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• Noone 2023 J Physiol  + (It is unclear how skeletal muscle metaboli … It is unclear how skeletal muscle metabolism and mitochondrial function adapt to long duration bed rest and whether changes can be prevented by nutritional intervention. The present study aimed (1) to assess the effect of prolonged bed rest on skeletal muscle mitochondrial function and dynamics and (2) to determine whether micronutrient supplementation would mitigate the adverse metabolic effect of bed rest. Participants were maintained in energy balance throughout 60 days of bed rest with micronutrient supplementation (INT) (body mass index: 23.747 ± 1.877 kg m^-2 ; 34.80 ± 7.451 years; n = 10) or without (control) (body mass index: 24.087 ± 2.088 kg m^-2 ; 33.50 ± 8.541 years; n = 10). Indirect calorimetry and dual-energy x-ray absorptiometry were used for measures of energy expenditure, exercise capacity and body composition. Mitochondrial respiration was determined by high-resolution respirometry in permeabilized muscle fibre bundles from ''vastus lateralis'' biopsies. Protein and mRNA analysis further examined the metabolic changes relating to regulators of mitochondrial dynamics induced by bed rest. INT was not sufficient in preserving whole body metabolic changes conducive of a decrease in body mass, fat-free mass and exercise capacity within both groups. Mitochondrial respiration, OPA1 and Drp1 protein expression decreased with bed rest, with an increase pDrp1^s616. This reduction in mitochondrial respiration was explained through an observed decrease in mitochondrial content (mtDNA:nDNA). Changes in regulators of mitochondrial dynamics indicate an increase in mitochondrial fission driven by a decrease in inner mitochondrial membrane fusion (OPA1) and increased pDrp1^s616.inner mitochondrial membrane fusion (OPA1) and increased pDrp1^s616.)
• Galli 2021 Front Physiol  + (It is well established that adult vertebra … It is well established that adult vertebrates acclimatizing to hypoxic environments undergo mitochondrial remodeling to enhance oxygen delivery, maintain ATP, and limit oxidative stress. However, many vertebrates also encounter oxygen deprivation during embryonic development. The effects of developmental hypoxia on mitochondrial function are likely to be more profound, because environmental stress during early life can permanently alter cellular physiology and morphology. To this end, we investigated the long-term effects of developmental hypoxia on mitochondrial function in a species that regularly encounters hypoxia during development-the common snapping turtle (''Chelydra serpentina''). Turtle eggs were incubated in 21 % or 10 % oxygen from 20 % of embryonic development until hatching, and both cohorts were subsequently reared in 21 % oxygen for 8 months. Ventricular mitochondria were isolated, and mitochondrial respiration and reactive oxygen species (ROS) production were measured with a microrespirometer. Compared to normoxic controls, juvenile turtles from hypoxic incubations had lower LEAK respiration, higher P:O ratios, and reduced rates of ROS production. Interestingly, these same attributes occur in adult vertebrates that acclimatize to hypoxia. We speculate that these adjustments might improve mitochondrial hypoxia tolerance, which would be beneficial for turtles during breath-hold diving and overwintering in anoxic environments. and overwintering in anoxic environments.)
• Groennebaek 2018 Front Physiol  + (It is well established that high-load resi … It is well established that high-load resistance exercise (HLRE) can stimulate myofibrillar accretion. Additionally, recent studies suggest that HLRE can also stimulate mitochondrial biogenesis and respiratory function. However, in several clinical situations, the use of resistance exercise with high loading may not constitute a viable approach. Low-load blood flow restricted resistance exercise (BFRRE) has emerged as a time-effective low-load alternative to stimulate myofibrillar accretion. It is unknown if BFRRE can also stimulate mitochondrial biogenesis and respiratory function. If so, BFRRE could provide a feasible strategy to stimulate muscle metabolic health. </br></br>To study this, 34 healthy previously untrained individuals (24 ± 3 years) participated in BFRRE, HLRE, or non-exercise control intervention (CON) 3 times per week for 6 weeks. Skeletal muscle biopsies were collected; (1) before and after the 6-week intervention period to assess mitochondrial biogenesis and respiratory function and; (2) during recovery from single-bout exercise to assess myocellular signaling events involved in transcriptional regulation of mitochondrial biogenesis. During the 6-week intervention period, deuterium oxide (D₂O) was continuously administered to the participants to label newly synthesized skeletal muscle mitochondrial proteins. Mitochondrial respiratory function was assessed in permeabilized muscle fibers with high-resolution respirometry. Mitochondrial content was assessed with a citrate synthase activity assay. Myocellular signaling was assessed with immunoblotting. </br></br>Mitochondrial protein synthesis rate was higher with BFRRE (1.19%/day) and HLRE (1.15%/day) compared to CON (0.92%/day) (P < 0.05) but similar between exercise groups. Mitochondrial respiratory function increased to similar degree with both exercise regimens and did not change with CON. For instance, coupled respiration supported by convergent electron flow from complex I and II increased 38% with BFRRE and 24% with HLRE (P < 0.01). Training did not alter citrate synthase activity compared to CON. BFRRE and HLRE elicited similar myocellular signaling responses.</br></br>These results support recent findings that resistance exercise can stimulate mitochondrial biogenesis and respiratory function to support healthy skeletal muscle and whole-body metabolism. Intriquingly, BFRRE produces similar mitochondrial adaptations at a markedly lower load, which entail great clinical perspective for populations in whom exercise with high loading is untenable.populations in whom exercise with high loading is untenable.)
• Chen 2016 Nat Chem Biol  + (It is well established that lactate secret … It is well established that lactate secreted by fermenting cells can be oxidized or used as a gluconeogenic substrate by other cells and tissues. It is generally assumed, however, that within the fermenting cell itself, lactate is produced to replenish NAD⁺ and then is secreted. Here we explore the possibility that cytosolic lactate is metabolized by the mitochondria of fermenting mammalian cells. We found that fermenting HeLa and H460 cells utilize exogenous lactate carbon to synthesize a large percentage of their lipids. Using high-resolution mass spectrometry, we found that both ¹³C and 2-²H labels from enriched lactate enter the mitochondria. The lactate dehydrogenase (LDH) inhibitor oxamate decreased respiration of isolated mitochondria incubated in lactate, but not of isolated mitochondria incubated in pyruvate. Additionally, transmission electron microscopy (TEM) showed that LDHB localizes to the mitochondria. Taken together, our results demonstrate a link between lactate metabolism and the mitochondria of fermenting mammalian cells.between lactate metabolism and the mitochondria of fermenting mammalian cells.)
• Rodriguez 2013 Int J Mol Sci  + (It is well established that melatonin exer … It is well established that melatonin exerts antitumoral effects in many cancer types, mostly decreasing cell proliferation at low concentrations. On the other hand, induction of apoptosis by melatonin has been described in the last few years in some particular cancer types. The cytotoxic effect occurs after its administration at high concentrations, and the molecular pathways involved have been only partially determined. Moreover, a synergistic effect has been found in several cancer types when it is administered in combination with chemotherapeutic agents. In the present review, we will summarize published work on the pro-apoptotic effect of melatonin in cancer cells and the reported mechanisms involved in such action. We will also construct a hypothesis on how different cell signaling pathways may relate each other on account for such effect.ate each other on account for such effect.)
• Ferraretti 2023 bioRxiv  + (It is well established that several ''Homo … It is well established that several ''Homo sapiens'' populations experienced admixture with extinct human species during their evolutionary history. Sometimes, such a gene flow could have played a role in modulating their capability to cope with a variety of selective pressures, thus resulting in archaic adaptive introgression events. A paradigmatic example of this evolutionary mechanism is offered by the EPAS1 gene, whose most frequent haplotype in Himalayan highlanders was proved to reduce their susceptibility to chronic mountain sickness and to be introduced in the gene pool of their ancestors by admixture with Denisovans. In this study, we aimed at further expanding the investigation of the impact of archaic introgression on more complex adaptive responses to hypobaric hypoxia evolved by populations of Tibetan and Sherpa ancestry, which have been plausibly mediated by soft selective sweeps and/or polygenic adaptations rather than by hard selective sweeps. For this purpose, we used a combination of composite-likelihood and gene network-based methods to detect adaptive loci in introgressed chromosomal segments from Tibetan whole genome sequence data and to shortlist those enriched for Denisovan-like derived alleles that participate to the same functional pathways. According to this approach, we identified multiple genes putatively involved in archaic introgression events and that, especially as regards EP300 and NOS2, have plausibly contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in high-altitude Himalayan peoples. These findings provided unprecedented evidence about the complexity of the adaptive phenotype evolved by these human groups to cope with challenges imposed by hypobaric hypoxia, offering new insights into the tangled interplay of genetic determinants that mediates the physiological adjustments crucial for human adaptation to the high-altitude environment.aptation to the high-altitude environment.)
• Joergensen 2015 J Cereb Blood Flow Metab  + (It is well known that few weeks of high fa … It is well known that few weeks of high fat (HF) diet may induce metabolic disturbances and mitochondrial dysfunction in skeletal muscle. However, little is known about the effects of long-term HF exposure and effects on brain mitochondria are unknown. Wistar rats were fed either chow (13E% fat) or HF diet (60E% fat) for 1 year. The HF animals developed obesity, dyslipidemia, insulin resistance, and dysfunction of isolated skeletal muscle mitochondria: state 3 and state 4 were 30% to 50% increased (''p''<0.058) with palmitoyl carnitine (PC), while there was no effect with pyruvate as substrate. Adding also succinate in state 3 resulted in a higher substrate control ratio (SCR) with PC, but a lower SCR with pyruvate (''p''<0.05). The P/O₂ ratio was lower with PC (''p''<0.004). However, similar tests on isolated brain mitochondria from the same animal showed no changes with the substrates relevant for brain (pyruvate and 3-hydroxybutyrate). Thus, long-term HF diet was associated with obesity, dyslipidemia, insulin resistance, and significantly altered mitochondrial function in skeletal muscle. Yet, brain mitochondria were unaffected. We suggest that the relative isolation of the brain due to the blood-brain barrier may play a role in this strikingly different phenotype of mitochondria from the two tissues of the same animal.notype of mitochondria from the two tissues of the same animal.)
• Dos Santos Escaliante 2021 Int J Biol Macromol  + (It is well known that the chemical structu … It is well known that the chemical structure of polysaccharides is important to their final biological effect. In this study we investigated the cytotoxic effect of xyloglucan from ''Copaifera langsdorffii'' seeds (XGC) and its complex with oxovanadium (XGC:VO) on hepatocellular carcinoma cells (HepG2). After 72 h of incubation, XGC and XGC:VO (200 μg/mL) reduced cell viability in ~20% and ~40%, respectively. At same conditions, only XGC:VO increased in ~20% the LDH enzyme release. In permeabilized cells, incubated with XGC and XGC:VO (200 μg/mL) for 72 h, NADH oxidase activity was reduced by ~45% with XGC and XGC:VO. The succinate oxidase activity was reduced by ~35% with XGC and ~65% with XGC:VO, evidencing that polysaccharide complexation with vanadium could intensify its effects on the respiratory chain. According to this result, the mitochondrial membrane potential was also reduced by ~9% for XGC and ~30% for XGC:VO, when compared to the control group. Interestingly, ATP levels were more elevated for XGC:VO in respect to XGC, probably due the enhance in glycolytic flux evidenced by increased levels of lactate. These results show that the xyloglucan complexation with oxovanadium (IV/V) potentiates the cytotoxic effect of the native polysaccharide, possibly by impairment of oxidative phosphorylation.y impairment of oxidative phosphorylation.)
• Duicu 2013 Can J Physiol Pharmacol  + (It is widely recognized that mitochondrial … It is widely recognized that mitochondrial dysfunction is a key component of the multifactorial process of ageing. The effects of age on individual components of mitochondrial function vary across species and strains. In the present study we investigated and compared oxygen consumption, membrane potential (Δψ), the sensitivity of the mitochondrial permeability transition pore (mPTP) to calcium overload and production of reactive oxygen species (ROS) in heart mitochondria isolated from old vs. adult healthy Sprague-Dawley (SD) rats.</br></br>Respirometry studies and Δψ measurements were performed with the Oxygraph-2k (Oroboros, Austria) equipped with a tetraphenylphosphonium electrode. ROS production and calcium retention capacity (CRC) were measured spectrofluorimetrically.</br></br>Our results showed an important decline for all bioenergetic parameters for both Complex I and Complex II supported-respiration, a decreased Δ''ψ'' in mitochondria energized with Complex I substrates and an increased mitochondrial ROS production in old vs. the adult group. Mitochondrial sensitivity to Ca2+-induced mtPTP opening was also increased in the old vs. adult animals. Moreover, the protective effect of cyclosporine A on mtPTP opening was significantly reduced in the old group.</br></br>Healthy ageing is associated with heart mitochondria dysfunction in Sprague Dawley rats.ondria dysfunction in Sprague Dawley rats.)
• Baker 2016b Nature  + (It may not be sexy, but quality assurance is becoming a crucial part of lab life. <small> © 2016 Macmillan Publishers Limited. All rights reserved </small>)
• Chance 1962 Science  + (It now appears to be possible to continuou … It now appears to be possible to continuously record changes in intracellular oxidation-reduction levels in terms of the fluorescence of reduced pyridine nucleotide in mitochondria of various tissues and organs in situ. Studies of kidney and brain cortex in the rat show that changes in fluorescence are not measurably affected by the presence of oxyhemoglobin. Nitrogen, sulfide, cyanide, and carbon monoxide cause increases in fluorescence to very nearly the same levels, and the increases are attributed to larger reduction of mitochondrial diphosphopyridine nucleotide. Amytal at a low blood concentration causes increased reduction in the kidney cortex, and at a high blood concentration, in the brain cortex. The qualitative response of the pyridine nucleotide to low oxygen concentrations shows the brain to be more sensitive than the kidney. The first measurable increase in pyridine nucleotide reduction observed on the brain occurs at a concentration of inspired oxygen of 8 percent. Breathing stops when the percentage increase of pyridine nucleotide reduction on the brain reaches about 90; at this point the percentage increase for the kidney is only about 30. This difference corresponds roughly to a tenfold difference in oxygen tension. Half-maximal increase in pyridine nucleotide reduction on the brain occurs at a concentration of inspired oxygen of about 4 percent and corresponds to an intracellular oxygen tension of about 0.2 mm.racellular oxygen tension of about 0.2 mm.)
• Robach 2012 Br J Sports Med  + (It remains unclear by which mechanism 'liv … It remains unclear by which mechanism 'live high-train low' (LHTL) altitude training increases exercise performance. Haematological and skeletal muscle adaptations have both been proposed. To test the hypotheses that (i) LHTL improves maximal oxygen uptake (VO_2max ) and (ii) this improvement is related to hypoxia-induced increases in total haemoglobin mass (Hb(mass)) and not to improved maximal oxidative capacity of skeletal muscle, we determined VO_2max before LHTL and after LHTL, before and after the altitude-induced increases in Hb(mass) (measured by carbon-monoxide rebreathing) had been abolished by isovolumic haemodilution. We obtained skeletal muscle biopsies to quantify mitochondrial oxidative capacity and efficiency. Sixteen endurance-trained athletes were assigned (double-blinded, placebo controlled) to ≥16;h/day over 4;weeks to normoxia (placebo, n=6) or normobaric hypoxia equivalent to 3000;m altitude (LHTL, n=10). Four-week LHTL did not increase VO_2max , irrespective of treatment (LHTL: 1.5%; placebo: 2.0%). Hb(mass) was slightly increased (4.6%) in 5 (of 10) LHTL subjects but this was not accompanied by a concurrent increase in VO_2max . In the subjects demonstrating an increase in Hb(mass), isovolumic haemodilution elicited a 5.8% decrease in VO_2max . Cycling efficiency was altered neither with time nor by LHTL. Neither maximal capacity of oxidative phosphorylation nor mitochondrial efficiency was modified by time or LHTL. The present results suggest that LHTL has no positive effect on VO_2max in endurance-trained athletes because (i) muscle maximal oxidative capacity is not improved following LHTL and (ii) erythrocyte volume expansion after LHTL, if any, is too small to alter O₂ transport.ing LHTL and (ii) erythrocyte volume expansion after LHTL, if any, is too small to alter O₂ transport.)
• Trewin 2018 Am J Physiol Regul Integr Comp Physiol  + (It remains unclear whether high-intensity … It remains unclear whether high-intensity interval exercise (HIIE) elicits distinct molecular responses to traditional endurance exercise relative to the total work performed. We aimed to investigate the influence of exercise intensity on acute perturbations to skeletal muscle mitochondrial function (respiration and reactive oxygen species), metabolic and redox signaling responses. In a randomized, repeated measures crossover design, eight recreationally active individuals (24 ± 5 years; VO_2peak 48 ± 11 mL.kg^-1.min^-1) undertook continuous moderate-intensity (CMIE: 30 min, 50% peak power output [PPO]), high-intensity interval (HIIE: 5x4 min, 75% PPO, work-matched to CMIE), and low-volume sprint interval (SIE: 4x30 s) exercise, ≥7 days apart. Each session included muscle biopsies at baseline, immediately and 3 h post-exercise for high-resolution mitochondrial respirometry (JO₂) and H₂O₂ emission (JH₂O₂), gene and protein expression analysis. Immediately post-exercise and irrespective of protocol, JO₂ increased during complex I+II leak/state-4 respiration but JH₂O₂ decreased (p<0.05). AMP-activated protein kinase (AMPK) and acetyl co-A carboxylase (ACC) phosphorylation increased ~1.5 and 2.5-fold respectively, while thioredoxin-reductase-1 protein abundance was ~35% lower after CMIE vs. SIE (p<0.05). At 3 hours post-exercise, regardless of protocol, JO₂ was lower during both ADP-stimulated state-3 OXPHOS and uncoupled respiration (p<0.05) but JH₂O₂ trended higher (p<0.08); PPARGC1A mRNA increased ~13-fold, and peroxiredoxin-1 protein decreased ~35%. In conclusion, intermittent exercise performed at high intensities has similar dynamic effects on muscle mitochondrial function compared with endurance exercise, irrespective of whether total workload is matched. This suggests exercise prescription can accommodate individual preferences while generating comparable molecular signals known to promote beneficial metabolic adaptations.irrespective of whether total workload is matched. This suggests exercise prescription can accommodate individual preferences while generating comparable molecular signals known to promote beneficial metabolic adaptations.)
• Holloway 2018 Cell Rep  + (It remains unknown if mitochondrial bioene … It remains unknown if mitochondrial bioenergetics are altered with aging in humans. We established an ''in vitro'' method to simultaneously determine mitochondrial respiration and H₂O₂ emission in skeletal muscle tissue across a range of biologically relevant ADP concentrations. Using this approach, we provide evidence that, although the capacity for mitochondrial H₂O₂ emission is not increased with aging, mitochondrial ADP sensitivity is impaired. This resulted in an increase in mitochondrial H₂O₂ and the fraction of electron leak to H₂O₂, in the presence of virtually all ADP concentrations examined. Moreover, although prolonged resistance training in older individuals increased muscle mass, strength, and maximal mitochondrial respiration, exercise training did not alter H₂O₂ emission rates in the presence of ADP, the fraction of electron leak to H₂O₂, or the redox state of the muscle. These data establish that a reduction in mitochondrial ADP sensitivity increases mitochondrial H₂O₂ emission and contributes to age-associated redox stress.muscle. These data establish that a reduction in mitochondrial ADP sensitivity increases mitochondrial H₂O₂ emission and contributes to age-associated redox stress.)
• Cook 2013 J Exp Biol  + (It was hypothesised that chronic hypoxia a … It was hypothesised that chronic hypoxia acclimation (preconditioning) would alter the behavioural low-O₂ avoidance strategy of fish as a result of both aerobic and anaerobic physiological adaptations. Avoidance and physiological responses of juvenile snapper (''Pagrus auratus'') were therefore investigated following a 6 week period of moderate hypoxia exposure (10.2–12.1 kPa P_O₂, 21±1°C) and compared with those of normoxic controls (P_O₂=20–21 kPa, 21±1°C). The critical oxygen pressure (P_crit) limit of both groups was unchanged at ~7 kPa, as were standard, routine and maximum metabolic rates. However, hypoxia-acclimated fish showed increased tolerances to hypoxia in behavioural choice chambers by avoiding lower P_O₂ levels (3.3±0.7 vs 5.3±1.1 kPa) without displaying greater perturbations of lactate or glucose. This behavioural change was associated with unexpected physiological adjustments. For example, a decrease in blood O₂ carrying capacity was observed after hypoxia acclimation. Also unexpected was an increase in whole-blood P₅₀ following acclimation to low-O₂, perhaps facilitating Hb–O₂ off-loading to tissues. In addition, cardiac mitochondria measured ''in situ'' using permeabilised fibres showed improved O₂ uptake efficiencies. The proportion of the anaerobic enzyme lactate dehydrogenase, at least relative to the aerobic marker enzyme citrate synthase, also increased in heart and skeletal red muscle, indicating enhanced anaerobic potential, or ''in situ'' lactate metabolism, in these tissues. Overall, these data suggest that a prioritization of O₂ delivery and O₂ utilisation over O₂ uptake during long-term hypoxia may convey a significant survival benefit to snapper in terms of behavioural low-O₂ tolerance.;2</sub> delivery and O₂ utilisation over O₂ uptake during long-term hypoxia may convey a significant survival benefit to snapper in terms of behavioural low-O₂ tolerance.)
• Galina 2013 Abstract MiP2013  + (It was proposed that the alkylating agent … It was proposed that the alkylating agent 3-bromopyruvate (3-BrPA) could act as an antitumor agent in different cell lines of hepatocellular carcinoma mainly by targeting the mitochondrial hexokinase type 2 that is overexpressed in many tumor cells. Several revisions of drug therapy for cancer treatment have taken this as the main mechanism of action. Despite the potent negative effects of 3-BrPA on cell viability of the tumors, the analogue of pyruvate/lactate alkyl is oxidizing, as expected, other enzymes in energy transducing metabolism in tumor cells. However, little attention has been given to these side effects of 3-BrPA on tumor mitochondria, glycolysis and calcium pump SERCA. A dataset of high-resolution respirometry, analysis of flux, recovery of enzyme activities and metabolomics evaluated by our group in human hepatoma HepG2, isolated liver mitochondria and activities measured of calcium transport in sarcoplasmic reticulum vesicles mediated by SERCA, point to different metabolic targets with significant implications for the mechanism of cell death in tumor. Among the enzymes as targets we list the main ones: monocarboxylate transporter (MCT), glyceraldehyde dehydrogenase (GA3PDH); 3-phosphoglycerate kinase (3PGK); succinate dehydrogenase (SDH); pyruvate dehydrogenase (PDH); glutamate dehydrogenase (GDH); malate dehydrogenase (MDH) and SERCA 2a. Interestingly, mt-HK 1 and 2 are not significantly inhibited by 3-BrPA, but on the contrary contribute to depletion of the cytosolic ATP pool of the ATP-consuming path of glycolysis. Importantly, the mt-HK acts by modulating the rate of oxidative phosphorylation putting succinate dehydrogenase in a state of greater reactivity and inhibition by 3-BrPA. Given these observations we postulate that the mitochondrial hexokinase is not the primary molecular target of tumor cells but a potent depletory agent of cellular ATP and modulator of succinate dehydrogenase inhibition in mitochondrial supported respiration and inducer of permeability transition pore formation involved in cell death in tumor cells.ion involved in cell death in tumor cells.)
• Chinopoulos 2011 J Neurosci Res  + (It was recently shown that, in progressive … It was recently shown that, in progressively depolarizing mitochondria, the F(0) -F(1) ATP synthase and the adenine nucleotide translocase (ANT) may change directionality independently from each other (Chinopoulos et al. [2010] FASEB J. 24:2405). When the membrane potentials at which these two molecular entities reverse directionality, termed reversal potential (Erev), are plotted as a function of matrix ATP/ADP ratio, an area of the plot is bracketed by the Erev_ATPase and the Erev_ANT, which we call "B space". Both reversal potentials are dynamic, in that they depend on the fluctuating values of the participating reactants; however, Erev_ATPase is almost always more negative than Erev_ANT. Here we review the conditions that define the boundaries of the "B space". Emphasis is placed on the role of matrix substrate-level phosphorylation, because during metabolic compromise this mechanism could maintain mitochondrial membrane potential and prevent the influx of cytosolic ATP destined for hydrolysis by the reversed F(0) -F(1) ATP synthase.s by the reversed F(0) -F(1) ATP synthase.)
• West 1996 J Appl Physiol  + (It would be valuable to have model atmosph … It would be valuable to have model atmospheres that allow barometric pressures (PB) to be predicted at high altitudes. Attempts to do this in the past using the International Civil Aviation Organizations or United States Standard Atmosphere model have brought such models into disrepute because the predicted pressures at high altitudes are usually much too low. However, other model atmospheres have been developed by geophysicists. The critical variable is the change of air temperature with altitude, and, therefore, model atmospheres have been constructed for different latitudes and seasons of the year. These different models give a large range of pressures at a given altitude. For example, the maximum difference of pressure at an altitude of 9 km is from 206 to 248 Torr, i.e., approximately 20%. However, the mean of the model atmospheres for latitude of 15 degrees (in all seasons) and 30 degrees (in the summer) predicts PB at many locations of interest at high altitude very well, with predictions within 1%. The equation is PB (Torr) = exp (6.63268 - 0.1112 h - 0.00149 h²), were h is the altitude in kilometers. The predictions are good because many high mountain sites are within 30 degrees of the equator and also many studies are made during the summer. Other models should be used for latitudes of 45 degrees and above. Model atmospheres have considerable value in predicting PB at high altitude if proper account is take of latitude and season of the year.er account is take of latitude and season of the year.)
• Nemeth 2016 FASEB J  + (Itaconate is a nonamino organic acid exhib … Itaconate is a nonamino organic acid exhibiting antimicrobial effects. It has been recently identified in cells of macrophage lineage as a product of an enzyme encoded by immunoresponsive gene 1 (Irg1), acting on the citric acid cycle intermediate cis-aconitate. In mitochondria, itaconate can be converted by succinate-coenzyme A (CoA) ligase to itaconyl-CoA at the expense of ATP (or GTP), and is also a weak competitive inhibitor of complex II. Here, we investigated specific bioenergetic effects of increased itaconate production mediated by LPS-induced stimulation of Irg1 in murine bone marrow-derived macrophages (BMDM) and RAW-264.7 cells. In rotenone-treated macrophage cells, stimulation by LPS led to impairment in substrate-level phosphorylation (SLP) of ''in situ'' mitochondria, deduced by a reversal in the directionality of the adenine nucleotide translocase operation. In RAW-264.7 cells, the LPS-induced impairment in SLP was reversed by short-interfering RNA(siRNA)-but not scrambled siRNA-treatment directed against Irg1. LPS dose-dependently inhibited oxygen consumption rates (61-91%) and elevated glycolysis rates (>21%) in BMDM but not RAW-264.7 cells, studied under various metabolic conditions. In isolated mouse liver mitochondria treated with rotenone, itaconate dose-dependently (0.5-2 mM) reversed the operation of adenine nucleotide translocase, implying impairment in SLP, an effect that was partially mimicked by malonate. However, malonate yielded greater ADP-induced depolarizations (3-19%) than itaconate. We postulate that itaconate abolishes SLP due to 1) a "CoA trap" in the form of itaconyl-CoA that negatively affects the upstream supply of succinyl-CoA from the α-ketoglutarate dehydrogenase complex; 2) depletion of ATP (or GTP), which are required for the thioesterification by succinate-CoA ligase; and 3) inhibition of complex II leading to a buildup of succinate which shifts succinate-CoA ligase equilibrium toward ATP (or GTP) utilization. Our results support the notion that Irg1-expressing cells of macrophage lineage lose the capacity of mitochondrial SLP for producing itaconate during mounting of an immune defense.aconate during mounting of an immune defense.)
• Belosludtsev 2020 Biochimie  + (Itaconic acid (methylene-succinic acid, It … Itaconic acid (methylene-succinic acid, ItA) is an unsaturated dicarboxylic acid that is secreted by mammalian macrophages in response to a pro-inflammatory stimulus and shows an anti-inflammatory/antibacterial effect. Being a mitochondrial metabolite, it exhibits an inhibitory activity on succinate dehydrogenase and subsequently induces mitochondrial dysfunction. The present study has shown that ItA dose-dependently inhibited ADP- and DNP-stimulated (uncoupled) respiration of rat liver mitochondria energized with succinate. This effect of ItA could be related to the suppression of the activity of complex II and the combined activity of complexes II + III of the respiratory chain. At the same time, ItA had no effect on the activity of the dicarboxylate carrier, which catalyzes the transport of succinate across the inner mitochondrial membrane. It was found that 4 mM ItA diminished the rates of ADP- and DNP-stimulated mitochondrial respiration supported by the substrates of complex I glutamate and malate. A study of the effect of ItA on the activity of complexes of the respiratory chain showed that it significantly decreases the activity of complex IV. It was observed that 4 mM ItA inhibited the rate of H₂O₂ production by mitochondria. At the same time, ItA promoted the opening of the cyclosporin A-sensitive Ca²⁺-dependent permeability transition pore. The latter was revealed as the decrease in the calcium retention capacity of mitochondria and the stimulation of release of cytochrome c from the organelles. ItA by itself promotes the cytochrome c release from mitochondria. Possible mechanisms of the effect of ItA on mitochondrial function are discussed.sible mechanisms of the effect of ItA on mitochondrial function are discussed.)
• Nemeth 2017 Thesis  + (Itaconic acid, matrix substrate-level phos … Itaconic acid, matrix substrate-level phosphorylation (SLP) and macrophages represent the main focus of this thesis. From a more general point of view, it is about immune cell specific metabolism.</br>Usually, metabolism is viewed as the function of cells generating a store of energy by catabolism, and to synthesizing macromolecules for cell maintenance and growth through anabolic pathways. However, today we know that there are some disorders, such as diabetes, atherosclerosis, cancer, inflammatory conditions, in which there are obvious dysfunctions in metabolism.</br>...re obvious dysfunctions in metabolism. ...)
• Reynolds 2016 Am J Physiol Endocrinol Metab  + (Iβ-cell insulin secretion is dependent on … Iβ-cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle and adipose. We have previously demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic β-cells. In this study we examined whether Nr4a expression impacts pancreatic β-cell mitochondrial function. Here we show that β-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in β-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose stimulated insulin secretion rates is observed with deletion of Nr4a1 or Nr4a3. Interestingly, the changes in respiration and insulin secretion occur without a reduction in mitochondrial content, suggesting decreased mitochondrial function. We establish that knockdown of Nr4a1 and Nr4a3 results in decreased expression of the mitochondrial dehydrogenase subunits Idh3g and Sdhb. We demonstrate that loss of Nr4a1 and Nr4a3 impedes production of ATP, and ultimately inhibits glucose stimulated insulin secretion. These data demonstrate for the first time that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for β-cell mitochondrial function and insulin secretion.</br></br>Copyright © 2016, American Journal of Physiology - Endocrinology and Metabolism.Physiology - Endocrinology and Metabolism.)
• JASIS 2017 Chiba JP  + (JASIS - Japan Analytical & Scientific Instruments Show, Chiba, Japan)
• Weir 2005 N Engl J Med  + (JOSEPH PRIESTLEY, ONE OF THE THREE SCIENTI … JOSEPH PRIESTLEY, ONE OF THE THREE SCIENTISTS CREDITED WITH THE</br>discovery of oxygen, described the death of mice that were deprived of oxygen. However, he</br>was also well aware of the toxicity of too much oxygen, stating, “For as a candle burns much</br>faster in dephlogisticated [oxygen-enriched] than in common air, so we might live out too fast,</br>and the animal powers be too soon exhausted in this pure kind of air. A moralist, at least, may</br>say, that the air which nature has provided for us is as good as we deserve.”1</br>In this review we examine the remarkable mechanisms by which different organs detect and</br>respond to acute changes in oxygen tension. Specialized tissues that sense the local oxygen</br>tension include glomus cells of the carotid body, neuroepithelial bodies in the lungs, chromaffin</br>cells of the fetal adrenal medulla, and smooth-muscle cells of the resistance pulmonary arteries,</br>fetoplacental arteries, systemic arteries, and the ductus arteriosus. Together, they constitute a</br>specialized homeostatic oxygen-sensing system. Although all tissues are sensitive to severe</br>hypoxia, these specialized tissues respond rapidly to moderate changes in oxygen tension</br>within the physiologic range (roughly 40 to 100 mm Hg in an adult and 20 to 40 mm Hg in a</br>fetus) (Fig. 1).t and 20 to 40 mm Hg in a fetus) (Fig. 1).)
• Indian Academy of Pediatrics Growth Charts Committee 2015 Indian Pediatr  + (JUSTIFICATION: The need to revise Indian A … JUSTIFICATION: The need to revise Indian Academy of Pediatrics (IAP) growth charts for 5- to 18-year-old Indian children and adolescents was felt as India is in nutrition transition and previous IAP charts are based on data which are over two decades old.</br></br>PROCESS: The Growth Chart Committee was formed by IAP in January 2014 to design revised growth charts. Consultative meeting was held in November 2014 in Mumbai. Studies performed on Indian children's growth, nutritional assessment and anthropometry from upper and middle socioeconomic classes in last decade were identified. Committee contacted 13 study groups; total number of children in the age group of 5 to 18 years were 87022 (54086 boys). Data from fourteen cities (Agartala, Ahmadabad, Chandigarh, Chennai, Delhi, Hyderabad, Kochi, Kolkata, Madurai, Mumbai, Mysore, Pune, Raipur and Surat) in India were collated. Data of children with weight for height Z scores >2 SD were removed from analyses. Data on 33148 children (18170 males, 14978 females) were used to construct growth charts using Cole's LMS method.</br></br>OBJECTIVE: To construct revised IAP growth charts for 5-18 year old Indian children based on collated national data from published studies performed on apparently healthy children and adolescents in the last 10 years.</br></br>RECOMMENDATIONS: The IAP growth chart committee recommends these revised growth charts for height, weight and body mass index (BMI) for assessment of growth of 5-18 year old Indian children to replace the previous IAP charts; rest of the recommendations for monitoring height and weight remain as per the IAP guidelines published in 2007. To define overweight and obesity in children from 5-18 years of age, adult equivalent of 23 and 27 cut-offs presented in BMI charts may be used. IAP recommends use of WHO standards for growth assessment of children below 5 years of age. assessment of children below 5 years of age.)

• ASMRM & J-mit 2019 Fukuoka JP  + (Joint ASMRM and J-mit Conference, Fukuoka, Japan, 2019)

• Yamada 2016 J Physiol  + (KEY POINTS: Mitochondrial respiration is r … KEY POINTS:</br>Mitochondrial respiration is regulated by multiple elaborate mechanisms. It has been shown that muscle specific O₂ binding protein, Myoglobin (Mb), is localized in mitochondria and interacts with respiratory chain complex IV, suggesting that Mb could be a factor that regulates mitochondrial respiration. Here, we demonstrate that muscle mitochondrial respiration is improved by Mb overexpression via up-regulation of complex IV activity in cultured myoblasts; in contrast, suppression of Mb expression induces a decrease in complex IV activity and mitochondrial respiration compared with the overexpression model. The present data are the first to show the biological significance of mitochondrial Mb as a potential modulator of mitochondrial respiratory capacity.</br></br>ABSTRACT:</br>Mitochondria are important organelles for metabolism, and their respiratory capacity is a primary factor in the regulation of energy expenditure. Deficiencies of cytochrome c oxidase complex IV, which reduces O₂ in mitochondria, are linked to several diseases, such as mitochondrial myopathy. Moreover, mitochondrial respiration in skeletal muscle tissue tends to be susceptible to complex IV activity. Recently, we showed that the muscle-specific protein myoglobin (Mb) interacts with complex IV. The precise roles of mitochondrial Mb remain unclear. Here, we demonstrate that Mb facilitates mitochondrial respiratory capacity in skeletal muscles. Although mitochondrial DNA copy numbers were not altered in Mb-overexpressing myotubes, O₂ consumption was greater in these myotubes than that in mock cells (Mock vs. Mb-Flag::GFP: state 4, 1.00 ± 0.09 vs. 1.77 ± 0.34; state 3, 1.00 ± 0.29; Mock: 1.60 ± 0.53; complex 2-3-4: 1.00 ± 0.30 vs. 1.50 ± 0.44; complex IV: 1.00 ± 0.14 vs. 1.87 ± 0.27). This improvement in respiratory capacity could be because of the activation of enzymatic activity of respiratory complexes. Moreover, mitochondrial respiration was up-regulated in myoblasts transiently overexpressing Mb; complex IV activity was solely activated in Mb-overexpressing myoblasts, and complex IV activity was decreased in the myoblasts in which Mb expression was suppressed by Mb-siRNA transfection (Mb vector transfected vs. Mb vector, control siRNA transfected vs. Mb vector, Mb siRNA transfected: 0.15 vs. 0.15 vs. 0.06). Therefore, Mb enhances the enzymatic activity of complex IV to ameliorate mitochondrial respiratory capacity, and could play a pivotal role in skeletal muscle metabolism.iratory capacity, and could play a pivotal role in skeletal muscle metabolism.)
• Montero 2015 J Physiol  + (KEY POINTS: This study assessed the respec … KEY POINTS:</br>This study assessed the respective contributions of haematological and skeletal muscle adaptations to any observed improvement in peak oxygen uptake (VO₂ peak ) induced by endurance training (ET). VO₂ peak , peak cardiac output (Q̇ peak ), blood volumes and skeletal muscle biopsies were assessed prior (pre) to and after (post) 6 weeks of ET. Following the post-ET assessment, red blood cell volume (RBCV) reverted to the pre-ET level following phlebotomy and VO₂ peak and Q̇ peak were determined again. We speculated that the contribution of skeletal muscle adaptations to an ET-induced increase in VO₂ peak could be identified when offsetting the ET-induced increase in RBCV. VO₂ peak , Q̇ peak , blood volumes, skeletal muscle mitochondrial volume density and capillarization were increased after ET. Following RBCV normalization, VO₂ peak and Q̇ peak reverted to pre-ET levels. These results demonstrate the predominant contribution of haematological adaptations to any increase in VO₂ peak induced by ET.</br></br>ABSTRACT:</br>It remains unclear whether improvements in peak oxygen uptake (V̇O2 peak ) following endurance training (ET) are primarily determined by central and/or peripheral adaptations. Herein, we tested the hypothesis that the improvement in V̇O2 peak following 6 weeks of ET is mainly determined by haematological rather than skeletal muscle adaptations. Sixteen untrained healthy male volunteers (age = 25 ± 4 years, V̇O2 peak = 3.5 ± 0.5 l min-1 ) underwent supervised ET (6 weeks, 3-4 sessions per week). V̇O2 peak , peak cardiac output (Q̇ peak ), haemoglobin mass (Hbmass ) and blood volumes were assessed prior to and following ET. Skeletal muscle biopsies were analysed for mitochondrial volume density (MitoVD ), capillarity, fibre types and respiratory capacity (OXPHOS). After the post-ET assessment, red blood cell volume (RBCV) was re-established at the pre-ET level by phlebotomy and V̇O2 peak and Q̇ peak were measured again. We speculated that the contribution of skeletal muscle adaptations to the ET-induced increase in V̇O2 peak would be revealed when controlling for haematological adaptations. V̇O2 peak and Q̇ peak were increased (P < 0.05) following ET (9 ± 8 and 7 ± 6%, respectively) and decreased (P < 0.05) after phlebotomy (-7 ± 7 and -10 ± 7%). RBCV, plasma volume and Hbmass all increased (P < 0.05) after ET (8 ± 4, 4 ± 6 and 6 ± 5%). As for skeletal muscle adaptations, capillary-to-fibre ratio and total MitoVD increased (P < 0.05) following ET (18 ± 16 and 43 ± 30%), but OXPHOS remained unaltered. Through stepwise multiple regression analysis, Q̇ peak , RBCV and Hbmass were found to be independent predictors of V̇O2 peak . In conclusion, the improvement in V̇O2 peak following 6 weeks of ET is primarily attributed to increases in Q̇ peak and oxygen-carrying capacity of blood in untrained healthy young subjects.g 6 weeks of ET is primarily attributed to increases in Q̇ peak and oxygen-carrying capacity of blood in untrained healthy young subjects.)
• Airik 2023 Antioxidants (Basel)  + (Karyomegalic interstitial nephritis (KIN) … Karyomegalic interstitial nephritis (KIN) is a genetic adult-onset chronic kidney disease (CKD) characterized by genomic instability and mitotic abnormalities in the tubular epithelial cells. KIN is caused by recessive mutations in the FAN1 DNA repair enzyme. However, the endogenous source of DNA damage in FAN1/KIN kidneys has not been identified. Here we show, using FAN1-deficient human renal tubular epithelial cells (hRTECs) and FAN1-null mice as a model of KIN, that FAN1 kidney pathophysiology is triggered by hypersensitivity to endogenous reactive oxygen species (ROS), which cause chronic oxidative and double-strand DNA damage in the kidney tubular epithelial cells, accompanied by an intrinsic failure to repair DNA damage. Furthermore, persistent oxidative stress in FAN1-deficient RTECs and FAN1 kidneys caused mitochondrial deficiencies in oxidative phosphorylation and fatty acid oxidation. The administration of subclinical, low-dose cisplatin increased oxidative stress and aggravated mitochondrial dysfunction in FAN1-deficient kidneys, thereby exacerbating KIN pathophysiology. In contrast, treatment of FAN1 mice with a mitochondria-targeted ROS scavenger, JP4-039, attenuated oxidative stress and accumulation of DNA damage, mitigated tubular injury, and preserved kidney function in cisplatin-treated FAN1-null mice, demonstrating that endogenous oxygen stress is an important source of DNA damage in FAN1-deficient kidneys and a driver of KIN pathogenesis. Our findings indicate that therapeutic modulation of kidney oxidative stress may be a promising avenue to mitigate FAN1/KIN kidney pathophysiology and disease progression in patients.ology and disease progression in patients.)
• Frey 2016 Biochim Biophys Acta  + (Ketogenic Diet used to treat refractory ep … Ketogenic Diet used to treat refractory epilepsy for almost a century may represent a treatment option for mitochondrial disorders for which effective treatments are still lacking. Mitochondrial complex I deficiencies are involved in a broad spectrum of inherited diseases including Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes syndrome leading to recurrent cerebral insults resembling strokes and associated with a severe complex I deficiency caused by mitochondrial DNA (mtDNA) mutations. The analysis of MELAS neuronal cybrid cells carrying the almost homoplasmic m.3243A>G mutation revealed a metabolic switch towards glycolysis with the production of lactic acid, severe defects in respiratory chain activity and complex I disassembly with an accumulation of assembly intermediates. Metabolites, NADH/NAD⁺ ratio, mitochondrial enzyme activities, oxygen consumption and BN-PAGE analysis were evaluated in mutant compared to control cells. A severe complex I enzymatic deficiency was identified associated with a major complex I disassembly with an accumulation of assembly intermediates of 400kDa. We showed that Ketone Bodies (KB) exposure for 4weeks associated with glucose deprivation significantly restored complex I stability and activity, increased ATP synthesis and reduced the NADH/NAD⁺ ratio, a key component of mitochondrial metabolism. In addition, without changing the mutant load, mtDNA copy number was significantly increased with KB, indicating that the absolute amount of wild type mtDNA copy number was higher in treated mutant cells. Therefore KB may constitute an alternative and promising therapy for MELAS syndrome, and could be beneficial for other mitochondrial diseases caused by complex I deficiency.</br></br>Copyright © 2016 Elsevier B.V. All rights reserved.ex I deficiency. Copyright © 2016 Elsevier B.V. All rights reserved.)
• Geffroy 2018 Biochim Biophys Acta  + (Ketogenic diet (KD) which combined carbohy … Ketogenic diet (KD) which combined carbohydrate restriction and the addition of ketone bodies has emerged as an alternative metabolic intervention used as an anticonvulsant therapy or to treat different types of neurological or mitochondrial disorders including MELAS syndrome. MELAS syndrome is a severe mitochondrial disease mainly due to the m.3243A > G mitochondrial DNA mutation. The broad success of KD is due to multiple beneficial mechanisms with distinct effects of very low carbohydrates and ketones. To evaluate the metabolic part of carbohydrate restriction, transmitochondrial neuronal-like cybrid cells carrying the m.3243A > G mutation, shown to be associated with a severe complex I deficiency was exposed during 3 weeks to glucose restriction. Mitochondrial enzyme defects were combined with an accumulation of complex I (CI) matrix intermediates in the untreated mutant cells, leading to a drastic reduction in CI driven respiration. The severe reduction of CI was also paralleled in post-mortem brain tissue of a MELAS patient carrying high mutant load. Importantly, lowering significantly glucose concentration in cell culture improved CI assembly with a significant reduction of matrix assembly intermediates and respiration capacities were restored in a sequential manner. In addition, OXPHOS protein expression and mitochondrial DNA copy number were significantly increased in mutant cells exposed to glucose restriction. The accumulation of CI matrix intermediates appeared as a hallmark of MELAS pathophysiology highlighting a critical pathophysiological mechanism involving CI disassembly, which can be alleviated by lowering glucose fuelling and the induction of mitochondrial biogenesis, emphasizing the usefulness of metabolic interventions in MELAS syndrome.ss of metabolic interventions in MELAS syndrome.)
• Dilliraj 2022 Nutrients  + (Ketone bodies are small compounds derived … Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies' brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.d metabolic consequences of ketone bodies.)
• Wojtala 2014 Abstract MiP2014  + (Key mitochondrial energy-providing reactio … Key mitochondrial energy-providing reactions are carried out by the oxidative phosphorylation system (OXPHOS), involving the electron transfer and phosphorylation systems including F₁F_o-ATP synthase. The most common OXPHOS disorder in humans is associated with Complex I deficiency, leading to fatal encephalomyopathies of early childhood- Leigh-like syndrome [1]. The growth factor adaptor protein p66Shc has a substantial impact on mitochondrial metabolism through regulation of cellular responses to oxidative stress. A low level of p66Shc protein or its complete ablation protects against numerous age-related disorders and may partially prevent pathologies caused by reactive oxygen species (ROS). On the other hand, a high level of p66Shc phosphorylation is correlated with increased intracellular ROS production [2,3].</br></br>Organs from NDUFS4^-/- mice with Complex I deficiency were used as a model of self-propelling intracellular oxidative stress. The status of the antioxidant defense system, oxidative stress markers and the p66Shc-Ser36 phosphorylation pathway were measured in these tissues. Mass spectrometry analysis was also performed for selected NDUFS4^-/- mouse tissues. </br></br>In our study, mice with defective Complex I were characterized by attenuated intracellular oxidative stress, connected with increased p66Shc phosphorylation. Mass spectrometry revealed aberrations in the level of Complex I proteins and oxidative stress- related proteins, as well as other proteins involved in metabolic processes.ative stress- related proteins, as well as other proteins involved in metabolic processes.)
• Ortiz-Jimenez 2019 MethodsX  + (Key mitochondrial processes are known to b … Key mitochondrial processes are known to be widely conserved throughout the eukaryotic domain. However, the scarce availability of working materials may restrict the assessment of such mitochondrial activities in several working models. Pollen tube mitochondrial studies represent one example of this, where tests have been often restricted due the physical impossibility of performing experiments with isolated mitochondria in enough quantities. Here we detail a method to measure ''in situ'' mitochondrial respiratory chain activity and calcium transport in tobacco pollen tubes. Digitonin-mediated plasmalemma permeabilization allows efficient assessment of mitochondrial respiration and calcium uptake. This method allows quick, reliable and portable measurements from low to high cellular densities, versus methods requiring intracellular calcium reporters.requiring intracellular calcium reporters.)
• Keystone Symposia 2014  + (Keystone Symposia - Mitochondrial Dynamics and Physiology (Q5), Santa Fee, New Mexico, USA [http://www.keystonesymposia.org/index.cfm?e=web.meeting.program&meetingid=1266 Keystone Symposia 2014])
• Keystone Symposia 2015  + (Keystone Symposia - Obesity and the Metabolic Syndrome: Mitochondria and Energy Expenditure (X7) Whistler, CA [http://www.keystonesymposia.org/15X7 Keystone Symposia 2015])
• Keystone symposium: “Hypoxia: from basic mechanisms to therapeutics”  + (Keystone Symposium: “Hypoxia: from basic mechanisms to therapeutics” Dublin, Ireland [http://www.keystonesymposia.org/index.cfm?e=web.Meeting.Program&meetingid=1323 Keystone Symposium: “Hypoxia: from basic mechanisms to therapeutics”])
• Kezic 2016 Oxid Med Cell Longev  + (Kidney ischemia/reperfusion injury emerges … Kidney ischemia/reperfusion injury emerges in various clinical settings as a great problem complicating the course and outcome. Ischemia/reperfusion injury is still an unsolved puzzle with a great diversity of investigational approaches, putting the focus on oxidative stress and mitochondria. Mitochondria are both sources and targets of ROS. They participate in initiation and progression of kidney ischemia/reperfusion injury linking oxidative stress, inflammation, and cell death. The dependence of kidney proximal tubule cells on oxidative mitochondrial metabolism makes them particularly prone to harmful effects of mitochondrial damage. The administration of antioxidants has been used as a way to prevent and treat kidney ischemia/reperfusion injury for a long time. Recently a new method based on mitochondria-targeted antioxidants has become the focus of interest. Here we review the current status of results achieved in numerous studies investigating these novel compounds in ischemia/reperfusion injury which specifically target mitochondria such as MitoQ, Szeto-Schiller (SS) peptides (Bendavia), SkQ1 and SkQR1, and superoxide dismutase mimics. Based on the favorable results obtained in the studies that have examined myocardial ischemia/reperfusion injury, ongoing clinical trials investigate the efficacy of some novel therapeutics in preventing myocardial infarct. This also implies future strategies in preventing kidney ischemia/reperfusion injury.enting kidney ischemia/reperfusion injury.)
• Bugarski 2018 Am J Physiol Renal Physiol  + (Kidney proximal tubules (PTs) are densely … Kidney proximal tubules (PTs) are densely packed with mitochondria, and defects in mitochondrial function are implicated in many kidney diseases. However, little is known about intrinsic mitochondrial function within PT cells. Here, using intravital multiphoton microscopy and live slices of mouse kidney cortex, we show that autofluorescence signals provide important functional readouts of redox state and substrate metabolism and that there are striking axial differences in signals along the PT. Mitochondrial NAD(P)H intensity was similar in both PT segment (S)1 and S2 and was sensitive to changes in respiratory chain (RC) redox state, whereas cytosolic NAD(P)H intensity was significantly higher in S2. Mitochondrial NAD(P)H increased in response to lactate and butyrate but decreased in response to glutamine and glutamate. Cytosolic NAD(P)H was sensitive to lactate and pyruvate and decreased dramatically in S2 in response to inhibition of glucose metabolism. Mitochondrial flavoprotein (FP) intensity was markedly higher in S2 than in S1 but was insensitive to changes in RC redox state. Mitochondrial FP signal increased in response to palmitate but decreased in response to glutamine and glutamate. Fluorescence lifetime decays were similar in both S1 and S2, suggesting that intensity differences are explained by differences in abundance of the same molecular species. Expression levels of known fluorescent mitochondrial FPs were higher in S2 than S1. In summary, substantial metabolic information can be obtained in kidney tissue using a label-free live imaging approach, and our findings suggest that metabolism is tailored to the specialized functions of S1 and S2 PT segments.alized functions of S1 and S2 PT segments.)
• Shrum 2019 Biomolecules  + (Kidneys from deceased donors used for tran … Kidneys from deceased donors used for transplantation are placed in cold storage (CS) solution during the search for a matched recipient. However, CS causes mitochondrial injury, which may exacerbate renal graft dysfunction. Here, we explored whether adding NS11021, an activator of the mitochondrial big-conductance calcium-activated K⁺ (mitoBK) channel, to CS solution can mitigate CS-induced mitochondrial injury. We used normal rat kidney proximal tubular epithelial (NRK) cells as an ''in vitro'' model of renal cold storage (18 h) and rewarming (2 h) (CS + RW). Western blots detected the pore-forming α subunit of the BK channel in mitochondrial fractions from NRK cells. The fluorescent K⁺-binding probe, PBFI-AM, revealed that isolated mitochondria from NRK cells exhibited mitoBK-mediated K⁺ uptake, which was impaired ~70% in NRK cells subjected to CS + RW compared to control NRK cells maintained at 37 °C. Importantly, the addition of 1 M NS11021 to CS solution prevented CS + RW-induced impairment of mitoBK-mediated K⁺ uptake. The NS11021-treated NRK cells also exhibited less cell death and mitochondrial injury after CS + RW, including mitigated mitochondrial respiratory dysfunction, depolarization, and superoxide production. In summary, these new data show for the first time that mitoBK channels may represent a therapeutic target to prevent renal CS-induced injury.hat mitoBK channels may represent a therapeutic target to prevent renal CS-induced injury.)
• Stefan 2022 Abstract Bioblast  + (Kinases function as molecular switches for … Kinases function as molecular switches for coordinating spatiotemporal signal transmission. Genomic alterations affect kinase abundance and/or their activities which contribute to the etiology and progression of diseases such as distinct cancers and Parkinson’s disease (PD). Thus, major drug discovery efforts aim to identify lead molecules targeting the clinically relevant kinase entity. The concept of personalized medicine aims to apply the therapeutic agent with the highest efficacy towards a patient-specific target protein mutation. We have recently implemented a cell-based reporter system which fosters the decision-making process for identifying and selecting efficient lead molecules. We have engineered a modular kinase conformation (KinCon) biosensor platform for live-cell analyses of kinase activity states. This biosensor facilitates the recording of kinase activity conformations of the wild-type and the respective mutated kinase upon lead-molecule or approved-drug exposure. First, in proof-of-principle studies we have demonstrated that this technology is suitable for the systematic determination of melanoma drug efficacies using the full-length KinCon reporters for BRAF and MEK which harbor distinct cancer patient mutations (Röck et al., Science Advances 2019, Mayrhofer et al., PNAS 2020, Fleischmann et al., Biomolecules 2021). Second, we have extended KinCon reporters to quantify the activity-relevant formation of multimeric kinase complexes, involving members of the RIPK [inflammation] or CDK [cancer] kinase families. Third, recently we have engineered mitochondria associated biosensors to analyze and categorize PD kinase mutations. Thus, with new KinCon reporters we are setting out to characterize PD causing kinase gain-of-function mutations and to reactivate a PD kinase displaying a collection of loss-of-function mutations, directly in an intact cell setting. Finally, we would like to underline that this precision-medicine-oriented KinCon biosensor concept is not restricted to recordings of kinase drug efficacies/specificities. We have first evidence that such conformation reporter can extended to other (pseudo)enzyme categories.tended to other (pseudo)enzyme categories.)
• Klinische Mitochondrienmedizin und Umweltmedizin 2017 Heidelberg DE  + (Klinische Mitochondrienmedizin und Umweltmedizin 2017, Heidelberg, Germany.)
• Ernster 1981 J Cell Biol  + (Known for over a century, mitochondria hav … Known for over a century, mitochondria have become during the last three decades an important subject of research within several disciplines of experimental biology. For the cytologist, they represented the ideal test objects for applying electron microscopy to the exploration of cellular ultrastructure and for the elaboration of tissue-fractionation techniques with the aim of isolating cytoplasmic organelles. For the biochemist, the identification of mitochondria as the site of cell respiration and respiration-linked phosphorylation implied a decisive step towards the resolution and reconstitution of these processes at a molecular level and the elucidation of their relationship to cellular membranes. For the physiologist, mitochondria afforded the first opportunity for an experimental approach to structure-function relationships, in particular those involved in active transport, vectorial metabolism, and metabolic control mechanisms on a subcellular level. And for the molecular biologist, the discovery of mitochondrial DNA and protein synthesis and the study of mitochondrial biogenesis opened up a new chapter of eukaryotic gene expression. The purpose of this review is to give a brief account of these developments by selecting some of the highlights of the long and eventful history of mitochondrial research.ventful history of mitochondrial research.)
• MiPNet20.06 IsolationMouseHeart-mt  + (Komlodi T, Cardoso LHD, Gnaiger E (2021) … Komlodi T, Cardoso LHD, Gnaiger E (2021) Laboratory protocol: Isolation of mouse heart mitochondria. Mitochondr Physiol Network 20.06(02):1-4. </br><br/></br></br><div style="padding:0px;border: 1px solid #aaaaaa;margin-bottom:0px;margin-right:10px"></br><div style="font-size:100%;font-weight:bold;padding:0.2em;padding-right: 0.4em;padding-left: 0.4em;background-color:#eeeeee;border-bottom:1px solid #aaaaaa;text-align:left;"></br>[[Image:O2k-support system.jpg|right|150px|link=http://wiki.oroboros.at/index.php/O2k-technical_support_and_open_innovation|O2k-technical support and open innovation]]</br>: <big>Open the '''pdf document''' above.</big></br></div></br><div style="background-color:#ffffff;padding-top:0.2em;padding-right: 0.4em;padding-bottom: 0.2em;padding-left: 0.4em;"></br>::::» Current O2k-series: '''[https://www.oroboros.at/index.php/product-category/products/o2k-packages/ NextGen-O2k Series XB and O2k Series J]'''</br>::::» Current software versions DatLab 8.0: [[MitoPedia: DatLab]]</br>::::* ''Further details:'' '''» [[MitoPedia: O2k-Open Support]]'''</br></div></br></div></br>:» Product: [[Oroboros O2k]], [[O2k-Catalogue]]k-Catalogue]])
• MiPNet24.10 H2O2 flux analysis  + (Komlodi T, Cardoso LHD, Gnaiger E (2021) H … Komlodi T, Cardoso LHD, Gnaiger E (2021) Hydrogen peroxide flux analysis using Amplex UltraRed assay in MiR05-Kit with DatLab 7.4. Mitochondr Physiol Network 24.10(03):1-5. </br><br/></br></br><div style="padding:0px;border: 1px solid #aaaaaa;margin-bottom:0px;margin-right:10px"></br><div style="font-size:100%;font-weight:bold;padding:0.2em;padding-right: 0.4em;padding-left: 0.4em;background-color:#eeeeee;border-bottom:1px solid #aaaaaa;text-align:left;"></br>[[Image:O2k-support system.jpg|right|150px|link=http://wiki.oroboros.at/index.php/O2k-technical_support_and_open_innovation|O2k-technical support and open innovation]]</br>: <big>Open the '''pdf document''' above.</big></br></div></br><div style="background-color:#ffffff;padding-top:0.2em;padding-right: 0.4em;padding-bottom: 0.2em;padding-left: 0.4em;"></br>::::» Current O2k-series: '''[https://www.oroboros.at/index.php/product-category/products/o2k-packages/ NextGen-O2k Series XB and O2k Series J]'''</br>::::» Current software versions DatLab 8.0: [[MitoPedia: DatLab]]</br>::::* ''Further details:'' '''» [[MitoPedia: O2k-Open Support]]'''</br></div></br></div>itoPedia: O2k-Open Support]]''' </div> </div>)
• MiPNet24.09 Data analysis of mt-membrane potential  + (Komlodi T, Cardoso LHD, Gnaiger E (2021) D … Komlodi T, Cardoso LHD, Gnaiger E (2021) Data analysis of mitochondrial membrane potential estimation using various fluorescence dyes. Mitochondr Physiol Network 24.09(03):1-6.</br><br/></br></br><div style="padding:0px;border: 1px solid #aaaaaa;margin-bottom:0px;margin-right:10px"></br><div style="font-size:100%;font-weight:bold;padding:0.2em;padding-right: 0.4em;padding-left: 0.4em;background-color:#eeeeee;border-bottom:1px solid #aaaaaa;text-align:left;"></br>[[Image:O2k-support system.jpg|right|150px|link=http://wiki.oroboros.at/index.php/O2k-technical_support_and_open_innovation|O2k-technical support and open innovation]]</br>: <big>Open the '''pdf document''' above.</big></br></div></br><div style="background-color:#ffffff;padding-top:0.2em;padding-right: 0.4em;padding-bottom: 0.2em;padding-left: 0.4em;"></br>::::» Current O2k-series: '''[https://www.oroboros.at/index.php/product-category/products/o2k-packages/ NextGen-O2k Series XB and O2k Series J]'''</br>::::» Current software versions DatLab 8.0: [[MitoPedia: DatLab]]</br>::::* ''Further details:'' '''» [[MitoPedia: O2k-Open Support]]'''</br></div></br></div></br></br>:» Product: [[DatLab]], [[Oroboros O2k]], [[Oroboros O2k-Catalogue |O2k-Catalogue]]oboros O2k-Catalogue |O2k-Catalogue]])
• MiPNet24.12 NextGen-O2k: Q-Module  + (Komlodi T, Cardoso LHD, Gollner M, Merth A, Niedenzu W, Haider M, Doerrier C, Tindle-Solomon L, Schwaninger H, Walter-Vracevic M, Gradl P, Moore AL, Rich P, Gnaiger E (2021) Mitochondr Physiol Network 24.12(04):1-20.)
• MiPNet24.08 Safranin Analysis Template  + (Komlodi T, Gnaiger E (2020) Excel template … Komlodi T, Gnaiger E (2020) Excel template for safranin data analysis. Mitochondr Physiol Network 24.08(02):1-8. </br><br/></br></br><div style="padding:0px;border: 1px solid #aaaaaa;margin-bottom:0px;margin-right:10px"></br><div style="font-size:100%;font-weight:bold;padding:0.2em;padding-right: 0.4em;padding-left: 0.4em;background-color:#eeeeee;border-bottom:1px solid #aaaaaa;text-align:left;"></br>[[Image:O2k-support system.jpg|right|150px|link=http://wiki.oroboros.at/index.php/O2k-technical_support_and_open_innovation|O2k-technical support and open innovation]]</br>: <big>Open the '''pdf document''' above.</big></br></div></br><div style="background-color:#ffffff;padding-top:0.2em;padding-right: 0.4em;padding-bottom: 0.2em;padding-left: 0.4em;"></br>::::» Current O2k-series: '''[https://www.oroboros.at/index.php/product-category/products/o2k-packages/ NextGen-O2k Series XB and O2k Series J]'''</br>::::» Current software versions DatLab 8.0: [[MitoPedia: DatLab]]</br>::::* ''Further details:'' '''» [[MitoPedia: O2k-Open Support]]'''</br></div></br></div></br>:» Product: [[DatLab]], [[Oroboros O2k]], [[Oroboros O2k-Catalogue |O2k-Catalogue]]oboros O2k-Catalogue |O2k-Catalogue]])
• MiPNet24.16 DatLab8.0: CV-Module  + (Komlodi T, Niedenzu W, Haider M, Cardoso L … Komlodi T, Niedenzu W, Haider M, Cardoso LHD, Tindle-Solomon L, Gnaiger E (2021) DatLab8.0:Cyclic voltammetry manual. Mitochondr Physiol Network 24.16(03):1-4. </br><br/></br></br><div style="padding:0px;border: 1px solid #aaaaaa;margin-bottom:0px;margin-right:10px"></br><div style="font-size:100%;font-weight:bold;padding:0.2em;padding-right: 0.4em;padding-left: 0.4em;background-color:#eeeeee;border-bottom:1px solid #aaaaaa;text-align:left;"></br>[[Image:O2k-support system.jpg|right|150px|link=http://wiki.oroboros.at/index.php/O2k-technical_support_and_open_innovation|O2k-technical support and open innovation]]</br>: <big>Open the '''pdf document''' above.</big></br></div></br><div style="background-color:#ffffff;padding-top:0.2em;padding-right: 0.4em;padding-bottom: 0.2em;padding-left: 0.4em;"></br>::::» For O2k-series: '''[https://wiki.oroboros.at/index.php/NextGen-O2k NextGen-O2k]'''</br>::::» For software version: [[MitoPedia: DatLab |'''DatLab 8''']]</br>::::* ''Further details:'' '''» [[MitoPedia: O2k-Open Support]]'''</br></div></br></div></br>:>> Product: [[Oroboros O2k]], [[NextGen-O2k]]extGen-O2k]])
• MiPNet15.03 O2k-MultiSensor-ISE  + (Komlodi T, Schmitt S, Gnaiger E (2021) O2k … Komlodi T, Schmitt S, Gnaiger E (2021) O2k-MultiSensor system with ion selective electrodes (ISE). Mitochondr Physiol Network 15.03(09): 1-21.</br><br/></br></br><div style="padding:0px;border: 1px solid #aaaaaa;margin-bottom:0px;margin-right:10px"></br><div style="font-size:100%;font-weight:bold;padding:0.2em;padding-right: 0.4em;padding-left: 0.4em;background-color:#eeeeee;border-bottom:1px solid #aaaaaa;text-align:left;"></br>[[Image:O2k-support system.jpg|right|150px|link=http://wiki.oroboros.at/index.php/O2k-technical_support_and_open_innovation|O2k-technical support and open innovation]]</br>: <big>Open the '''pdf document''' above.</big></br></div></br><div style="background-color:#ffffff;padding-top:0.2em;padding-right: 0.4em;padding-bottom: 0.2em;padding-left: 0.4em;"></br>::::» Current O2k-series: '''[https://www.oroboros.at/index.php/product-category/products/o2k-packages/ NextGen-O2k Series XB and O2k Series J]'''</br>::::» Current software versions DatLab 8.0: [[MitoPedia: DatLab]]</br>::::* ''Further details:'' '''» [[MitoPedia: O2k-Open Support]]'''</br></div></br></div></br>:» Product: [[O2k-TPP+ ISE-Module]], [[Oroboros O2k-Catalogue]]oboros O2k-Catalogue]])
• Murphy 2018 Cell  + (Krebs cycle intermediates traditionally li … Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act as signals. Succinate plays an important role in inflammatory, hypoxic, and metabolic signaling, while itaconate (from another Krebs cycle intermediate, cis-aconitate) has an anti-inflammatory role.-aconitate) has an anti-inflammatory role.)