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• Racker 1971 J Biol Chem  + (A complex was reconstituted with hydrophob … A complex was reconstituted with hydrophobic proteins from bovine heart mitochondrial membranes, cytochrome c, cytochrome oxidase, phospholipids, and coupling factors. These vesicular structures catalyzed oxidative phosphorylation with reduced N-methylphenazinium methyl sulfate as substrate.ylphenazinium methyl sulfate as substrate.)
• Sobotka 2016 J Bioenerg Biomembr  + (A compound with promising anticancer prope … A compound with promising anticancer properties, 3-bromopyruvate (3-BP) is a synthetic derivative of a pyruvate molecule; however, its toxicity in non-malignant cells has not yet been fully elucidated. Therefore, we elected to study the effects of 3-BP on primary hepatocytes in monolayer cultures, permeabilized hepatocytes and isolated mitochondria. After a 1-h treatment with 100 μM 3-BP cell viability of rat hepatocytes was decreased by 30 % as measured by the WST-1 test (p < 0.001); after 3-h exposure to ≥200 μM 3-BP lactate dehydrogenase leakage was increased (p < 0.001). Reactive oxygen species production was increased in the cell cultures after a 1-h treatment at concentrations ≥100 μmol/l (p < 0.01), and caspase 3 activity was increased after a 20-h incubation with 150 μM and 200 μM 3-BP (p < 0.001). This toxic effect of 3-BP was also proved using primary mouse hepatocytes. In isolated mitochondria, 3-BP induced a dose- and time-dependent decrease of mitochondrial membrane potential during a 10-min incubation both with Complex I substrates glutamate + malate or Complex II substrate succinate, although this decrease was more pronounced with the latter. We also measured the effect of 3-BP on respiration of isolated mitochondria. ADP-activated respiration was inhibited by 20 μM 3-BP within 10 min. Similar effects were also found in permeabilized hepatocytes of both species.so found in permeabilized hepatocytes of both species.)
• Monaco 2018b Diabetologia  + (A comprehensive assessment of skeletal mus … A comprehensive assessment of skeletal muscle ultrastructure and mitochondrial bioenergetics has not been undertaken in individuals with type 1 diabetes. This study aimed to systematically assess skeletal muscle mitochondrial phenotype in young adults with type 1 diabetes.</br></br>Physically active, young adults (men and women) with type 1 diabetes (HbA_1c 63.0 ± 16.0 mmol/mol [7.9% ± 1.5%]) and without type 1 diabetes (control), matched for sex, age, BMI and level of physical activity, were recruited (''n'' = 12/group) to undergo vastus lateralis muscle microbiopsies. Mitochondrial respiration (high-resolution respirometry), site-specific mitochondrial H₂O₂ emission and Ca²⁺ retention capacity (CRC) (spectrofluorometry) were assessed using permeabilised myofibre bundles. Electron microscopy and tomography were used to quantify mitochondrial content and investigate muscle ultrastructure. Skeletal muscle microvasculature was assessed by immunofluorescence.</br></br>Mitochondrial oxidative capacity was significantly lower in participants with type 1 diabetes vs the control group, specifically at Complex II of the electron transport chain, without differences in mitochondrial content between groups. Muscles of those with type 1 diabetes also exhibited increased mitochondrial H₂O₂ emission at Complex III and decreased CRC relative to control individuals. Electron tomography revealed an increase in the size and number of autophagic remnants in the muscles of participants with type 1 diabetes. Despite this, levels of the autophagic regulatory protein, phosphorylated AMP-activated protein kinase (p-AMPKα^Thr172), and its downstream targets, phosphorylated Unc-51 like autophagy activating kinase 1 (p-ULK1^Ser555) and p62, was similar between groups. In addition, no differences in muscle capillary density or platelet aggregation were observed between the groups.</br></br>Alterations in mitochondrial ultrastructure and bioenergetics are evident within the skeletal muscle of active young adults with type 1 diabetes. It is yet to be elucidated whether more rigorous exercise may help to prevent skeletal muscle metabolic deficiencies in both active and inactive individuals with type 1 diabetes.rigorous exercise may help to prevent skeletal muscle metabolic deficiencies in both active and inactive individuals with type 1 diabetes.)
• Metelkin 2009 FEBS J  + (A computational model for the ATP-ADP stea … A computational model for the ATP-ADP steady-state exchange rate mediated by adenine nucleotide translocase (ANT) versus mitochondrial membrane potential dependence in isolated rat liver mitochondria is presented. The model represents the system of three ordinary differential equations, and the basic components included are ANT, F(0)/F(1)-ATPase, and the phosphate carrier. The model reproduces quantitatively the relationship between mitochondrial membrane potential and the ATP-ADP steady-state exchange rate mediated by the ANT operating in the forward mode, with the assumption that the phosphate carrier functions under rapid equilibrium. Furthermore, the model can simulate the kinetics of experimentally measured data on mitochondrial membrane potential titrated by an uncoupler. Verified predictions imply that the ADP influx rate is highly dependent on the mitochondrial membrane potential, and in the 0-100 mV range it is close to zero, owing to extremely low matrix ATP values. In addition to providing theoretical values of free matrix ATP and ADP, the model explains the diminished ADP-ATP exchange rate in the presence of nigericin, a condition in which there is hyperpolarization of the inner mitochondrial membrane at the expense of the mitochondrial Delta pH gradient; the latter parameter influences matrix inorganic phosphate and ATP concentrations in a manner also described.concentrations in a manner also described.)
• Beard 2005 PLOS Comput Biol  + (A computational model for the mitochondria … A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at Complexes I, III, and IV of the electron transport system, ATP synthesis at F1FO ATPase, substrate transporters including adenine nucleotide translocase and the phosphate-hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K⁺/H⁺ antiporter and passive H⁺ and K⁺ permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphate-dependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of Complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.stigating complex physiological and pathophysiological interactions in cardiac energetics.)
• Wu 2007 J Biol Chem  + (A computational model of mitochondrial met … A computational model of mitochondrial metabolism and electrophysiology is introduced and applied to analysis of data from isolated cardiac mitochondria and data on phosphate metabolites in striated muscle in vivo. This model is constructed based on detailed kinetics and thermodynamically balanced reaction mechanisms and a strict accounting of rapidly equilibrating biochemical species. Since building such a model requires introducing a large number of adjustable kinetic parameters, a correspondingly large amount of independent data from isolated mitochondria respiring on different substrates and subject to a variety of protocols is used to parameterize the model and ensure that it is challenged by a wide range of data corresponding to diverse conditions. The developed model is further validated by both in vitro data on isolated cardiac mitochondria and in vivo experimental measurements on human skeletal muscle. The validated model is used to predict the roles of NAD and ADP in regulating the tricarboxylic acid cycle dehydrogenase fluxes, demonstrating that NAD is the more important regulator. Further model predictions reveal that a decrease of cytosolic pH value results in decreases in mitochondrial membrane potential and a corresponding drop in the ability of the mitochondria to synthesize ATP at the hydrolysis potential required for cellular function. potential required for cellular function.)
• Kaambre 2015 Abstract MiP2015  + (A considerable part of previous studies ab … A considerable part of previous studies about tumor bioenergetics were performed on several ''in vitro'' models with the conclusion that cancer cells present increased rates of glucose consumption and metabolize it to lactate even in the presence of O₂ – a phenomenon called “Warburg effect”. ''In vitro'' studies cannot give the correct information about the functional activity and significance of OXPHOS versus glycolysis in malignancies and ignore host factors, which could exert significant effects. In our study we compare respiratory parameters of two very prevalent human tumors: breast cancer (HBC) and colorectal cancer (HCC).</br></br>Primary tumor samples were provided by the Oncology and Hematology Clinic at the North Estonia Medical Centre and were analysed immediately after surgery. In this work we investigated mitochondrial respiration of tumor and control tissues ''in situ'' using the skinned sample technique [1,2]. Rates of O₂ consumption were assayed at 25 °C by an Oxygraph-2k high-resolution respirometer (Oroboros Instruments, Innsbruck Austria). The solubility of oxygen at 25 °C was taken as 240 nmol/ml. All respiration rates were normalized per mg dry weight of tissue.</br></br>Multiple substrate-inhibitor titration protocol was used for the measurement of respiratory capacities of different respiratory chain (RC) segments (Fig. 1). To analyze these changes, the respiration rates for different RC complexes and ratios of respiration rates for different substrates were calculated. The HBC is not accompanied with suppression of complex I-dependent respiration as it is shown in colorectal cancer.</br></br>Apparent Michaelis-Menten constant (Km) and maximal rate of respiration (Vm) for ADP were calculated to characterize the affinity of mitochondria for exogenous ADP (permeability of mitochondrial outer membrane). Healthy colon tissue displayed low affinity for ADP (apparent Michaelis-Menten constant Km=256 ± 3 µM), whereas the affinity for ADP of tumor mitochondria (Km=93.6 ± 7.7 µM) and nearby tissue (junction area between cancer and normal mucosa) (Km=84.9 ± 9.9 µM) is significantly higher. Average Km value for HBC tissue samples was similar - 114.8±13.6 μM. Differences in Vmax correspond, to large extent, to the differences in number of mitochondria in these cell types. Measured rates of O₂ consumption (normalized to Vm) were plotted vs. ADP concentration in medium as double reciprocal Lineweaver–Burk plots (Figure 2 A,B). </br></br>This data is showing that formation of colorectal cancer is associated with relative changes in the activities of individual respiratory chain complexes which may be the result of mitochondrial DNA mutations and/or variations in the assembly of respiratory chain supercomplexes.</br></br>Two subpopulations of mitochondria in HBC (Fig 2B) confirm the theory of two-compartment metabolism (“reversed Warburg”) proposed by several groups of cancer research [3,4]. During formation of HCC colon smooth muscle can participate in the carcinogenesis like energy reservoir and mitochondria lose the diffusion restrictions in the outer membrane. From all these results we can conclude that each type of cancer has its own special bioenergetic fingerprint.onclude that each type of cancer has its own special bioenergetic fingerprint.)
• Hughey 2013 Thesis University of Calgary - Canada  + (A constant provision of adenosine triphosp … A constant provision of adenosine triphosphate (ATP) is of necessity for cardiac contraction. If the heart progresses towards failure following a myocardial infarction (MI) it may undergo metabolic alterations that have the potential to compromise its ability to meet energetic demands. The main focus of this dissertation was to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in energy metabolism that contribute to ATP synthesis post-MI in the presence and absence of diet-induced insulin resistance. </br></br>C57BL/6 mice were chow or high-fat fed prior to induction of a MI via chronic ligation of the left anterior descending coronary artery. Post-ligation, MSCs were transplanted via intramyocardial injection. Serial echocardiography was performed prior to and up to 28 days post-MI to evaluate cardiac systolic function. Hyperinsulinemic-euglycemic clamps coupled with the administration of isotopic tracers were employed post-MI to assess systemic insulin sensitivity and insulin-mediated, tissue-specific substrate uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponinpermeabilized cardiac fibers. Western blotting was completed to assist in identifying molecular mechanisms through which the MSC therapy may modulate cardiac and systemic metabolic phenotypes. </br></br>The improved systolic performance in MSC-treated mice was associated with a lessening of non-pathological ''in vivo'' insulin-stimulated cardiac glucose uptake. The changes in glucose uptake may have been via the MSC-mediated alterations in fatty acid availability/utilization. MSC therapy preserved fatty acid uptake in the absence of diet-induced insulin resistance. Conversely, the cell-based treatment reduced circulating nonesterified fatty acid concentration in high-fat fed mice. Additionally, potential impairments in insulin signalling may have been minimized as indicated by conservation of the p-Akt/Akt ratio. Down-stream of glucose uptake, the administration of MSCs conferred protective effects to mitochondrial oxidative phosphorylation efficiency, maximal function and mitochondrial content. Conclusions: The experiments conducted in this dissertation provide insight into the utility of MSC transplantation as a metabolic therapy for the metabolic perturbations that characterize insulin resistance in the infarcted heart. Also, these studies propose potential mechanisms of action that lead to an enhanced energetic and functional state in the infarcted heart following MSC transplantation.rcted heart following MSC transplantation.)
• Seok 2013 Proc Natl Acad Sci U S A  + (A cornerstone of modern biomedical researc … A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.dels to study human inflammatory diseases.)
• Logan 2018 Mol Metab  + (A decline in mitochondrial function and bi … A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory.</br></br>Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-Cre^TAM/igfr^f/f). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfr^f/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays.</br></br>Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30-50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H₂O₂-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain.</br></br>Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies.</br></br>Copyright © 2018 The Authors. Published by Elsevier GmbH. All rights reserved.cognitive pathologies. Copyright © 2018 The Authors. Published by Elsevier GmbH. All rights reserved.)
• Elliehausen 2021 Exp Gerontol  + (A decline in skeletal muscle mitochondrial … A decline in skeletal muscle mitochondrial function is associated with the loss of skeletal muscle size and function during knee osteoarthritis (OA). We have recently reported that 12-weeks of dietary rapamycin (Rap, 14 ppm), with or without metformin (Met, 1000 ppm), increased plasma glucose and OA severity in male Dunkin Hartley (DH) guinea pigs, a model of naturally occurring, age-related OA. The purpose of the current study was to determine if increased OA severity after dietary Rap and Rap+Met was accompanied by impaired skeletal muscle mitochondrial function. Mitochondrial respiration and hydrogen peroxide (H₂O₂) emissions were evaluated in permeabilized muscle fibers via high-resolution respirometry and fluorometry using either a saturating bolus or titration of ADP. Rap and Rap+Met decreased complex I (CI)-linked respiration and tended to increase ADP sensitivity, consistent with previous findings in patients with end-stage OA. The decrease in CI-linked respiration was accompanied with lower CI protein abundance. Rap and Rap+Met did not change mitochondrial H₂O₂ emissions. There were no differences between mitochondrial function in Rap versus Rap+Met suggesting that Rap was likely driving the change in mitochondrial function. This is the first inquiry into how lifespan extending treatments Rap and Rap+Met can influence skeletal muscle mitochondria in a model of age-related OA. Collectively, our data suggest that Rap with or without Met inhibits CI-linked capacity and increases ADP sensitivity in DH guinea pigs that have greater OA severity.ed capacity and increases ADP sensitivity in DH guinea pigs that have greater OA severity.)
• Logan 2018 Thesis  + (A decline in the oxygen cost of exercise e … A decline in the oxygen cost of exercise enhances exercise tolerance and performance. Substantial research has shown that dietary nitrate lowers the oxygen cost of exercise in sedentary humans; however, the metabolic determinants regarding how dietary nitrate influences oxygen consumption in skeletal muscle is not known. We addressed this gap in knowledge by employing a zebrafish (''Danio rerio'') model to study the effect of nitrate and nitrite supplementation. We hypothesize that zebrafish treated with nitrate and nitrite will respond with a decrease in oxygen consumption during exercise. We exposed zebrafish to 606.9 mg/L sodium nitrate (100 mg/L nitrate-nitrogen), 19.5 mg/L sodium nitrite (13 mg/liter nitrite-nitrogen), and control (no treatment) conditions. Using a Sievers Nitric Oxide Analyzer, we confirmed treatment by quantifying nitrate and nitrite levels in fish water before and after treatment, and in fish blood. We subjected these animals to a swim test to determine the effect of nitrate and nitrite treatment on oxygen consumption and found that nitrate exposure decreased, while nitrite exposure increased, the oxygen cost of exercise. To determine whether mitochondrial function could explain the differing effect of nitrate and nitrite on oxygen consumption, we isolated skeletal muscle mitochondria from each group and analyzed oxygen consumption using high resolution respirometry. Isolated mitochondria, exposed to various substrates of respiration exhibited no change in oxygen consumption, or ATP production during uncoupled states of respiration. We found no significant differences in the ratio of ADP:O, or mitochondrial proteins citrate synthase and ATP5A as a result of exposure. Future research will explore other aspects of energy metabolism and utilization to describe mechanisms that explain the differential oxygen consumption observed during nitrate and nitrite treatment.rved during nitrate and nitrite treatment.)
• Kiss 2013 FASEB J  + (A decline in α-ketoglutarate dehydrogenase … A decline in α-ketoglutarate dehydrogenase complex (KGDHC) activity has been associated with neurodegeneration. Provision of succinyl-CoA by KGDHC is essential for generation of matrix ATP (or GTP) by substrate-level phosphorylation catalyzed by succinyl-CoA ligase. Here, we demonstrate ATP consumption in respiration-impaired isolated and ''in situ'' neuronal somal mitochondria from transgenic mice with a deficiency of either dihydrolipoyl succinyltransferase (DLST) or dihydrolipoyl dehydrogenase (DLD) that exhibit a 20-48 % decrease in KGDHC activity. Import of ATP into the mitochondrial matrix of transgenic mice was attributed to a shift in the reversal potential of the adenine nucleotide translocase toward more negative values due to diminished matrix substrate-level phosphorylation, which causes the translocase to reverse prematurely. Immunoreactivity of all three subunits of succinyl-CoA ligase and maximal enzymatic activity were unaffected in transgenic mice as compared to wild-type littermates. Therefore, decreased matrix substrate-level phosphorylation was due to diminished provision of succinyl-CoA. These results were corroborated further by the finding that mitochondria from wild-type mice respiring on substrates supporting substrate-level phosphorylation exhibited ∼30 % higher ADP-ATP exchange rates compared to those obtained from DLST+/- or DLD+/- littermates. We propose that KGDHC-associated pathologies are a consequence of the inability of respiration-impaired mitochondria to rely on "in-house" mitochondrial ATP reserves. on "in-house" mitochondrial ATP reserves.)
• Correa 2017 Crit Care  + (A decrease in blood lactate levels (Lac) & … A decrease in blood lactate levels (Lac) >10% during the first hours of resuscitation in sepsis is associated with better outcomes, but the mechanisms are unclear. Our objective was to investigate the relationship between the time course of Lac, inflammatory response, and mitochondrial respiration during experimental sepsis.</br></br>Original data from two previously published studies were reanalyzed. In cohort 1, pigs were randomized to be resuscitated for 48 h starting at 6, 12, and 24 h, respectively, after fecal peritonitis induction (n = 8 each). Animals were categorized according to the decrease in Lac during the first 6 h of resuscitation (early if ≥10% [Lac ≥10%] or late if <10% or increased [Lac <10%]), and systemic hemodynamics, inflammatory parameters, and mitochondrial function were compared between groups. In a second group of animals with fecal peritonitis and 24 h of resuscitation (n = 16, cohort 2), abdominal regional Lac exchange was measured, and animals were categorized according to the decrease in Lac as in cohort 1.</br></br>Overall mortality was 20% (4 of 20) in the Lac ≥10% group and 60% (12 of 20) in the Lac <10% group (p = 0.022). In cohort 1, systemic hemodynamics were similar in the Lac ≥10% (n = 13) and Lac <10% (n = 11) groups. Plasma interleukin-6 levels increased during unresuscitated sepsis and decreased during resusciation in both groups, but they were lower at study end in the Lac ≥10% group (p = 0.047). Complexes I and II maximal (state 3) and resting (state 4) isolated brain mitochondrial respiration at study end was higher in the Lac ≥10% group than in the Lac <10% group, whereas hepatic, myocardial, and skeletal muscle mitochondrial respiration was similar in both groups. In cohort 2, mesenteric, total hepatic, and renal blood flow at study end was higher in the Lac ≥10% group (n = 7) than in the Lac <10% group (n = 9), despite similar cardiac output. Hepatic lactate influx and uptake in the Lac ≥10% group were approximately 1.5 and 3 times higher, respectively, than in the Lac <10% group (p = 0.066 for both).</br></br>A decrease in Lac >10% during early resuscitation (6 h) after abdominal sepsis is associated with lower levels of plasma interleukin-6 and improved brain but not hepatic or muscle mitochondrial respiration. Blood flow redistribution to abdominal organs in animals with early decrease in Lac concentrations increases the potential to both deliver and extract Lac.ncentrations increases the potential to both deliver and extract Lac.)
• Hervouet 2008 Carcinogenesis  + (A decrease in oxidative phosphorylation (O … A decrease in oxidative phosphorylation (OXPHOS) is characteristic of many cancer types and, in particular, of clear cell renal carcinoma (CCRC) deficient in von Hippel–Lindau (''vhl'') gene. In the absence of functional pVHL, hypoxia-inducible factor (HIF) 1-α and HIF2-α subunits are stabilized, which induces the transcription of many genes including those involved in glycolysis and reactive oxygen species (ROS) metabolism. Transfection of these cells with ''vhl'' is known to restore HIF-α subunit degradation and to reduce glycolytic genes transcription. We show that such transfection with vhl of 786-0 CCRC (which are devoid of HIF1-α) also increased the content of respiratory chain subunits. However, the levels of most transcripts encoding OXPHOS subunits were not modified. Inhibition of HIF2-α synthesis by RNA interference in pVHL-deficient 786-0 CCRC also restored respiratory chain subunit content and clearly demonstrated a key role of HIF in OXPHOS regulation. In agreement with these observations, stabilization of HIF-α subunit by CoCl₂ decreased respiratory chain subunit levels in CCRC cells expressing pVHL. In addition, HIF stimulated ROS production and mitochondrial manganese superoxide dismutase content. OXPHOS subunit content was also decreased by added H₂O₂. Interestingly, desferrioxamine (DFO) that also stabilized HIF did not decrease respiratory chain subunit level. While CoCl₂ significantly stimulates ROS production, DFO is known to prevent hydroxyl radical production by inhibiting Fenton reactions. This indicates that the HIF-induced decrease in OXPHOS is at least in part mediated by hydroxyl radical production.IF-induced decrease in OXPHOS is at least in part mediated by hydroxyl radical production.)
• Callaway 2013 Nature  + (A dedicated website for sharing biology pa … A dedicated website for sharing biology papers before peer review leaves journals divided. What are biologists so afraid of? Physicists, mathematicians and social scientists routinely post their research to preprint servers such as arXiv.org before publication, yet few life scientists follow suit. A website that goes live this week is hoping to change that. The site, bioRχiv.org, launched by Cold Spring Harbor Laboratory Press in New York, bills itself as “the preprint server for biology”. It will operate similarly to arXiv, with scientists depositing papers as soon as they are ready to share them, weeks or months before formal publication.weeks or months before formal publication.)
• Kula 2017 J Photochem Photobiol  + (A density in algal suspension causes a sig … A density in algal suspension causes a significant change in the intensity and spectral composition of light reaching individual cells. Measurements of chlorophyll fluorescence allow us to observe any general changes in the bioenergetic status of photosynthesis. The aim of the study was to determine the effect of cultivation density on the PSII photochemical efficiency of three species of algae (Chlorella vulgaris, Botryococcus braunii and Chlorella emersonii), each with a different rate of growth - high, medium and low - respectively. The cell density of algae in suspension differentiated through the cultivation time (2, 4, and 8days) and the spectral composition of light. The results showed that the density of cultivation led to change in the photosynthetic apparatus of algae. The differences described between each day of cultivation (2, 4, and 8) in the kinetics of chlorophyll a fluorescence intensity in cells of the algal strains under study probably resulted from the different phases of growth of these cultures. In addition the results showed the beneficial effect of far red light on the photosynthetic apparatus and the growth of biomass in investigated algal strains. of biomass in investigated algal strains.)
• Halangk 1997 Zentralbl Chir  + (A disturbed energy metabolism in pancreati … A disturbed energy metabolism in pancreatic acinar cells is discussed as factor contributing to the development of acute pancreatitis (AP). In this study, we investigated to what extent the mitochondrial ATP producing capacity is impaired in the pancreatic tissue of rats with experimental AP. For preparation of mitochondria from rat pancreas, routine isolation procedures (tissue homogenization and differential centrifugation) were applied. Mitochondria were isolated from rats with edematous pancreatitis produced by hyperstimulation with caerulein, and from rats with mild necrotizing acute pancreatitis. The latter form of AP was induced by a temporary occlusion of the biliary pancreatic duct accompanied by a simultaneous intravenous injection of caerulein plus secretin and an intraabdominal administration of ethanol. As functional parameters of oxidative phosphorylation, the respiration rate, the mitochondrial membrane potential, and the activity of the complex I of the respiratory chain were determined. Mitochondria from rats with caerulein AP showed an enhanced respiration (61% vs. saline control) and a diminished membrane potential (-17 mV) if respiring with succinate in the non-phosphorylating state. This indicates an increased proton leak across the mitochondrial inner membrane. In the mild necrotizing AP, mitochondria were characterized by a decreased respiration with NAD(+)-linked substrates (-33% vs. sham-operated animals). This inhibition of respiration was confirmed by the reduced activity measured for the NADH-cytochrome c reductase (-32%). In both models of experimental AP the potency of mitochondria to produce ATP was significantly diminished. The stronger impairment of mitochondrial functions were found in the necrotizing form of AP. Reactive oxygen species may lead to the observed alterations--to the enhanced permeability of the mitochondrial inner membrane as well as to the inhibition of the complex I of the respiratory chain.of the complex I of the respiratory chain.)
• Mizushima 2016 J Mol Cell Cardiol  + (A failing heart shows severe energy insuff … A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction. Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure. Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure. role in the development of heart failure.)
• Fridovich 1997 J Biol Chem  + (A field of inquiry may be said to have com … A field of inquiry may be said to have come of age when conclusions initially viewed as remarkable or even unbelievable are accepted as commonplace. Study of the biology of the superoxide anion radical and of related free radicals, and the defenses thereto, has now reached this happy state of maturity. Superoxide and even hydroxyl radicals are now known to be produced in living systems, and elaborate systems of defense and repair, which minimize the ravages of these reactive species, have been described. New members of the superoxide dismutase, catalase, and peroxidase families of defensive enzymes are being found, as are new targets that are modified by O·̄2. In addition, the involvement of O·̄2 in both physiological and pathological processes is being established. A weighty tome would be needed to encompass a comprehensive coverage of this field of study. This review will describe only aspects of the biology of oxygen radicals that currently engage the interest of the writer. Hopefully they will also be of interest to the reader. Other recent reviews may serve to fill the gaps in this one.ws may serve to fill the gaps in this one.)
• Klosterhoff 2017 Int J Biol Macromol  + (A fraction composed of an arabinan-rich pe … A fraction composed of an arabinan-rich pectin was extracted from acerola fruit (''Malpighia emarginata'') and named ACWS. This fraction presented 93% of total carbohydrate, relative molecular weight of 7.5×10⁴g/mol, galacturonic acid, arabinose, galactose, xylose and rhamnose in 52.1:32.4:7.2:4.8:3.5 molar ratio and had its structure confirmed by NMR analysis. The anti-fatigue activity of ACWS was evaluated using the weight load swim test on trained mice. ACWS was orally administered at doses of 50mg/kg, 100mg/kg and 200mg/kg for 28days. Plasma biochemical parameters, respiration of permeabilized skeletal muscle fibers, and GSH levels and lipoperoxidation in the brain (pre-frontal cortex, hippocampus, striatum and hypothalamus) were determined. ACWS could lengthen the swimming time, increase the plasma levels of glucose, triglycerides, lactate, and the GSH levels in the hippocampus at all tested doses. The mitochondrial respiratory capacity of the skeletal muscle was increased at middle and high ACWS doses. This study provides strong evidence that ''M. emarginata'' pectic polysaccharide supplementation has anti-fatigue activity, can modify the kinetics of energy substrates (carbohydrate and fat) mobilization and the respiratory capacity of the skeletal muscle, as well the antioxidant status in the hippocampus of ACWS treated animals.ant status in the hippocampus of ACWS treated animals.)
• Ejarque 2018 Int J Obes (Lond)  + (A functional population of adipocyte precu … A functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs.</br></br>Using epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. ''TBX15'' loss- and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals.</br></br>We found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified ''TBX15'' as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that ''TBX15'' is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number.</br></br>We identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes. metabolic phenotype of mature adipocytes.)
• Gasmi 2021 Arch Toxicol  + (A fundamental metabolic feature of cancero … A fundamental metabolic feature of cancerous tissues is high glucose consumption. The rate of glucose consumption in a cancer cell can be 10-15 times higher than in normal cells. Isolation and cultivation of tumor cells in vitro highlight properties that are associated with intensive glucose utilization, the presence of minimal oxidative metabolism, an increase in lactate concentrations in the culture medium and a reduced rate of oxygen consumption. Although glycolysis is suggested as a general feature of malignant cells and recently identified as a possible contributing factor to tumor progression, several studies highlight distinct metabolic characteristics in some tumors, including a relative decrease in avidity compared to glucose and/or a glutamine dependency of lactate and even proliferative tumor cells. The aim of this review is to determine the particularities in the energy metabolism of cancer cells, focusing on the main nutritional substrates, such as glucose and glutamine, evaluating lactate dehydrogenase as a potential marker of malignancy and estimating activators and inhibitors in cancer treatment.vators and inhibitors in cancer treatment.)
• Freyer 2012 Nat Genet  + (A genetic bottleneck explains the marked c … A genetic bottleneck explains the marked changes in mitochondrial DNA (mtDNA) heteroplasmy that are observed during the transmission of pathogenic mutations, but the precise timing of these changes remains controversial, and it is not clear whether selection has a role. These issues are important for the genetic counseling of prospective mothers and for the development of treatments aimed at disease prevention. By studying mice transmitting a heteroplasmic single-base-pair deletion in the mitochondrial tRNA(Met) gene, we show that the extent of mammalian mtDNA heteroplasmy is principally determined prenatally within the developing female germline. Although we saw no evidence of mtDNA selection prenatally, skewed heteroplasmy levels were observed in the offspring of the next generation, consistent with purifying selection. High percentages of mtDNA genomes with the tRNA(Met) mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.plaining why fecundity is not compromised.)
• Chawla 2017 Nature  + (A geneticist's decision not to publish his … A geneticist's decision not to publish his finalized preprint in a journal gets support from scientists online. Preprint papers posted on servers such as [[arXiv]] and [[bioRxiv]] are designed to get research results out for discussion before they are formally peer reviewed and published in journals. But for some scientists, the term is now a misnomer — their preprint papers will never be submitted for formal publication.never be submitted for formal publication.)

• Munro 2022 Mitochondrion  + (A greater capacity of endogenous matrix an … A greater capacity of endogenous matrix antioxidants has recently been hypothesized to characterize mitochondria of long-lived species, curbing bursts of reactive oxygen species (ROS) generated in this organelle. Evidence for this has been obtained from studies comparing the long-lived naked mole rat to laboratory mice. We tested this hypothesis by comparing the longest-lived metazoan, the marine bivalve ''Arctica islandica'' (MLSP=507 y), with shorter-lived and evolutionarily related species. We used a recently developed fluorescent technique to assess mantle and gill tissue mitochondria's capacity to consume hydrogen peroxide (H₂O₂) in multiple physiological states ''ex vivo''. Depending on the type of respiratory substrate provided, mitochondria of ''Arctica islandica'' could consume between 3-14 times more H₂O₂ than shorter-lived species. These findings support the contention that a greater capacity for the elimination of ROS characterizes long-lived species, a novel property of mitochondria thus far demonstrated in two key biogerontological models from distant evolutionary lineages.s far demonstrated in two key biogerontological models from distant evolutionary lineages.)
• Goalstone 2010 Biochemical and Biophysical Research Communication  + (A growing body of evidence implicates smal … A growing body of evidence implicates small G-proteins [e.g., Cdc42 and Rac1] in glucose-stimulated insulin secretion [GSIS] in the islet beta-cell. These signaling proteins undergo post-translational modifications [e.g., prenylation] at their C-terminal cysteine residue and appear to be essential for the transport and fusion of insulin-containing secretory granules with the plasma membrane and the exocytotic secretion of insulin. However, potential regulation of the prenylating enzymes by physiological insulin secretogues [e.g., glucose] has not been investigated thus far. Herein, we report immunological localization, sub-cellular distribution and regulation of farnesyltransferases [FTases] and geranylgeranyltransferase [GGTase] by glucose in insulin-secreting INS 832/13 beta-cells and normal rat islets. Our findings suggest that an insulinotropic concentration of glucose [20mM] markedly stimulated the expression of the alpha-subunits of FTase/GGTase-1, but not the beta-subunits of FTase or GGTase-1 without significantly affecting the predominantly cytosolic distribution of these holoenzymes in INS 832/13 cells and rodent islets. Under these conditions, glucose significantly stimulated [2.5- to 4.0-fold over basal] the activities of both FTase and GGTase-1 in both cell types. Together, these findings provide the first evidence to suggest that GSIS involves activation of the endogenous islet prenyltransferases by glucose, culminating in the activation of their respective G-protein substrates, which is necessary for cytoskeletal rearrangement, vesicular transport, fusion and secretion of insulin.ransport, fusion and secretion of insulin.)
• Borutaite MiP2010  + (A growing body of evidence suggests that n … A growing body of evidence suggests that neurodegeneration in Alzheimer‘s disease (AD) is related to extracellular and intracellular accumulation of amyloid beta peptide (Aβ), mitochondrial dysfunction, increased neuronal loss, however the molecular pathways from Aβ to the main pathological hallmarks of AD are still elusive. Aβ molecules tend to aggregate and form complexes of varying size - from small soluble oligomers, bigger protofibrils and large insoluble fibrils. It is commonly assumed that formation of Aβ fibrils is the crucial event in the pathogenesis of AD. However, there is accumulating evidence that soluble oligomers are the most cytotoxic forms of Aβ though it is still unclear particles of which size and morphology exert most neurotoxicity. In our study we aimed to investigate a link between the size of soluble Aβ oligomers and their toxicity to rat cerebellar granule cells (CGC), cortical neurons and other non-neuronal cells. Variation in conditions during ''in vitro'' oligomerization of Aβ1-42 resulted in peptide assemblies with different particle size. Small oligomeric forms of Aβ1-42 with a particle z-height of 1-2 nm (as measured by atomic force microscopy) were found to be the most toxic species, inducing rapid neuronal necrosis at submicromolar concentrations, whereas the bigger aggregates (above 4-5 nm) did not cause detectable neuronal death. Aβ1-42 oligomers, monomers and fibrils were non-toxic to glial cells in CGC cultures or macrophage J774 cells. Small oligomers of Aβ exhibited tendency to bind to the phospholipid vesicles which composition was similar to reported neuronal plasma membrane composition. In contrast, bigger, non-toxic oligomers did not bind to phospholipid vesicles.</br></br>We also found that mitochondrial respiratory functions were not affected by Aβ1-42 irrespective of the aggregate state: monomers, oligomers or fibrils of Aβ at concentrations up to 2 µM did not inhibit state 3 and state 4 respiration of isolated brain mitochondria and did not cause permeabilization of mitochondrial outer membrane as measured by the exogenous cytochrome c test on mitochondrial respiration. This suggests that Aβ1-42 at pathophysiologically relevant concentrations has no acute effect on mitochondria.</br></br>In conclusion, our data demonstrate that small oligomers of Aβ at submicromolar concentrations induce rapid neuronal necrosis most likely due to the effect on neuronal plasma membranes, whereas bigger aggregates are not directly toxic to neurons.regates are not directly toxic to neurons.)
• Mu 2022 Biochim Biophys Acta Mol Basis Dis  + (A growing body of evidence supports a role … A growing body of evidence supports a role of the gut microbiota in regulating diverse physiological processes, including neural function and metabolism via the gut-brain axis. Infantile spasms syndrome is an early-onset epileptic encephalopathy associated with perturbed brain mitochondrial bioenergetics. Employing a neonatal rat model of infantile spasms, mitochondria respirometry and biochemical analyses, the present study reveals that gut microbiota manipulation by diet, antibiotics and probiotics have the potential to enhance hippocampal mitochondrial bioenergetics. Although preliminary in nature, our data reveal that microbial manipulation that regulates brain mitochondrial function may be a novel strategy for the treatment of epileptic disorders. for the treatment of epileptic disorders.)
• Perry 2013 Diabetes  + (A growing body of research is investigatin … A growing body of research is investigating the potential contribution of mitochondrial function to the etiology of type 2 diabetes. Numerous ''in vitro'', in situ, and ''in vivo'' methodologies are available to examine various aspects of mitochondrial function, each requiring an understanding of their principles, advantages, and limitations. This review provides investigators with a critical overview of the strengths, limitations and critical experimental parameters to consider when selecting and conducting studies on mitochondrial function. ''In vitro'' (isolated mitochondria) and in situ (permeabilized cells/tissue) approaches provide direct access to the mitochondria, allowing for study of mitochondrial bioenergetics and redox function under defined substrate conditions. Several experimental parameters must be tightly controlled, including assay media, temperature, oxygen concentration, and in the case of permeabilized skeletal muscle, the contractile state of the fibers. Recently developed technology now offers the opportunity to measure oxygen consumption in intact cultured cells. Magnetic resonance spectroscopy provides the most direct way of assessing mitochondrial function ''in vivo'' with interpretations based on specific modeling approaches. The continuing rapid evolution of these technologies offers new and exciting opportunities for deciphering the potential role of mitochondrial function in the etiology and treatment of diabetes.in the etiology and treatment of diabetes.)
• Ludzki 2014 Thesis  + (A hallmark of improved metabolic control i … A hallmark of improved metabolic control is a reduced free ADP requirement for</br>a given workload (increased ADP sensitivity). In contrast to ''in vivo'' data, </br>in situ assessments suggest that mitochondrial ADP sensitivity is decreased following exercise training, implying external regulat ion that is not recapitulated in situ. One previously unexplored regulator is palmitoyl-CoA (P-</br>CoA), a lipid metabolism intermediate that inhibits the mitochondrial ADP transport protein adenine nucleotide transferase (ANT). This thesis: 1) established reduced mitochondrial ADP sensitivity following exercise training</br>in middle aged males using permeabilized muscle fibre bundles (PmFB), 2) determined a methodology to evaluate ADP kinetics in PmFB in the presence of P</br>-CoA, and 3) found increased mitochondrial ADP sensitivity in the presence of P</br>-CoA following training. These data suggest that P- CoA is a key regulator of oxidative phosphorylation and direct future exploration of mitochondrial function towards the control of ADP transport via ANT and the effects of exercise on the P-CoA-ANT interaction. of exercise on the P-CoA-ANT interaction.)
• Rowley 2017 J Nutr Biochem  + (A hallmark of type 2 diabetes (T2D) is β-c … A hallmark of type 2 diabetes (T2D) is β-cell dysfunction and the eventual loss of functional β-cell mass. Therefore, mechanisms that improve or preserve β-cell function could be used to improve the quality of life of individuals with T2D. Studies have shown that monomeric, oligomeric and polymeric cocoa flavanols have different effects on obesity, insulin resistance and glucose tolerance. We hypothesized that these cocoa flavanols may have beneficial effects on β-cell function. INS-1 832/13-derived β-cells and primary rat islets cultured with a monomeric catechin-rich cocoa flavanol fraction demonstrated enhanced glucose-stimulated insulin secretion, while cells cultured with total cocoa extract and with oligomeric or polymeric procyanidin-rich fraction demonstrated no improvement. The increased glucose-stimulated insulin secretion in the presence of the monomeric catechin-rich fraction corresponded with enhanced mitochondrial respiration, suggesting improvements in β-cell fuel utilization. Mitochondrial complex III, IV and V components are up-regulated after culture with the monomer-rich fraction, corresponding with increased cellular ATP production. The monomer-rich fraction improved cellular redox state and increased glutathione concentration, which corresponds with nuclear factor, erythroid 2 like 2 (Nrf2) nuclear localization and expression of Nrf2 target genes including nuclear respiratory factor 1 (Nrf1) and GA binding protein transcription factor alpha subunit (GABPA), essential genes for increasing mitochondrial function. We propose a model by which monomeric cocoa catechins improve the cellular redox state, resulting in Nrf2 nuclear migration and up-regulation of genes critical for mitochondrial respiration, glucose-stimulated insulin secretion and ultimately improved β-cell function. These results suggest a mechanism by which monomeric cocoa catechins exert their effects as an effective complementary strategy to benefit T2D patients.</br></br>Copyright © 2017 Elsevier Inc. All rights reserved. © 2017 Elsevier Inc. All rights reserved.)
• Rowley 2017 Thesis  + (A hallmark of type 2 diabetes (T2D) is β-c … A hallmark of type 2 diabetes (T2D) is β-cell dysfunction and the eventual loss of functional β-cell mass. Therefore, mechanisms that improve or preserve β-cell function could be used to improve the quality of life of individuals with T2D. Studies have shown that monomeric, oligomeric and polymeric cocoa flavanols have different effects on obesity, insulin resistance and glucose tolerance. We hypothesized that these cocoa flavanols may have beneficial effects on β-cell function. INS-1 832/13 derived β-cells and primary rat islets cultured with a monomeric catechin-rich cocoa flavanol fraction demonstrated enhanced glucose-stimulated insulin secretion, while cells cultured with total cocoa extract, oligomeric, or polymeric procyanidin-rich fractions demonstrated no improvement. The increased glucose-stimulated insulin secretion in the presence of the monomeric catechin-rich fraction corresponded with enhanced mitochondrial respiration, suggesting improvements in β-cell fuel utilization. Mitochondrial complex III, IV and V components were upregulated after culture with the monomer-rich fraction, corresponding with increased cellular ATP production. The monomer-rich fraction improved cellular redox state and increased glutathione concentration, which corresponds with Nrf2 nuclear localization and expression of Nrf2 target genes, including NRF-1 and GABPA, essential genes for increasing mitochondrial function. We propose a model by which monomeric cocoa catechins improve the cellular redox state, resulting in Nrf2 nuclear migration and upregulation of genes critical for mitochondrial respiration, and, ultimately, enhanced glucose-stimulated insulin secretion and β-cell function. These results suggest a mechanism by which monomeric cocoa catechins exert their effects as an effective complementary strategy to benefit T2D patients.ementary strategy to benefit T2D patients.)
• Hoeks 2008 FEBS Lett  + (A high intake of dietary fat has been sugg … A high intake of dietary fat has been suggested to diminish mitochondrial functioning in skeletal muscle, possibly attributing to muscular fat accumulation. Here we show however, that an 8-week high-fat dietary intervention did not affect intrinsic functioning of rat skeletal muscle mitochondria assessed by respirometry, neither on a carbohydrate- nor on a lipid-substrate. Interestingly, PPARGC1A protein increased by approximately 2-fold upon high-fat feeding and we observed inconsistent results on different markers of mitochondrial density. Mitochondrial ROS production, assessed by electron spin resonance spectroscopy remained unaffected. Intramyocellular lipid levels increased significantly illustrating that a reduced innate mitochondrial function is not a prerequisite for intra-muscular fat accumulation.isite for intra-muscular fat accumulation.)
• Park 2017 Metab Brain Dis  + (A high-fat diet induces obesity in mice, l … A high-fat diet induces obesity in mice, leading to insulin resistance, decreased mitochondrial function, and increased apoptosis in the hippocampus, which eventually result in memory loss. The present study investigated the effect of physical exercise on memory, hippocampal mitochondrial function, and apoptosis in mice with in insulin resistance caused by obesity due to high-fat diet. Mice were randomly divided into four groups: control (CON), control and exercise (CON + EX), high fat diet (HFD), and high fat diet and exercise (HFD + EX). After receiving a high-fat (60%) diet for 20 weeks to induce obesity, the animals were subjected to an exercise routine 6 times per week, for 12 weeks. The exercise duration and intensity gradually increased over 4-week intervals. Hippocampal memory was examined using the step-down avoidance task. Mitochondrial function and apoptosis were also examined in the hippocampus and dentate gyrus. We found that obesity owing to a high-fat diet induced insulin resistance and caused a decrease in memory function. Insulin resistance also caused a decrease in mitochondrial function in the hippocampus by reducing Ca²⁺ retention and O₂, respiration, increasing the levels of H₂O₂, and Cyp-D, and mPTP opening. In addition, apoptosis in the hippocampus increased owing to decreased expression of Bcl-2 and increased expression of Bax, cytochrome c, and caspase-3 and TUNEL-positive cells. In contrast, physical exercise led to reduced insulin resistance, improved mitochondrial function, and reduced apoptosis in the hippocampus. The results suggest that physiological stimulations such as exercise improve hippocampal function and suppress apoptosis, potentially preventing the memory loss associated with obesity-induced insulin resistance.potentially preventing the memory loss associated with obesity-induced insulin resistance.)
• Kwon 2009 Thesis  + (A high-fat diet leads to an accumulation o … A high-fat diet leads to an accumulation of lipid in skeletal muscle, and the development of both mitochondrial dysfunction and insulin resistance. Recently, our lab reported that lipid overload leads to elevated H₂O₂ emission from muscle mitochondria, and that mitochondrial-targeted scavenging of H₂O₂ completely prevents the development of high fat diet-induced insulin resistance. These findings raise the possibility that interventions which acutely restore cellular metabolic balance in muscle may also acutely restore insulin sensitivity. We hypothesized that mitochondrial function and insulin sensitivity can be restored in skeletal muscle of high-fat fed rats by creating an acute deficit in metabolic balance via 2 h low-intensity treadmill exercise or 16 h fasting. Male Sprague-Dawley rats (125-150g) were either maintained on a standard high carbohydrate- diet or fed a high-fat (60%) diet for 6 weeks and divided into three groups the day before the study: one group was maintained on the normal high-fat diet, another group was fasted overnight (16 h), and a third group completed a single 2 h bout of low-intensity treadmill exercise (10 m/min) and then were given normal overnight ad libitum access to the high-fat diet. Oral glucose tolerance tests were administrated to assess insulin action. Red gastrocnemius muscles were harvested and permeabilized fibers prepared for determination of mitochondrial respiratory function and H₂O₂ emission. A single 16 h fast significantly (P<0.05) improved insulin sensitivity in rats maintained on a high-fat diet (P<0.05). Oxygen consumption rate in permeabilized fibers in response to submaximal and maximal ADP concentration when supported exclusively with complex I substrates were not different among groups. However, when respiration was supported by fatty acids (palmitoylcarnitine plus malate, complex I + II substrates), high-fat diet plus exercise group showed higher (P<0.05) rates compared with high-fat diet group. There were no significant differences in H₂O₂ emission among the 4 groups. In conclusion, a single 16 h overnight fast is sufficient to restore insulin sensitivity in high fat diet-induced insulin resistant rats, providing evidence that insulin action in muscle is acutely sensitive to the metabolic state of cells. A single bout of low-intensity treadmill exercise in high-fat fed rats failed to restore insulin action but increased ADP-stimulated respiratory capacity, providing evidence of an as yet unidentified regulatory mechanism of the respiratory system. Somewhat surprisingly however, neither fasting nor exercise altered the H₂O₂ emitting potential in permeabilized fibers, suggesting that further work is required to better understand the factors influencing mitochondrial function and their potential link to insulin sensitivity.lized fibers, suggesting that further work is required to better understand the factors influencing mitochondrial function and their potential link to insulin sensitivity.)
• Cavadas 2015 Hum Mutat  + (A high-resolution mtDNA phylogenetic tree … A high-resolution mtDNA phylogenetic tree allowed us to look backward in time to investigate purifying selection. Purifying selection was very strong in the last 2,500 years, continuously eliminating pathogenic mutations back until the end of the Younger Dryas (∼11,000 years ago), when a large population expansion likely relaxed selection pressure. This was preceded by a phase of stable selection until another relaxation occurred in the out-of-Africa migration. Demography and selection are closely related: expansions led to relaxation of selection and higher pathogenicity mutations significantly decreased the growth of descendants. The only detectible positive selection was the recurrence of highly pathogenic nonsynonymous mutations (m.3394T>C-m.3397A>G-m.3398T>C) at interior branches of the tree, preventing the formation of a dinucleotide STR (TATATA) in the MT-ND1 gene. At the most recent time scale in 124 mother-children transmissions, purifying selection was detectable through the loss of mtDNA variants with high predicted pathogenicity. A few haplogroup-defining sites were also heteroplasmic, agreeing with a significant propensity in 349 positions in the phylogenetic tree to revert back to the ancestral variant. This nonrandom mutation property explains the observation of heteroplasmic mutations at some haplogroup-defining sites in sequencing datasets, which may not indicate poor quality as has been claimed.</br></br>© 2015 WILEY PERIODICALS, INC.s has been claimed. © 2015 WILEY PERIODICALS, INC.)
• Djafarzadeh 2017 J Vis Exp  + (A high-resolution oxygraph is a device for … A high-resolution oxygraph is a device for measuring cellular oxygen consumption in a closed-chamber system with very high resolution and sensitivity in biological samples (intact and permeabilized cells, tissues or isolated mitochondria). The high-resolution oxygraph device is equipped with two chambers and uses polarographic oxygen sensors to measure oxygen concentration and calculate oxygen consumption within each chamber. Oxygen consumption rates are calculated using software and expressed as picomoles per second per number of cells. Each high-resolution oxygraph chamber contains a stopper with injection ports, which makes it ideal for substrate-uncoupler-inhibitor titrations or detergent titration protocols for determining effective and optimum concentrations for plasma membrane permeabilization. The technique can be applied to measure respiration in a wide range of cell types and also provides information on mitochondrial quality and integrity, and maximal mitochondrial respiratory electron transport system capacity.ratory electron transport system capacity.)
• Hatefi 1961 Biochim Biophys Acta  + (A highly active DPNH-cytochrome c reductas … A highly active DPNH-cytochrome c reductase has been isolated from beef-heart mitochondria. The best preparations of the enzyme catalyze the reduction by DPNH of approx. 50–60 μmoles cytochrome c/min/mg protein at 38°. The enzymic activity is completely inhibited by Amytal, p-chloromercuriphenyl sulfonate, antimycin A, SN-5949 or 2-nonyl-4-hydroxyquinoline-N-oxide, and is stimulated by EDTA. The preparation contains DPNH flavoprotein, cytochromes b and c1, Coenzyme Q and non-heme iron and is essentially free of succinic-cytochrome c reductase as well as cytochrome oxidase activity.se as well as cytochrome oxidase activity.)
• Kotarsky 2010 Mitochondrion  + (A homozygous mutation in the complex III c … A homozygous mutation in the complex III chaperone BCS1L causes GRACILE syndrome (intrauterine growth restriction, aminoaciduria, cholestasis, hepatic iron overload, lactacidosis). In control and patient fibroblasts we localized BCS1L in inner mitochondrial membranes. In patient liver, kidney, and heart BCS1L and Rieske protein levels, as well as the amount and activity of complex III, were decreased. Major histopathology was found in kidney and liver with cirrhosis and iron deposition, but of iron-related proteins only ferritin levels were high. In placenta from a GRACILE fetus, the ferrooxidases ceruloplasmin and hephaestin were upregulated suggesting association between iron overload and placental dysfunction.n iron overload and placental dysfunction.)
• Stodden 2020 Proc Natl Acad Sci U S A  + (A key component of scientific communicatio … A key component of scientific communication is sufficient information for other researchers in the field to reproduce published findings. For computational and data-enabled research, this has often been interpreted to mean making available the raw data from which results were generated, the computer code that generated the findings, and any additional information needed such as workflows and input parameters. Many journals are revising author guidelines to include data and code availability. This work evaluates the effectiveness of journal policy that requires the data and code necessary for reproducibility be made available postpublication by the authors upon request. We assess the effectiveness of such a policy by (i) requesting data and code from authors and (ii) attempting replication of the published findings. We chose a random sample of 204 scientific papers published in the journal Science after the implementation of their policy in February 2011. We found that we were able to obtain artifacts from 44 % of our sample and were able to reproduce the findings for 26 %. We find this policy—author remission of data and code postpublication upon request—an improvement over no policy, but currently insufficient for reproducibility.urrently insufficient for reproducibility.)
• Nissen 2017 Glia  + (A key enzyme in brain glutamate homeostasi … A key enzyme in brain glutamate homeostasis is glutamate dehydrogenase (GDH) which links carbohydrate and amino acid metabolism mediating glutamate degradation to CO2 and expanding tricarboxylic acid (TCA) cycle capacity with intermediates, i.e. anaplerosis. Humans express two GDH isoforms, GDH1 and 2, whereas most other mammals express only GDH1. hGDH1 is widely expressed in human brain while hGDH2 is confined to astrocytes. The two isoforms display different enzymatic properties and the nature of these supports that hGDH2 expression in astrocytes potentially increases glutamate oxidation and supports the TCA cycle during energy-demanding processes such as high intensity glutamatergic signaling. However, little is known about how expression of hGDH2 affects the handling of glutamate and TCA cycle metabolism in astrocytes. Therefore, we cultured astrocytes from cerebral cortical tissue of hGDH2-expressing transgenic mice. We measured glutamate uptake and metabolism using [3 H]glutamate, while the effect on metabolic pathways of glutamate and glucose was evaluated by use of 13 C and 14 C substrates and analysis by mass spectrometry and determination of radioactively labeled metabolites including CO2 , respectively. We conclude that hGDH2 expression increases capacity for uptake and oxidative metabolism of glutamate, particularly during increased workload and aglycemia. Additionally, hGDH2 expression increased utilization of branched-chain amino acids (BCAA) during aglycemia and caused a general decrease in oxidative glucose metabolism. We speculate, that expression of hGDH2 allows astrocytes to spare glucose and utilize BCAAs during substrate shortages. These findings support the proposed role of hGDH2 in astrocytes as an important fail-safe during situations of intense glutamatergic activity.uations of intense glutamatergic activity.)
• Andziak 2006 Aging Cell  + (A key tenet of the oxidative stress theory … A key tenet of the oxidative stress theory of aging is that levels of accrued oxidative damage increase with age. Differences in damage generation and accumulation therefore may underlie the natural variation in species longevity. We compared age-related profiles of whole-organism lipid peroxidation (urinary isoprostanes) and liver lipid damage (malondialdehyde) in long living naked mole-rats [maximum lifespan (MLS) > 28.3 years] and shorter-living CB6F1 hybrid mice (MLS approximately 3.5 years). In addition, we compared age-associated changes in liver non-heme iron to assess how intracellular conditions, which may modulate oxidative processes, are affected by aging. Surprisingly, even at a young age, concentrations of both markers of lipid peroxidation, as well as of iron, were at least twofold (P < 0.005) greater in naked mole tats than in mice. This refutes the hypothesis that prolonged naked mole-rat longevity is due to superior protection against oxidative stress. The age-related profiles of all three parameters were distinctly species specific. Rates of lipid damage generation in mice were maintained throughout adulthood, while accrued damage in old animals was twice that of young mice. In naked mole-rats, urinary isoprostane excretion declined by half with age (P < 0.001), despite increases in tissue iron (P < 0.05). Contrary to the predictions of the oxidative stress theory, lipid damage levels did not change with age in mole-rats. These data suggest that the patterns of age-related changes in levels of markers of oxidative stress are species specific, and that the pronounced longevity of naked mole-rats is independent of oxidative stress parameters.le-rats is independent of oxidative stress parameters.)
• Cottingham 1983 Biochim Biophys Acta  + (A kinetic analysis of oxygen uptake was ca … A kinetic analysis of oxygen uptake was carried out in order to investigate the role of ubiquinone pool behaviour in plant mitochondria. The interaction of the external NADH dehydrogenase with either the cytochrome system or the cyanide-insensitive oxidase was examined under various conditions. The involvement of a ubiquinone pool can be deduced from the shape of the titration curve as the appropriate oxidase system is inhibited, by antimycin A for the cytochrome system and salicylhydroxamic acid for the cyanide-insensitive oxidase, at different activities of the NADH dehydrogenase. In the absence of a specific inhibitor, the turnover of the external NADH dehydrogenase was adjusted using a novel NADH-generating system involving the recycling of a low concentration of NAD+ by added glucose 6-phosphate dehydrogenase in the presence of substrate. The results show that ubiquinone pool behaviour is observed between the external NADH dehydrogenase and either the cytochrome b-c1 complex or the cyanide-insensitive oxidase. However, there is a substantial departure from pool behaviour during the simultaneous operation of both oxidases.e simultaneous operation of both oxidases.)
• Laner 2017 Abstract EUROMIT2017 Cologne  + (A lack of physical activity associates wit … A lack of physical activity associates with decreased mitochondrial capacity and is a major cause underlying metabolic dysregulation and preventable diseases in modern societies. In contrast, an active lifestyle supports enhanced mitochondrial capacities and reduces the risk of degenerative diseases. Despite this well-known relation between health and mitochondrial function, there is no regimented, quantitative system, or database organised to routinely test, compare and monitor mitochondrial capacities within individuals or populations. Every study of mitochondrial (mt) function and disease in human tissues and cells is faced with Evolution, Age, Gender, Lifestyle and Environment ([[EAGLE]]) as essential background conditions characterizing the individual patient, subject, study group, species, tissue or – to some extent - cell line. Only a large and well-coordinated network can manage to generate the necessary number of consistent data to address the complexity of EAGLE. Using [[high-resolution respirometry]], the [[K-Regio MitoFit]] and [[MitoEAGLE]] initiatives develop novel lab standards and diagnostic methods for monitoring of a mitochondrial fitness score. SOPs are elaborated for sample preparation, respiratory evaluation and data documentation. Fresh and cryopreserved cells obtained non-invasively from blood samples broaden the scope for respirometric mitochondrial diagnosis.for respirometric mitochondrial diagnosis.)
• Gnaiger 2016 Abstract EBEC Riva del Garda 2016  + (A lack of physical activity associates wit … A lack of physical activity associates with decreased mitochondrial capacity and is a major cause underlying metabolic dysregulation and preventable diseases in modern societies. In contrast, an active lifestyle supports enhanced mitochondrial capacities and reduces the risk of degenerative diseases. Despite this well-known relation between health and mitochondrial function, there is no regimented, quantitative system, or database organised to routinely test, compare and monitor mitochondrial capacities within individuals or populations. Using high-resolution respirometry, the MitoFit and MitoEAGLE initiatives will develop novel lab standards and diagnostic methods for the monitoring of a mitochondrial fitness score. To this end, SOPs will be worked out regarding sample preparation, respiratory evaluation and data documentation. Fresh and cryopreserved cells obtained noninvasively from blood samples will serve as models, the latter allowing samples to be collected for later analysis, thereby broadening the scope for respirometric investigations.</br>This approach will then be expanded to all sorts of human tissues and cells of interest and assess aspects relating to Evolution, Age, Gender, Lifestyle and Environment (EAGLE) as essential background conditions characterizing the individual patient, subject, study group, and/or species. The huge scope of this endeavour requires an international network of laboratories capable of generating the necessary number of consistent data to address the complexity of EAGLE. Coping with the mass of the expected data necessitates a dedicated MitoEAGLE knowledge management network developing harmonization protocols towards generating a rigorously monitored data repository on mitochondrial respiratory function. The resulting MitoEAGLE data management system will enable to interrelate results of a large number of studies, to interpret pathological phenotypes, and to set results into the multidimensional context of EAGLE.nto the multidimensional context of EAGLE.)
• Lukasiak 2016 Eur J Pharmacol  + (A large conductance potassium (BKCa) chann … A large conductance potassium (BKCa) channel opener, NS1619 (1,3-dihydro-1- [2-hydroxy-5-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-2H-benzimidazole-2-one), is well known for its protective effects against ischemia-reperfusion injury; however, the exact mode of its action remains unclear. The aim of this study was to characterize the effect of NS1619 on endothelial cells. The endothelial cell line EA.hy926, guinea pig hearts and submitochondrial particles isolated from the heart were used. In the isolated guinea pig hearts, which were perfused using the Langendorff technique, NS1619 caused a dose-dependent increase in coronary flow that was inhibited by L-NAME. In EA.hy926 cells, NS1619 also caused a dose-dependent increase in the intracellular calcium ion concentration [Ca(2+)]i, as measured using the FURA-2 fluorescent probe. Moreover, NS1619 decreased the oxygen consumption rate in EA.hy926 cells, as assessed using a Clark-type oxygen electrode. However, when NS1619 was applied in the presence of oligomycin, the oxygen consumption increased. NS1619 also decreased the mitochondrial membrane potential, as measured using a JC-1 fluorescent probe in the presence and absence of oligomycin. Additionally, the application of NS1619 to submitochondrial particles inhibited ATP synthase. In summary, NS1619 has pleiotropic actions on EA.hy926 cells and acts not only as an opener of the BKCa channel in EA.hy926 cells but also as an inhibitor of the respiratory chain component, sarcoplasmic reticulum ATPase, which leads to the release of Ca(2+) from the endoplasmic reticulum. Furthermore, NS1619 has the oligomycin-like property of inhibiting mitochondrial ATP synthase.</br></br>Copyright © 2016 Elsevier B.V. All rights reserved. © 2016 Elsevier B.V. All rights reserved.)
• Sperl 1994 J Inher Metab Dis  + (A large number of enzyme systems are exami … A large number of enzyme systems are examined for the diagnosis of mitochondrial myopathies including the pyruvate dehidrogenase complex, tricarboxylic-acid-cycle enzymes and respiratory chain complexes. This investigation can be carried out in frozen tissue. For the study of oxidative phosphorilation in intact mitochondria, fresh muscle tissue is required, and isolation of mitochondria from large amounts of tissue (at least 500-1000 mg) is necessary. For ethical reason this imposes a serious limitation, especially in paediatric patients. Radiochemical measurements of oxidation rates in various substrates in 600 g supernatant from 100-300 mg amounts of muscle tissue has partly overcome this problem. (Bookelman ''et.al''., 1978). Owing to the low yield, the danger of selective isolation of different mitochondrial populations exists. In addition, since isolated mitochondria removed from their natural environment are more or less unstable, there is a possibility of artefacts. Recently, investigation of saponin-skinned muscle fibers by polarographic methods was reported for cardiac (Veksler ''et. al''., 1987) and human muscle tissue. In such permeabilized fibers, study of mitochondrial respiratory control is possible as in isolated mitochondria but without the disadvantages mentioned above (Letellier ''et.al''., 1992; Kunz ''et.al''., 1993).</br>We investigated saponin-skinned muscle fibers in three patients suspected of a mitochondrial encephalo-myopathy. For our studies we used a specially developed respirometer with a sensitivity ten times higher than the established instruments (Kunz ''et.al''., 1993).ished instruments (Kunz ''et.al''., 1993).)
• Lauterbach 2013 FEBS J  + (A large number of industrially relevant en … A large number of industrially relevant enzymes depend upon nicotinamide cofactors, which are too expensive to be added in stoichiometric amounts. Existing NAD(P)H-recycling systems suffer from low activity, or the generation of side products. H₂-driven cofactor regeneration has the advantage of 100% atom efficiency and the use of H₂ as a cheap reducing agent, in a world where sustainable energy carriers are increasingly attractive. The state of development of H₂-driven cofactor-recycling systems and examples of their integration with enzyme reactions are summarized in this article. The O₂-tolerant NAD⁺-reducing hydrogenase from Ralstonia eutropha is a particularly attractive candidate for this approach, and we therefore discuss its catalytic properties that are relevant for technical applications.t are relevant for technical applications.)
• Santoso 2019 Bioorg Med Chem  + (A library of thirty-two quinolinequinones … A library of thirty-two quinolinequinones (QQs) with various amine substituents at the 6- and 7-positions were synthesised efficiently and in good yields for evaluation as potential anti-tuberculosis agents. ''Mycobacterium tuberculosis'' growth inhibition assays demonstrated that QQs bearing moderate length alkyl chains (i.e. heptylphenylamino- and octylamino-QQs), and aryl groups (i.e. phenylethylamino- and benzylamino-QQs) exhibited encouraging inhibitory activity, while QQ analogue 7-chloro-6-propargylamino-quinoline-5,8-dione (16b) had excellent inhibitory activity (MIC = 8 μM). The cLogP values and redox activities of the QQs were determined, and neither readout correlated with the anti-mycobacterial activities of the compounds. Notwithstanding, mode of action studies of 16b revealed that treatment of ''M. tuberculosis'' with this compound led to activation of NADH-dependent oxygen consumption suggesting a redox cycling mechanism. To this end, the promising anti-mycobacterial activity of several QQs and their ability to perturb oxygen management leading to an uncontrolled respiratory burst, as identified in this work and by others, demonstrates the merit of further optimising the anti-mycobacterial activity of this readily synthesised class of compound.</br></br><small>Copyright © 2019. Published by Elsevier Ltd.</small>right © 2019. Published by Elsevier Ltd.</small>)