease-specific mortality. The purpose of this study is to examine obesity and fitness of the female staff of Ardebil Azad University in the northwest of Iran.METHODS:Thirty seven staff (medium age: 32.97+/-5.81 year, height: 158.21+/-5.88 cm, Body Mass Index [BMI]: 26.59+/-4.02 kg/m(2)) of Ardebil Azad University participated in this study voluntarily. Primary measurements of interest in the present study were height, BMI, subcutaneous skin folds, and cardio respiratory fitness determined by 1 609 meter (one mile) walk test.RESULTS:The subjects of the present study are more obese than some other population (fat percentage: 28.68+/-5.33) and cardio respiratory fitness of them is rather low (VO(2max): 33.43+/-6.90 mL/kg/min).CONCLUSION:Social/lifestyle factors such as the level of education, marital status, exercise, dietary and smoking habits may be related to overweight/obesity and cardio respiratory fitness in female staff of Ardebil Azad University.n female staff of Ardebil Azad University.)
Larsen 2012 Acta Physiol (Oxf) + (AIM: Mitochondrial function has previously … AIM: Mitochondrial function has previously been studied in ageing, but never in humans matched for maximal oxygen uptake (V·O2max). Furthermore, the influence of ageing on mitochondrial substrate sensitivity is not known.METHODS: Skeletal muscle mitochondrial respiratory capacity and mitochondrial substrate sensitivity was measured by respirometry in young (23±3 years) and middle-aged (53±3 years) male subjects with similar V·O2max. Protocols for respirometry included titration of substrates for complexI (glutamate), complexII (succinate) and both (octanoyl-carnitine) for calculation of substrate sensitivity (C(50) ). Myosin Heavy Chain (MHC) isoforms, citrate synthase (CS) and β-hydroxy-acyl-CoA-dehydrogenase (HAD) activity, mitochondrial DNA (mtDNA) content, protein levels of complexes I-V and antioxidant defense system (manganese superoxide dismutase (MnSOD)) was measured.RESULTS: No differences were found in maximal mitochondrial respiration or C(50) with glutamate (2.0±0.3 and 1.8±0.3 mmol/l), succinate (3.7±0.2 and 3.8±0.4 mmol/l) or octanoyl-carnitine (47±8 and 56±7 μmol/l) in young and middle-aged subjects, respectively. Normalising mitochondrial respiration to mtDNA young subjects had a higher (P<0.05) respiratory capacity per mitochondrion compared to middle-aged subjects. HAD activity and mtDNA per mg tissue were higher in middle-aged compared to young subjects. Middle-aged had a higher MHC I isoform and a lower MHC IIX isoform content compared to young subjects.CONCLUSION: Mitochondrial substrate sensitivity is not affected by ageing. When young and middle-aged men are carefully matched for V·O2max, mitochondrial respiratory capacity is also similar. However, per mitochondrion respiratory capacity was lower in middle-aged compared to young subjects. Thus, when matched for V·O2max middle-aged seems to require a higher mitochondrial content than young subjects.er mitochondrial content than young subjects.)
Raboel 2009 Diabetes Obes Metab + (AIM: Several mechanisms have been targeted … AIM: Several mechanisms have been targeted as culprits of weight gain during antihyperglycaemic treatment in type 2 diabetes (T2DM). These include reductions in glucosuria, increased food intake from fear of hypoglycaemia, the anabolic effect of insulin, decreased metabolic rate and increased efficiency in fuel usage. The purpose of the study was to test the hypothesis that mitochondrial efficiency increases as a result of insulin treatment in patients with type 2 diabetes.METHODS: We included ten patients with T2DM (eight males) on oral antidiabetic treatment, median age: 51.5 years (range: 39-67) and body mass index (BMI): 30.1 +/- 1.2 kg/m2 (mean +/- s.e.). Muscle biopsies from m. vastus lateralis and m. deltoideus were obtained before and after seven weeks of intensive insulin treatment, and mitochondrial respiration was measured using high-resolution respirometry. State 3 respiration was measured with the substrates malate, pyruvate, glutamate, succinate and ADP. State 4o was measured with addition of oligomycine. An age, sex and BMI-matched control group was also included.RESULTS: HbA1c improved significantly and the patients gained on average 3.4 +/- 0.9 kg. Before treatment, respiratory control ratios (RCRs) of the T2DM were lower than the obese controls [2.6 vs. 3.2 (p < 0.05)], but RCR returned to the levels of the control subjects during treatment. Average state 4o of arm and leg declined by 14% (p < 0.05) during insulin treatment.CONCLUSIONS: Tight glycaemic control leads to reductions in inner mitochondrial membrane leak and increased efficiency of mitochondria. This change in mitochondrial physiology could contribute to the weight gain seen with antihyperglycaemic treatment.ght gain seen with antihyperglycaemic treatment.)
Melzer 2010 Ann Nutr Metab + (AIM: The resting metabolic rate (RMR) vari … AIM: The resting metabolic rate (RMR) varies among pregnant women. The factors responsible for this variability are unknown. This study aimed to assess the influence of the prepregnancy body mass index (BMI) on the RMR during late pregnancy.METHODS: RMR, height, weight, and total (TEE) and activity (AEE) energy expenditures were measured in 46 healthy women aged 31 ± 5 years (mean ± SD) with low (<19.8), normal (19.8-26.0), and high (>26.0) prepregnancy BMI at 38.2 ± 1.5 weeks of gestation (t(gest)) and 40 ± 7 weeks postpartum (t(post)) (''n'' = 27).RESULTS: The mean t(gest) RMR for the low-, normal-, and high-BMI groups was 1,373, 1,807, and 2,191 kcal/day, respectively (''p'' = 0.001). The overall mean t(gest) RMR was 316 ± 183 kcal/day (21%), higher than the overall mean t(post) value and this difference was correlated with gestational weight gain (''r'' = 0.78, ''p'' < 0.001). The scaled metabolic rate by allometry (RMR/kilograms⁰·⁷³) was similar in the low-, normal-, and high-BMI groups, respectively (''p'' = 0.45). Changes in t(gest) TEE closely paralleled changes in t(gest) RMR (''r'' = 0.84, 'p'' < 0.001). AEE was similar among the BMI groups.CONCLUSION: The RMR is significantly increased in the third trimester of pregnancy. The absolute gestational RMR is higher in women with high prepregnancy BMI due to increased body weight. The scaled metabolic rate (RMR/kilograms⁰·⁷³) is similar among the BMI groups of pregnant women.⁷³) is similar among the BMI groups of pregnant women.)
WHO 2006 Acta Paediatr + (AIM: To describe the methods used to const … AIM: To describe the methods used to construct the WHO Child Growth Standards based on length/height, weight and age, and to present resulting growth charts.METHODS: The WHO Child Growth Standards were derived from an international sample of healthy breastfed infants and young children raised in environments that do not constrain growth. Rigorous methods of data collection and standardized procedures across study sites yielded very high-quality data. The generation of the standards followed methodical, state-of-the-art statistical methodologies. The Box-Cox power exponential (BCPE) method, with curve smoothing by cubic splines, was used to construct the curves. The BCPE accommodates various kinds of distributions, from normal to skewed or kurtotic, as necessary. A set of diagnostic tools was used to detect possible biases in estimated percentiles or z-score curves.RESULTS: There was wide variability in the degrees of freedom required for the cubic splines to achieve the best model. Except for length/height-for-age, which followed a normal distribution, all other standards needed to model skewness but not kurtosis. Length-for-age and height-for-age standards were constructed by fitting a unique model that reflected the 0.7-cm average difference between these two measurements. The concordance between smoothed percentile curves and empirical percentiles was excellent and free of bias. Percentiles and z-score curves for boys and girls aged 0-60 mo were generated for weight-for-age, length/height-for-age, weight-for-length/height (45 to 110 cm and 65 to 120 cm, respectively) and body mass index-for-age.CONCLUSION: The WHO Child Growth Standards depict normal growth under optimal environmental conditions and can be used to assess children everywhere, regardless of ethnicity, socio-economic status and type of feeding.socio-economic status and type of feeding.)
Larsen 2011 Acta Physiol (Oxf) + (AIM: To study whether the phenotypical cha … AIM: To study whether the phenotypical characteristics (exercise intolerance; reduced spontaneous activity) of the AMPKα2 kinase-dead (KD) mice can be explained by a reduced mitochondrial respiratory flux rates (JO(2) ) in skeletal muscle. Secondly, the effect of the maturation process on JO(2) was studied.METHODS: In tibialis anterior (almost exclusively type 2 fibres) muscle from young (12-17 weeks, n = 7) and mature (25-27 weeks, n = 12) KD and wild-type (WT) (12-17 weeks, n = 9; 25-27 weeks, n = 11) littermates, JO(2) was quantified in permeabilized fibres ex vivo by respirometry, using a substrate-uncoupler-inhibitor-titration (SUIT) protocol: malate, octanoyl carnitine, ADP and glutamate (GMO(3) ), + succinate (GMOS(3) ), + uncoupler (U) and inhibitor (rotenone) of complex I respiration. Citrate synthase (CS) activity was measured as an index of mitochondrial content.RESULTS: Citrate synthase activity was highest in young WT animals and lower in KD animals compared with age-matched WT. JO(2) per mg tissue was lower (P < 0.05) in KD animals (state GMOS(3) ). No uncoupling effect was seen in any of the animals. Normalized oxygen flux (JO(2) /CS) revealed a uniform pattern across the SUIT protocol with no effect of KD. However, JO(2) /CS was higher [GMO(3) , GMOS(3) , U and rotenone (only WT)] in the mature compared with the young mice - irrespective of the genotype (P < 0.05).CONCLUSION: Exercise intolerance and reduced activity level seen in KD mice may be explained by reduced JO(2) in the maximally coupled respiratory state. Furthermore, an enhancement of oxidative phosphorylation capacity per mitochondrion is seen with the maturation process.tochondrion is seen with the maturation process.)
Paglialunga 2012 Diabetologia + (AIMS/HYPOTHESIS: High-fat, high-sucrose d … AIMS/HYPOTHESIS: High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function.METHODS: The Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ), a mitochondria-specific antioxidant, was used to target ROS production in C2C12 muscle cells as well as in HF-fed (16 weeks old) male C57Bl/6 mice, compared with mice on low-fat chow diet (LF) or HF alone. Oxidative stress was measured as protein carbonylation levels. Glucose tolerance tests, glucose uptake assays and insulin-stimulated signalling were determined to assess muscle insulin sensitivity. Mitochondrial function was determined by high-resolution respirometry.RESULTS: SkQ treatment reduced oxidative stress in muscle cells (-23% p < 0.05), but did not improve insulin sensitivity and glucose uptake under insulin-resistant conditions. In HF mice, oxidative stress was elevated (56% vs LF p < 0.05), an effect completely blunted by SkQ. However, HF and HF+SkQ mice displayed impaired glucose tolerance (AUC HF up 33%, p < 0.001; HF+SkQ up 22%; p < 0.01 vs LF) and disrupted skeletal muscle insulin signalling. ROS sequestering did not improve mitochondrial function.CONCLUSIONS/INTERPRETATION:SkQ treatment reduced muscle mitochondrial ROS production and prevented HF-induced oxidative stress. Nonetheless, whole-body glucose tolerance, insulin-stimulated glucose uptake, muscle insulin signalling and mitochondrial function were not improved. These results suggest that HF-induced oxidative stress is not a prerequisite for the development of muscle insulin resistance.site for the development of muscle insulin resistance.)
Friederich-Persson 2012 Diabetologia + (AIMS/HYPOTHESIS: Increased oxygen consump … AIMS/HYPOTHESIS: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.METHODS: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.RESULTS: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 ± 0.1 vs 0.2 ± 0.1 pmol O(2) s(-1) [mg protein](-1)), glomerular hyperfiltration (502 ± 26 vs 385 ± 3 μl/min), increased proteinuria (21 ± 2 vs 14 ± 1, μg/24 h), mitochondrial fragmentation (fragmentation score 2.4 ± 0.3 vs 0.7 ± 0.1) and size (1.6 ± 0.1 vs 1 ± 0.0 μm) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 ± 0.1 pmol O(2) s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 ± 9 vs 67 ± 4 optical density; OD) but were reduced in CoQ10 treated groups (43 ± 2 and 38 ± 7 OD).CONCLUSIONS/INTERPRETATION: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress. of preventing increased oxidative stress.)
Flachs 2011 Diabetologia + (AIMS/HYPOTHESIS: Calorie restriction is an … AIMS/HYPOTHESIS: Calorie restriction is an essential component in the treatment of obesity and associated diseases. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice.METHODS: Male mice (C57BL/6J) were habituated to a corn-oil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF + F), ad libitum; (3) cHF with calorie restriction (CR; cHF + CR); and (4) cHF + F + CR. Mice fed a chow diet were also studied. RESULTS: We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ(12,15)-prostaglandin J(2) and protectin D1.CONCLUSIONS/INTERPRETATION: White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.apeutic strategies for metabolic syndrome.)
Rosca 2008 Cardiovasc Res + (AIMS: Mitochondrial dysfunction is a maj … AIMS: Mitochondrial dysfunction is a major factor in heart failure (HF). A pronounced variability of mitochondrial electron transport chain (ETC) defects is reported to occur in severe acquired cardiomyopathies without a consistent trend for depressed activity or expression. The aim of this study was to define the defect in the integrative function of cardiac mitochondria in coronary microembolization-induced HF.METHODS AND RESULTS:Studies were performed in the canine coronary microembolization-induced HF model of moderate severity. Oxidative phosphorylation was assessed as the integrative function of mitochondria, using a comprehensive variety of substrates in order to investigate mitochondrial membrane transport, dehydrogenase activity and electron-transport coupled to ATP synthesis. The supramolecular organization of the mitochondrial ETC also was investigated by native gel electrophoresis. We found a dramatic decrease in ADP-stimulated respiration that was not relieved by an uncoupler. Moreover, the ADP/O ratio was normal, indicating no defect in the phosphorylation apparatus. The data point to a defect in oxidative phosphorylation within the ETC. However, the individual activities of ETC complexes were normal. The amount of the supercomplex consisting of complex I/complex III dimer/complex IV, the major form of respirasome considered essential for oxidative phosphorylation, was decreased.CONCLUSIONS:We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.n in the individual components of the ETC.)
Wen 2017 Antioxid Redox Signal + (AIMS: We investigated the effects of mit … AIMS: We investigated the effects of mitochondrial reactive oxygen species (mtROS) on nuclear factor (erythroid 2)-like 2 (NFE2L2) transcription factor activity during Trypanosoma cruzi (Tc) infection and determined whether enhancing the mtROS scavenging capacity preserved the heart function in Chagas disease.RESULTS: C57BL/6 wild type (WT, female) mice infected with Tc exhibited myocardial loss of mitochondrial membrane potential, complex II (CII)-driven coupled respiration, and ninefold increase in mtROS production. In vitro and in vivo studies showed that Tc infection resulted in an ROS-dependent decline in the expression, nuclear translocation, antioxidant response element (ARE) binding, and activity of NFE2L2, and 35-99% decline in antioxidants' (gamma-glutamyl cysteine synthase [γGCS], heme oxygenase-1 [HO1], glutamate-cysteine ligase modifier subunit [GCLM], thioredoxin (Trx), glutathione S transferase [GST], and NAD(P)H dehydrogenase, quinone 1 [NQO1]) expression. An increase in myocardial and mitochondrial oxidative adducts, myocardial interventricular septum thickness, and left ventricle (LV) mass, a decline in LV posterior wall thickness, and disproportionate synthesis of collagens (COLI/COLIII), αSMA, and SM22α were noted in WT.Tc mice. Overexpression of manganese superoxide dismutase (MnSOD) in cultured cells (HeLa or cardiomyocytes) and MnSODtg mice preserved the NFE2L2 transcriptional activity and antioxidant/oxidant balance, and cardiac oxidative and fibrotic pathology were significantly decreased in MnSODtg.Tc mice. Importantly, echocardiography finding of a decline in LV systolic (stroke volume, cardiac output, ejection fraction) and diastolic (early/late peak filling ratio, myocardial performance index) function in WT. Tc mice was abolished in MnSODtg. Tc mice. Innovation and Conclusion: The mtROS inhibition of NFE2L2/ARE pathway constitutes a key mechanism in signaling the fibrotic gene expression and evolution of chronic cardiomyopathy. Preserving the NFE2L2 activity arrested the mitochondrial and cardiac oxidative stress, cardiac fibrosis, and heart failure in Chagas disease.osis, and heart failure in Chagas disease.)
Meinild Lundby 2018 Acta Physiol (Oxf) + (AIMS: 1) determine whether exercise induce … AIMS: 1) determine whether exercise induced increases in muscle mitochondrial volume density (MitoVD ) is related to enlargement of existing mitochondria or de novo biogenesis, 2) establish if measures of mitochondrial-specific enzymatic activities are valid biomarkers for exercise induced increases in MitoVD .METHOD: Skeletal muscle samples were collected from twenty-one healthy males prior to and following 6 weeks of endurance training. Transmission electron microscopy was used for estimation of mitochondrial densities and profiles. Biochemical assays, western blotting and high resolution respirometry were applied to detect changes in specific mitochondrial functions.RESULT: MitoVD increased with 55 ± 9% (''P'' < 0.001), whereas the number of mitochondrial profiles per area of skeletal muscle remained unchanged following training. Citrate synthase activity (CS) increased (44 ± 12%, ''P'' < 0.001) however, there were no functional changes in oxidative phosphorylation capacity (OXPHOS, CI+IIP ) or cytochrome c oxidase (COX) activity. Correlations were found between MitoVD and CS (''P''=0.01; ''r''=0.58), OXPHOS, CI+CIIP (''P''=0.01; ''r''=0.58) and COX (''P''=0.02; ''r''=0.52) before training, after training a correlation was found between MitoVD and CS activity only (''P''=0.04; ''r''=0.49). Intrinsic respiratory capacities decreased (''P'' < 0.05) with training when respiration was normalized to MitoVD. This was not the case when normalized to CS activity although the percentage change was comparable. CONCLUSIONS: MitoVD was increased by inducing mitochondrial enlargement rather than de novo biogenesis. CS activity may be appropriate to track training induced changes in MitoVD.priate to track training induced changes in MitoVD.)
Hafstad 2011 J Appl Physiol + (AIMS: Although exercise training induces h … AIMS: Although exercise training induces hypertrophy with improved contractile function, the effect of exercise on myocardial substrate metabolism and cardiac efficiency is less clear. High intensity training has been shown to produce more profound effects on cardiovascular function and aerobic capacity than isocaloric low and moderate intensity training. The aim of the present study was to explore metabolic and mechanoenergetic changes in the heart following endurance exercise training of both high and moderate intensity.METHODS AND RESULTS: C57BL/6J mice were subjected to 10 wk treadmill running, either high intensity interval training (HIT) or distance-matched moderate intensity training (MIT), where HIT led to a pronounced increase in maximal oxygen uptake. Although both modes of exercise were associated with a 10% increase in heart weight-to-body weight ratio, only HIT altered cardiac substrate utilization, as revealed by a 36% increase in glucose oxidation and a concomitant reduction in fatty acid oxidation. HIT also improved cardiac efficiency by decreasing work-independent myocardial oxygen consumption. In addition, it increased cardiac maximal mitochondrial respiratory capacity.CONCLUSION: This study shows that high intensity training is required for induction of changes in cardiac substrate utilization and energetics, which may contribute to the superior effects of high compared with moderate intensity training in terms of increasing aerobic capacity.g in terms of increasing aerobic capacity.)
Bouitbir 2016 Antioxid Redox Signal + (AIMS: Although statins are the most widely … AIMS: Although statins are the most widely used cholesterol-lowering agents, they are associated with a variety of muscle complaints. The goal of this study was to characterize the effects of statins on the mitochondrial apoptosis pathway induced by mitochondrial oxidative stress in skeletal muscle using human muscle biopsies as well as ''in vivo'' and ''in vitro'' models.RESULTS:Statins increased mitochondrial H2O2 production, the Bax/Bcl-2 ratio and TUNEL staining in deltoid biopsies of patients with statin-associated myopathy. Furthermore, atorvastatin treatment for two weeks at 10 mg/kg/day in rats increased H2O2 accumulation, and mRNA levels and immunostaining of the Bax/Bcl-2 ratio, as well as TUNEL staining and caspase 3 cleavage in glycolytic (plantaris) skeletal muscle but not in oxidative (soleus) skeletal muscle, which has a high antioxidative capacity. Atorvastatin also decreased the GSH/GSSG ratio, but only in glycolytic skeletal muscle. Co-treatment with the antioxidant quercetin at 25 mg/kg/d abolished these effects in plantaris. An ''in vitro'' study with L6 myoblasts directly demonstrated the link between mitochondrial oxidative stress following atorvastatin exposure and activation of the mitochondrial apoptosis signaling pathway.INNOVATION:Treatment with atorvastatin is associated with mitochondrial oxidative stress, which activates apoptosis and contributes to myopathy. Glycolytic muscles are more sensitive to atorvastatin than oxidative muscles, which may be due to the higher antioxidative capacity in oxidative muscles.CONCLUSION:There is a link between statin-induced mitochondrial oxidative stress and activation of the mitochondrial apoptosis signaling pathway in glycolytic skeletal muscle, which may be associated with statin-associated myopathy.ay in glycolytic skeletal muscle, which may be associated with statin-associated myopathy.)
Lancel 2012 PLoS One + (AIMS: Metabolic syndrome induces cardiac d … AIMS: Metabolic syndrome induces cardiac dysfunction associated with mitochondria abnormalities. As low levels of carbon monoxide (CO) may improve myocardial and mitochondrial activities, we tested whether a CO-releasing molecule (CORM-3) reverses metabolic syndrome-induced cardiac alteration through changes in mitochondrial biogenesis, dynamics and autophagy. METHODS AND RESULTS: Mice were fed with normal diet (ND) or high-fat diet (HFD) for twelve weeks. Then, mice received two intraperitoneal injections of CORM-3 (10 mg x kg(-1)), with the second one given 16 hours after the first. Contractile function in isolated hearts and mitochondrial parameters were evaluated 24 hours after the last injection. Mitochondrial population was explored by electron microscopy. Changes in mitochondrial dynamics, biogenesis and autophagy were assessed by western-blot and RT-qPCR. Left ventricular developed pressure was reduced in HFD hearts. Mitochondria from HFD hearts presented reduced membrane potential and diminished ADP-coupled respiration. CORM-3 restored both cardiac and mitochondrial functions. Size and number of mitochondria increased in the HFD hearts but not in the CORM-3-treated HFD group. CORM-3 modulated HFD-activated mitochondrial fusion and biogenesis signalling. While autophagy was not activated in the HFD group, CORM-3 increased the autophagy marker LC3-II. Finally, ''ex vivo'' experiments demonstrated that autophagy inhibition by 3-methyladenine abolished the cardioprotective effects of CORM-3. CONCLUSION: CORM-3 may modulate pathways controlling mitochondrial quality, thus leading to improvements of mitochondrial efficiency and HFD-induced cardiac dysfunction.iency and HFD-induced cardiac dysfunction.)
Haram 2009 Cardiovasc Res + (AIMS: The recent development of a rat mode … AIMS: The recent development of a rat model that closely resembles the metabolic syndrome allows to study the mechanisms of amelioration of the syndrome by exercise training. Here, we compared the effectiveness for reducing cardiovascular risk factors by exercise training programmes of different exercise intensities.METHODS AND RESULTS: Metabolic syndrome rats were subjected to either continuous moderate-intensity exercise (CME) or high-intensity aerobic interval training (AIT). AIT was more effective than CME at reducing cardiovascular disease risk factors linked to the metabolic syndrome. Thus, AIT produced a larger stimulus than CME for increasing maximal oxygen uptake (VO2max; 45 vs. 10%, ''P'' < 0.01), reducing hypertension (20 vs. 6 mmHg, ''P'' < 0.01), HDL cholesterol (25 vs. 0%, ''P'' < 0.05), and beneficially altering metabolism in fat, liver, and skeletal muscle tissues. Moreover, AIT had a greater beneficial effect than CME on sensitivity of aorta ring segments to acetylcholine (2.7- vs. 2.0-fold, ''P'' < 0.01), partly because of intensity-dependent effects on expression levels of nitric oxide synthase and the density of caveolae, and a greater effect than CME on the skeletal muscle Ca2+ handling (50 vs. 0%, ''P'' < 0.05). The two exercise training programmes, however, were equally effective at reducing body weight and fat content.CONCLUSION: High-intensity exercise training was more beneficial than moderate-intensity exercise training for reducing cardiovascular risk in rats with the metabolic syndrome. This was linked to more superior effects on VO2max, endothelial function, blood pressure, and metabolic parameters in several tissues. These results demonstrate that exercise training reduces the impact of the metabolic syndrome and that the magnitude of the effect depends on exercise intensity.of the metabolic syndrome and that the magnitude of the effect depends on exercise intensity.)
Garcia-Roves 2008 J Biol Chem + (AMP-activated protein kinase (AMPK) is a h … AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (α) and two regulatory subunits (β and γ), that works as a cellular energy sensor. The existence of multiple heterotrimeric complexes provides a molecular basis for the multiple roles of this highly conserved signaling system. The AMPKγ3 subunit is predominantly expressed in skeletal muscle, mostly in type II glycolytic fiber types. We determined whether the AMPKγ3 subunit has a role in signaling pathways that mediate mitochondrial biogenesis in skeletal muscle. We provide evidence that overexpression or ablation of the AMPKγ3 subunit does not appear to play a critical role in defining mitochondrial content in resting skeletal muscle. However, overexpression of a mutant form (R225Q) of the AMPKγ3 subunit (Tg-AMPKγ3225Q) increases mitochondrial biogenesis in glycolytic skeletal muscle. These adaptations are associated with an increase in expression of the co-activator [[PGC-1α]] and several transcription factors that regulate mitochondrial biogenesis, including NRF-1, NRF-2, and TFAM. Succinate dehydrogenase staining, a marker of the oxidative profile of individual fibers, was also increased in transversal skeletal muscle sections of white gastrocnemius muscle from Tg-AMPKγ3225Q mice, independent of changes in fiber type composition. In conclusion, a single nucleotide mutation (R225Q) in the AMPK gamma3 subunit is associated with mitochondrial biogenesis in glycolytic skeletal muscle, concomitant with increased expression of the co-activator [[PGC-1α]] and several transcription factors that regulate mitochondrial proteins, without altering fiber type composition. and several transcription factors that regulate mitochondrial proteins, without altering fiber type composition.)
Mungai 2011 Mol Cell Biol + (AMP-activated protein kinase (AMPK) is an … AMP-activated protein kinase (AMPK) is an energy sensor activated by increases in [AMP] or by oxidant stress (reactive oxygen species [ROS]). Hypoxia increases cellular ROS signaling, but the pathways underlying subsequent AMPK activation are not known. We tested the hypothesis that hypoxia activates AMPK by ROS-mediated opening of calcium release-activated calcium (CRAC) channels. Hypoxia (1.5% O2) augments cellular ROS as detected by the redox-sensitive green fluorescent protein (roGFP) but does not increase the [AMP]/[ATP] ratio. Increases in intracellular calcium during hypoxia were detected with Fura2 and the calcium-calmodulin fluorescence resonance energy transfer (FRET) sensor YC2.3. Antioxidant treatment or removal of extracellular calcium abrogates hypoxia-induced calcium signaling and subsequent AMPK phosphorylation during hypoxia. Oxidant stress triggers relocation of stromal interaction molecule 1 (STIM1), the endoplasmic reticulum (ER) Ca2+ sensor, to the plasma membrane. Knockdown of STIM1 by short interfering RNA (siRNA) attenuates the calcium responses to hypoxia and subsequent AMPK phosphorylation, while inhibition of L-type calcium channels has no effect. Knockdown of the AMPK upstream kinase LKB1 by siRNA does not prevent AMPK activation during hypoxia, but knockdown of CaMKKβ abolishes the AMPK response. These findings reveal that hypoxia can trigger AMPK activation in the apparent absence of increased [AMP] through ROS-dependent CRAC channel activation, leading to increases in cytosolic calcium that activate the AMPK upstream kinase CaMKKβ. activate the AMPK upstream kinase CaMKKβ.)