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• Manko 2013 Acta Physiol (Oxf)  + (Acetylcholine as one of the main secretago … Acetylcholine as one of the main secretagogues modulates mitochondrial functions in acinar pancreacytes, presumably due to increase in ATP hydrolysis or Ca²⁺ transport into mitochondria. The aim of this work was to investigate the mechanisms of carbachol (CCh) action on respiration and oxidative phosphorylation of isolated pancreatic acini.</br></br>Respiration of intact or permeabilized rat pancreatic acini was studied at 37 °C using a Clark oxygen electrode.</br></br>Respiration rate of isolated acini in rest was 0.27 ± 0.01 nmol O2 s^-1 10^-6 cells. Addition of 10 μM CCh into respiration chamber evoked biphasic stimulation of respiration. Rapid increase of respiration by 20.1% lasted for approx. 1 min, followed by decrease to level by 11.5% higher than control. Addition of 1 μm CCh caused monophasic increase by 11.5%. Preincubation (5 min) with 1 or 10 μm CCh elevated respiration rate by 12.5 or 11.2% respectively. FCCP prevented the effect of CCh. Preincubation with 1 (but not 10) μm CCh increased FCCP-uncoupled respiration rate. Thapsigargin slightly elevated respiration, but ryanodine did not. Application of 2-aminoethoxydiphenyl borate or ruthenium red prevented the effects of CCh on respiration, while oligomycin abolished them. Preincubation with 1 μm CCh prior to cell permeabilization increased respiration rate at pyruvate+malate oxidation, but not at succinate oxidation. In contrast, preincubation with 10 μm CCh decreased pyruvate+malate oxidation.</br></br>Medium CCh dose (1 μm) intensifies respiration and oxidative phosphorylation of acinar pancreacytes by feedforward mechanism via Ca²⁺ transport into mitochondria and activation of Ca²⁺ /ADP-sensitive mitochondrial dehydrogenases. Prolonged action of high CCh dose (10 μm) might impair mitochondrial functions.ndrial dehydrogenases. Prolonged action of high CCh dose (10 μm) might impair mitochondrial functions.)
• Walker 1970 J Biol Chem  + (Acid hydrolysis of flavin peptides from th … Acid hydrolysis of flavin peptides from the active center of mammalian succinate dehydrogenase yields a substituted riboflavin which was isolated in pure form. It contains a substituent attached to position 8a of riboflavin. Drastic acid hydrolysis of this compound and catalytic hydrogenation yield nearly 1 mole of free histidine. Histidine is also liberated on neutral photolysis. The presence of histidine is confirmed by behavior on high voltage electrophoresis at various pH values and by acid titration curves. Linkage of the 8cr-CHs group of riboflavin is to one of the imidazole ring nitrogens since neither the flavin peptide nor its acid derivative give a Pauly reaction. This assignment is in full accord with the characteristic pH-fluorescence curve of covalently bound flavin. The pK of the fluorescence quenching agrees with that expected for the imidazole nitrogen in histidyl flavin.the imidazole nitrogen in histidyl flavin.)
• Boushel 2011 Mitochondrion  + (Across a wide range of species and body ma … Across a wide range of species and body mass a close matching exists between maximal conductive oxygen delivery and mitochondrial respiratory rate. In this study we investigated in humans how closely ''in vivo'' maximal oxygen consumption (''V''O(2)max) is matched to muscle tissue-specific OXPHOS capacity ([[State 3]]) respiration. High-resolution respirometry was used to quantify mitochondrial respiration from the biopsies of arm and leg muscles while ''in vivo'' arm and leg ''V''O(2) were determined by the Fick method during leg cycling and arm cranking. We hypothesized that muscle mitochondrial respiratory rate exceeds that of systemic oxygen delivery. OXPHOS capacity of the deltoid muscle (4.3±0.4 mmol O(2)kg(-1)min(-1)) was similar to the ''in vivo'' ''V''O(2) during maximal arm cranking (4.7±0.5 mmol O(2)kg(-1)min(-1)) with 6 kg muscle. In contrast, the mitochondrial OXPHOS capacity of the quadriceps was 6.9±0.5 mmol O(2)kg(-1)min(-1), exceeding the ''in vivo'' leg ''V''O(2)max (5.0±0.2mmolO(2)kg(-1)min(-1)) during leg cycling with 20 kg muscle (''P''<0.05). Thus, when half or more of the body muscle mass is engaged during exercise, muscle mitochondrial respiratory capacity surpasses ''in vivo'' ''V''O(2)max. The findings reveal an excess capacity of muscle mitochondrial respiratory rate over O(2) delivery by the circulation in the cascade defining maximal oxidative rate in humans.de defining maximal oxidative rate in humans.)
• Mills 2016 Cell  + (Activated macrophages undergo metabolic re … Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.order to promote a pro-inflammatory state.)
• Droese 2006 J Biol Chem  + (Activation by diazoxide and inhibition by … Activation by diazoxide and inhibition by 5-hydroxydecanoate are the hallmarks of mitochondrial ATP-sensitive K⁺(K_ATP) channels. Opening of these channels is thought to trigger cytoprotection (preconditioning) through the generation of reactive oxygen species. However, we found that diazoxide-induced oxidation of the widely used reactive oxygen species indicator 2′,7′-dichlorodihydrofluorescein in isolated liver and heart mitochondria was observed in the absence of ATP or K⁺ and therefore independent of K_ATP channels. The response was blocked by stigmatellin, implying a role for the cytochrome ''bc''₁ complex (Complex III). Diazoxide, though, did not increase hydrogen peroxide (H₂O₂) production (quantitatively measured with Amplex Red) in intact mitochondria, submitochondrial particles, or purified cytochrome ''bc''₁ complex. We confirmed that diazoxide inhibited succinate oxidation, but it also weakly stimulated State 4 respiration even in K⁺-free buffer, excluding a role for K_ATP channels. Furthermore, we have shown previously that 5-hydroxydecanoate is partially metabolized, and we hypothesized that fatty acid metabolism may explain the ability of this putative mitochondrial K_ATP channel blocker to inhibit diazoxide-induced flavoprotein fluorescence, commonly used as an assay of K_ATP channel activity. Indeed, consistent with our hypothesis, we found that decanoate inhibited diazoxide-induced flavoprotein oxidation. Taken together, our data question the “mitochondrial K_ATP channel” hypothesis of preconditioning. Diazoxide did not evoke superoxide (which dismutates to H₂O₂) from the respiratory chain by a direct mechanism, and the stimulatory effects of this compound on mitochondrial respiration and 2′,7′-dichlorodihydrofluorescein oxidation were not due to the opening of K_ATP channels.the respiratory chain by a direct mechanism, and the stimulatory effects of this compound on mitochondrial respiration and 2′,7′-dichlorodihydrofluorescein oxidation were not due to the opening of K_ATP channels.)
• Bernhardt 2015 Abstract MiPschool Greenville 2015  + (Activation of mammalian embryonic developm … Activation of mammalian embryonic development relies on a series of fertilization-induced increases in intracellular Ca²⁺. Full egg activation also requires influx of extracellular Ca²⁺, but the channel or channels mediating this influx remain unknown. In these studies we examined whether T-type Ca²⁺ channels, including CACNA1H subunit-containing CaV3.2 channels, mediate Ca²⁺ entry after fertilization. We found that female mice lacking CACNA1H have reduced litter size. Careful analysis of Ca²⁺ oscillation patterns following ''in vitro'' fertilization (IVF) of ''Cacna1h^-/-'' eggs revealed shortening of the first Ca²⁺ transient length and reduction in Ca²⁺ oscillation persistence. Both total and endoplasmic reticulum (ER) Ca²⁺ stores in ''Cacna1h^-/-'' eggs were reduced, showing an impairment of Ca²⁺ accumulation during oocyte maturation in ''Cacna1h^-/-'' eggs. Pharmacological inhibition of T-type channels during ''in vitro'' maturation also reduced Ca²⁺ store accumulation, indicating that T-type channels are responsible for mediating Ca²⁺ entry and ER store accumulation during meiotic maturation. T-type channel inhibition also reduced oscillation persistence, frequency, and duration following IVF in wild-type eggs. Together, these data support previously unrecognized roles for T-type Ca²⁺ channels in mediating the maturation-associated increase in ER Ca²⁺ stores and allowing Ca²⁺ influx required for the activation of embryo development. In future studies, we plan to investigate how fluxes in oocyte Ca²⁺ and Zn²⁺ influence mitochondrial function, which is a critical determinant of oocyte and embryo quality. Developing better understanding of the interplay between these pathways may translate into clinical application to improve assisted reproductive technologies.;2+</sup> influence mitochondrial function, which is a critical determinant of oocyte and embryo quality. Developing better understanding of the interplay between these pathways may translate into clinical application to improve assisted reproductive technologies.)
• Svensson 2017 Acta Physiol (Oxf)  + (Activation of the NAD<sup>+</sup& … Activation of the NAD⁺ dependent protein deacetylase SIRT1 has been proposed as a therapeutic strategy to treat mitochondrial dysfunction and insulin resistance in skeletal muscle. However, lifelong overexpression of SIRT1 in skeletal muscle does not improve parameters of mitochondrial function and insulin sensitivity. In this study, we investigated whether temporal overexpression of SIRT1 in muscle of adult mice would affect skeletal muscle mitochondrial function and insulin sensitivity.</br></br>To circumvent potential effects of germline SIRT1 overexpression, we utilized an inducible model of SIRT1 overexpression in skeletal muscle of adult mice (i-mOX). Insulin sensitivity was assessed by 2-deoxyglucose uptake, muscle maximal respiratory function by high-resolution respirometry and systemic energy expenditure was assessed by whole body calorimetry.</br></br>Although SIRT1 was highly, and specifically, overexpressed in skeletal muscle of i-mOX compared to WT mice, glucose tolerance and skeletal muscle insulin sensitivity were comparable between genotypes. Additionally, markers of mitochondrial biogenesis, muscle maximal respiratory function and whole-body oxygen consumption were also unaffected by SIRT1 overexpression.</br></br>These results support previous work demonstrating that induction of SIRT1 in skeletal muscle, either at birth or in adulthood, does not impact muscle insulin action or mitochondrial function.</br></br>© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.iological Society. Published by John Wiley & Sons Ltd.)
• Magga 2019 Mol Ther  + (Activin A and myostatin, members of the tr … Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury ''in vivo'', ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.tions to protect the heart from IR injury.)
• Benard 2008 Int J Biochem Cell Biol  + (Activity defects in respiratory chain comp … Activity defects in respiratory chain complexes are responsible for a large variety of pathological situations, including neuromuscular diseases and multisystemic disorders. Their impact on energy production is highly variable and disproportional. The same biochemical or genetic defect can lead to large differences in clinical symptoms and severity between tissues and patients, making the pathophysiological analysis of mitochondrial diseases difficult. The existence of compensatory mechanisms operating at the level of the respiratory chain might be an explanation for the biochemical complexity observed for respiratory defects. Here, we analyzed the role of cytochrome c and coenzyme Q in the attenuation of complex III and complex IV pharmacological inhibition on the respiratory flux. Spectrophotometry, HPLC-EC, polarography and enzymology permitted the calculation of molar ratios between respiratory chain components, giving values of 0.8:61:3:12:6.8 in muscle and 1:131:3:9:6.5 in liver, for CII:CoQ:CIII:Cyt c:CIV. The results demonstrate the dynamic functional compartmentalization of respiratory chain substrates, with the existence of a substrate pool that can be recruited to maintain energy production at normal levels when respiratory chain complexes are inhibited. The size of this reserve was different between muscle and liver, and in proportion to the magnitude of attenuation of each respiratory defect. Such functional compartmentalization could result from the recently observed physical compartmentalization of respiratory chain substrates. The dynamic nature of the mitochondrial network may modulate this compartmentalization and could play a new role in the control of mitochondrial respiration as well as apoptosis.hondrial respiration as well as apoptosis.)
• Soendergaard 2016 Eur J Sport Sci  + (Actovegin, a deproteinized haemodialysate … Actovegin, a deproteinized haemodialysate of calf blood, is suggested to have ergogenic properties, but this potential effect has never been investigated in human skeletal muscle. To investigate this purported ergogenic effect, we measured the mitochondrial respiratory capacity in permeabilized human skeletal muscle fibres acutely exposed to Actovegin in a low and in a high dose. We found that Actovegin, in the presence of complex I-linked substrates increased the oxidative phosphorylation (OXPHOS) capacity significantly in a concentration-dependent manner (19 ± 3, 31 ± 4 and 45 ± 4 pmol/mg/s). Maximal OXPHOS capacity with complex I and II-linked substrate was increased when the fibres were exposed to the high dose of Actovegin (62 ± 6 and 77 ± 6 pmol/mg/s) (''p ''< .05). The respiratory capacity of the electron transfer-pathway as well as Vmax and Km were also increased in a concentration-dependent manner after Actovegin exposure (70 ± 6, 79 ± 6 and 88 ± 7 pmol/mg/s; 13 ± 2, 25 ± 3 and 37 ± 4 pmol/mg/s; 0.08 ± 0.02, 0.21 ± 0.03 and 0.36 ± 0.03 mM, respectively) (''p'' < .05). In summary, we report for the first time that Actovegin has a marked effect on mitochondrial oxidative function in human skeletal muscle. Mitochondrial adaptations like this are also seen after a training program in human subjects. Whether this improvement translates into an ergogenic effect in athletes and thus reiterates the need to include Actovegin on the World Anti-Doping Agency's active list remains to be investigated.Agency's active list remains to be investigated.)
• Soendergaard 2016 Abstract IOC109  + (Actovegin, a drug made from the deproteini … Actovegin, a drug made from the deproteinized hemodialysate of calf blood increases the mitochondrial respiratory capacity of untrained and overweight subjects, indicating that Actovegin may have the potential to improve performance. These findings are interesting because the drug is not on the World Anti-Doping Agency’s prohibited list, but used by athletes. Therefore, we wanted to investigate whether Actovegin had the same effect in trained subjects. Also, we wanted to compare the effect of Actovegin with the effect of erythropoietin (EPO; a banned substance) on the mitochondrial respiratory capacity. </br></br>We obtained basal muscle biopsies (''m. vastus lateralis'') from 8 trained subjects (VO2max: 54±2ml/min/kg). The skeletal muscle fibers were acutely exposed to either Actovegin (50µl/ml) or EPO (50µl/ml, 2000IU) during permeabilization, washing of the fibers and the respiratory analysis, resulting in a ~2h exposure time. Mitochondrial respiratory capacity was measured with high-resolution respirometry (Oxygraph-2k; Oroboros , Innsbruck, Austria) and by sequential addition of malate, glutamate, ADP, succinate and FCCP.</br></br>EPO and Actovegin increased maximal complex I activity (''P''<0.05) compared to control (22±4, 43±3, 61±5pmol/mg/s) with a significant difference between EPO and Actovegin (43±3, 61±5pmol/mg/s, respectively). Only Actovegin increased the maximal oxidative phosphorylation capacity significantly (72±5, 82±8, 95±4pmol/mg/s), but both EPO and Actovegin increased the maximal electron transport system capacity (77±5, 101±9, 112±10pmol/mg/s) (''P''<0.05). In regards to ADP kinetics, Vmax was significantly increased by EPO and Actovegin (18±2, 33±3, 50±4pmol/mg/s) (''P''<0.05), whereas Km was unaltered by EPO, but significantly increased by Actovegin (0.18±0.04, 0.21±0.04, 0.72±0.31mM).</br></br>The study demonstrates that acute exposure of human muscle fibers to EPO or Actovegin increases the mitochondrial respiratory capacity of trained subjects. The mechanism(s) are not clear, but EPO has been found to increase the NAD+ levels and the NAD+/NADH ratio in myoblasts (1), which could explain the observed increased complex I respiration with EPO (2). Actovegin contains succinate which in part can explain the effect of Actovegin on the mitochondrial respiration. It is not known whether Actovegin also contains NAD+, but it is intriguing to think that Actovegin and EPO might modulate mitochondrial function through the same mechanism, but this is only speculations. the same mechanism, but this is only speculations.)
• Arias-Mayenco 2018 Cell Metab  + (Acute O₂ sensing by … Acute O₂ sensing by peripheral chemoreceptors is essential for mammalian homeostasis. Carotid body glomus cells contain O₂-sensitive ion channels, which trigger fast adaptive cardiorespiratory reflexes in response to hypoxia. O₂-sensitive cells have unique metabolic characteristics that favor the hypoxic generation of mitochondrial complex I (MCI) signaling molecules, NADH and reactive oxygen species (ROS), which modulate membrane ion channels. We show that responsiveness to hypoxia progressively disappears after inducible deletion of the Ndufs2 gene, which encodes the 49 kDa subunit forming the coenzyme Q binding site in MCI, even in the presence of MCII substrates and chemical NAD+ regeneration. We also show contrasting effects of physiological hypoxia on mitochondrial ROS production (increased in the intermembrane space and decreased in the matrix) and a marked effect of succinate dehydrogenase activity on acute O₂ sensing. Our results suggest that acute responsiveness to hypoxia depends on coenzyme QH2/Q ratio-controlled ROS production in MCI.esponsiveness to hypoxia depends on coenzyme QH2/Q ratio-controlled ROS production in MCI.)
• Stampley 2023 Physiol Rep  + (Acute aerobic exercise increases the numbe … Acute aerobic exercise increases the number and proportions of circulating peripheral blood mononuclear cells (PMBC) and can alter PBMC mitochondrial bioenergetics. In this study, we aimed to examine the impact of a maximal exercise bout on immune cell metabolism in collegiate swimmers. Eleven (7 M/4F) collegiate swimmers completed a maximal exercise test to measure anaerobic power and capacity. Pre- and postexercise PBMCs were isolated to measure the immune cell phenotypes and mitochondrial bioenergetics using flow cytometry and high-resolution respirometry. The maximal exercise bout increased circulating levels of PBMCs, particularly in central memory (KLRG1+/CD57-) and senescent (KLRG1+/CD57+) CD8+ T cells, whether measured as a % of PMBCs or as absolute concentrations (all p < 0.05). At the cellularlevel, the routine oxygen flow (IO₂ [pmol·s^-1 ·10⁶ PBMCs^-1 ]) increased following maximal exercise (p = 0.042); however, there were no effects of exercise on the IO₂ measured under the LEAK, oxidative phosphorylation (OXPHOS), or electron transfer (ET) capacities. There were exercise-induced increases in the tissue-level oxygen flow (IO₂-tissue [pmol·s^-1 ·mL blood^-1 ]) for all respiratory states (all p < 0.01), except for the LEAK state, after accounting for the mobilization of PBMCs. Future subtype-specific studies are needed to characterize further maximal exercise's true impact on immune cell bioenergetics.zation of PBMCs. Future subtype-specific studies are needed to characterize further maximal exercise's true impact on immune cell bioenergetics.)
• Holsgrove 2019 Thesis  + (Acute changes in temperature have a signif … Acute changes in temperature have a significant impact on ectotherm metabolic function due to their inability to regulate internal temperatures. An alteration of metabolic rate will drive modulations in cardiac function in order to meet the changing oxygen demands of aerobically active tissues. The function of the fish heart therefore underpins an organisms ability to survive changing temperature. There have been multiple studies assessing the effects of temperature on the metabolism of fish tissue systems but relatively few on the heart. As such, the aims of this thesis were to study the effects of cooling and warming on cardiac metabolism of the rainbow trout. As mitochondria are responsible for producing the majority of ATP for cardiomyocytes and drive aerobic demand, the experiments in this thesis centred on the mitochondrial response to temperature change. </br></br>In chapter 3, I provide the first thorough investigation into the effect of cold and warm acclimation on cardiac mitochondria morphology in fish. Cold acclimation induced mitochondrial proliferation and an upregulation of mitochondrial fusion, whilst warm acclimation did not increase mitochondrial content but is suggested to increase fission events. A lack of change in internal mitochondrial ultrastructure however doesn't suggest any change in energetic capacity. In chapter 4, I demonstrate that mitochondria are sensitive to acute temperature changes, although their response did not fit expectations. Cold acclimated mitochondria decreased respiratory rates when acutely warmed whilst acute cooling caused an increase in mitochondrial function in warm acclimated fish. This acute response demonstrated a narrowing of the thermal performance window in the cold acclimated fish with warm acclimation shifting the thermal optimum and lowering upper thermal limits. This repression of mitochondrial function may have a significant impact on rainbow trout fitness if exposed to changing temperatures. We found that ROS production was insensitive to temperature changes which may be a result of complex I and III remodelling or due to changes in antioxidant capacity. Metabolic enzymes from the TCA cycle, electron transport chain and fatty acid oxidation pathways demonstrated a limited capacity for remodelling following temperature changes. We show that cold acclimation sensitised metabolic enzymes to acute changes in temperature whilst warm acclimation induced a desensitisation. Cold acclimation did not induce a switch to fatty acid metabolism as might be expected and we demonstrated that citrate synthase is a poor biomarker for mitochondrial content in the rainbow trout heart. </br></br>Overall, I have shown that the fish heart is sensitive to thermal changes which are reflected functionally and morphologically. Despite being sensitive to temperature changes rainbow trout mitochondria do not fi t traditional compensatory remodelling patterns and instead shift thermal optima. Cold acclimation leads a thermal sensitisation of metabolic enzymes which is not seen in the warm which displayed generally high metabolic activities. This metabolic remodelling may prove to be energetically costly and possibly detrimental to organismal fitness in the wild.imental to organismal fitness in the wild.)
• Johansen 2019 Comp Biochem Physiol C Toxicol Pharmacol  + (Acute exposure to crude oil and polycyclic … Acute exposure to crude oil and polycyclic aromatic hydrocarbons (PAH) can severely impair cardiorespiratory function and swim performance of larval, juvenile and adult fish. Interestingly, recent work has documented an oil induced decoupling of swim performance (Ucrit) and maximum metabolic rate (MMR) whereby oil causes a decline in Ucrit without a parallel reduction in MMR. We hypothesize that this uncoupling is due to impaired mitochondrial function in swimming muscles that results in increased proton leak, and thus less ATP generated per unit oxygen. Using high resolution mitochondrial respirometry, we assessed 11 metrics of mitochondrial performance in red and cardiac muscle from permeabilized fibers isolated from red drum following control or 24 h crude oil (high energy water accommodated fractions) exposure. Two experimental series were performed, a Deepwater Horizon relevant low dose (29.6 ± 7.4 μg L-1 ∑PAH50) and a proof-of-concept high dose (64.5 ± 8.9 μg L-1 ∑PAH50). No effects were observed on any mitochondrial parameter in either tissue at the low oil dose; however, high dose exposure provided evidence of impairment in the OXPHOS respiratory control ratio and OXPHOS spare capacity in red muscle following oil exposure, as well as a shift from Complex I to Complex II during OXPHOS respiration. No effects of the high dose oil treatment were observed in cardiac muscle. As such, mitochondrial dysfunction is unlikely to be the underlying mechanism for decoupling of Ucrit and MMR following acute oil exposure in red drum. Furthermore, mitochondrial dysfunction does not appear to be a relevant toxicological impairment in juvenile red drum with respect to the Deepwater Horizon oil spill, although impairments may be observed under higher dose exposure scenarios.</br></br><small>Copyright © 2019 Elsevier Inc. All rights reserved.</small> 2019 Elsevier Inc. All rights reserved.</small>)
• Banh 2015 Comp Biochem Physiol B Biochem Mol Biol  + (Acute heat challenge is known to induce ce … Acute heat challenge is known to induce cell-level oxidative stress in fishes. Mitochondria are well known for the capacity to make reactive oxygen species (ROS) and as such are often implicated as a source of the oxidants associated with this thermally-induced oxidative stress. This implication is often asserted, despite little direct data for mitochondrial ROS metabolism in fishes. Here we characterize mitochondrial ROS metabolism in three Actinopterygian fish species at two levels, the capacity for superoxide/H₂O₂ production and the antioxidant thiol-reductase enzyme activities. We find that red muscle mitochondria from all three species have measurable ROS production and respond to different assay conditions consistent with what might be anticipated; assuming similar relative contributions from difference ROS producing sites as found in rat skeletal muscle mitochondria. Although there are species and assay specific exceptions, fish mitochondria may have a greater capacity to produce ROS than that found in the rat when either normalized to respiratory capacity or determined at a common assay temperature. The interspecific differences in ROS production are not correlated with thiol-based antioxidant reductase activities. Moreover, mimicking an acute ''in vivo'' heat stress by comparing the impact of increasing assay temperature on these processes in vitro, we find evidence supporting a preferential activation of mitochondrial H₂O₂ production relative to the increase in the capacity of reductase enzymes to supply electrons to the mitochondrial matrix peroxidases. This supports the contention that mitochondria may be, at least in part, responsible for the ROS that lead to oxidative stress in fish tissues exposed to acute heat challenge.for the ROS that lead to oxidative stress in fish tissues exposed to acute heat challenge.)
• Calbet 2003 Am J Physiol Regul Integr Comp Physiol  + (Acute hypoxia (AH) reduces maximal O<su … Acute hypoxia (AH) reduces maximal O₂ consumption (''V''_O₂max), but after acclimatization, and despite increases in both hemoglobin concentration and arterial O₂ saturation that can normalize arterial O₂ concentration ([O₂]), ''V''_O₂max remains low. To determine why, seven lowlanders were studied at ''V''_O₂max (cycle ergometry) at sea level (SL), after 9-10 wk at 5260 m [chronic hypoxia (CH)], and 6 mo later at SL in AH (''F''_iO₂ = 0.105) equivalent to 5260 m. Pulmonary and leg indexes of O₂ transport were measured in each condition. Both cardiac output and leg blood flow were reduced by approximately 15 % in both AH and CH (''P'' < 0.05). At maximal exercise, arterial [O₂] in AH was 31 % lower than at SL (''P'' < 0.05), whereas in CH it was the same as at SL due to both polycythemia and hyperventilation. O₂ extraction by the legs, however, remained at SL values in both AH and CH. Although at both SL and in AH, 76 % of the cardiac output perfused the legs, in CH the legs received only 67 %. Pulmonary ''V''_O₂max (4.1 +/- 0.3 L/min at SL) fell to 2.2 +/- 0.1 L/min in AH (''P'' < 0.05) and was only 2.4 +/- 0.2 L/min in CH (''P'' < 0.05). These data suggest that the failure to recover ''V''_O₂max after acclimatization despite normalization of arterial [O₂] is explained by two circulatory effects of altitude: 1) failure of cardiac output to normalize and 2) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH.t;sub>2</sub>] is explained by two circulatory effects of altitude: 1) failure of cardiac output to normalize and 2) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH.)
• Wu 2007 Am J Physiol Lung Cell Mol Physiol  + (Acute hypoxia causes pulmonary vasoconstri … Acute hypoxia causes pulmonary vasoconstriction and coronary vasodilation. The divergent effects of hypoxia on pulmonary and coronary vascular smooth muscle cells suggest that the mechanisms involved in oxygen sensing and downstream effectors are different in these two types of cells. Since production of reactive oxygen species (ROS) is regulated by oxygen tension, ROS have been hypothesized to be a signaling mechanism in hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Furthermore, an increased ROS production is also implicated in arteriosclerosis. In this study, we determined and compared the effects of hypoxia on ROS levels in human pulmonary arterial smooth muscle cells (PASMC) and coronary arterial smooth muscle cells (CASMC). Our results indicated that acute exposure to hypoxia (Po(2) = 25-30 mmHg for 5-10 min) significantly and rapidly decreased ROS levels in both PASMC and CASMC. However, chronic exposure to hypoxia (Po(2) = 30 mmHg for 48 h) markedly increased ROS levels in PASMC, but decreased ROS production in CASMC. Furthermore, chronic treatment with endothelin-1, a potent vasoconstrictor and mitogen, caused a significant increase in ROS production in both PASMC and CASMC. The inhibitory effect of acute hypoxia on ROS production in PASMC was also accelerated in cells chronically treated with endothelin-1. While the decreased ROS in PASMC and CASMC after acute exposure to hypoxia may reflect the lower level of oxygen substrate available for ROS production, the increased ROS production in PASMC during chronic hypoxia may reflect a pathophysiological response unique to the pulmonary vasculature that contributes to the development of pulmonary vascular remodeling in patients with hypoxia-associated pulmonary hypertension.hypoxia-associated pulmonary hypertension.)
• Cortes 2023 Nat Commun  + (Acute inflammation can either resolve thro … Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.ulated inflammation and immunosuppression.)
• Tretter 2014 Abstract MiP2014  + (Acute ischemia-reperfusion injury of the b … Acute ischemia-reperfusion injury of the brain affects millions of people. Currently there is no really efficient neuroprotective therapy, however, a simple physical procedure, therapeutic hypothermia, can have beneficial effects. Although there is agreement that in this group of diseases oxidative stress is an important factor, the effects of temperature changes on the reactive oxygen species (ROS) formation and on the ROS elimination have not been clarified yet. A few publications in high profile journals claimed that mitochondrial ROS formation was inversely related to increasing temperature. In the present work, the effects of temperature changes on H₂O₂ formation and elimination were investigated in isolated guinea pig brain mitochondria in association with oxygen consumption.</br></br>Mitochondrial ROS production was measured using Amplex UltraRed fluorescence, the rate of H₂O₂ elimination was measured using a hydrogen peroxide-sensitive electrode (WPI). Oxygen consumption of mitochondria was measured using an Oroboros Oxygraph-2k. In order to energize mitochondria glutamate plus malate, succinate and alpha-glycerophosphate substrates were used. The bioenergetic and ROS parameters of mitochondria were investigated at 33, 37 and 41 °C.</br></br>The rate of substrate oxidation showed a strong increase with temperature, whereas the efficiency of oxidation was decreased. Considering the ROS homeostasis both the formation of H₂O₂ and the elimination of H₂O₂ became faster with increasing temperature. With Complex I substrates at resting respiration, H₂O₂ production was increased by 31%, as a consequence of elevating the temperature from 33 °C to 41 °C. Using succinate or alpha-glycerophosphate, results were similar. The biggest difference (59% between 33 °C and 41 °C) was detected when H₂O₂ production was measured in the presence of the Complex I inhibitor rotenone. The rate of H₂O₂ elimination was also elevated by 24% with increased temperature (from 33 °C to 41 °C), in glutamate+malate supported mitochondria. </br></br>Rising the temperature from hypothermic to hyperthermic conditions resulted in an increase in mitochondrial oxygen consumption, H₂O₂ production and H₂O₂ elimination. The increase of ROS production was higher than that of H₂O₂ elimination; thus, according to our results, the elevation of temperature created oxidative stress conditions. We conclude that the neuroprotective effects of therapeutic hypothermia are also based on the decreased rate of mitochondrial H₂O₂ production.ub> elimination; thus, according to our results, the elevation of temperature created oxidative stress conditions. We conclude that the neuroprotective effects of therapeutic hypothermia are also based on the decreased rate of mitochondrial H₂O₂ production.)
• Lopes 2022 Int J Mol Sci  + (Acute kidney injury (AKI) caused by ischem … Acute kidney injury (AKI) caused by ischemia followed by reperfusion (I/R) is characterized by intense anion superoxide (O₂^•-) production and oxidative damage. We investigated whether extracellular vesicles secreted by adipose tissue mesenchymal cells (EVs) administered during reperfusion can suppress the exacerbated mitochondrial O₂^•- formation after I/R. We used Wistar rats subjected to bilateral renal arterial clamping (30 min) followed by 24 h of reperfusion. The animals received EVs (I/R + EVs group) or saline (I/R group) in the kidney subcapsular space. The third group consisted of false-operated rats (SHAM). Mitochondria were isolated from proximal tubule cells and used immediately. Amplex Red™ was used to measure mitochondrial O₂^•- formation and MitoTracker™ Orange to evaluate inner mitochondrial membrane potential (Δψ). ''In vitro'' studies were carried out on human renal proximal tubular cells (HK-2) co-cultured or not with EVs under hypoxic conditions. Administration of EVs restored O₂^•- formation to SHAM levels in all mitochondrial functional conditions. The gene expression of catalase and superoxide dismutase-1 remained unmodified; transcription of heme oxygenase-1 (HO-1) was upregulated. The co-cultures of HK-2 cells with EVs revealed an intense decrease in apoptosis. We conclude that the mechanisms by which EVs favor long-term recovery of renal structures and functions after I/R rely on a decrease of mitochondrial O₂^•- formation with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, thus opening new vistas for the treatment of AKI.; formation with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, thus opening new vistas for the treatment of AKI.)
• Patil 2014 Am J Physiol Renal Physiol  + (Acute kidney injury (AKI) is a complicatio … Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 hours after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 hours. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 hours post CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 hours. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-hour survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. a promising approach to treat septic AKI.)
• Quoilin 2014 Dissertation  + (Acute kidney injury (AKI) is a frequent co … Acute kidney injury (AKI) is a frequent complication of sepsis that can increase mortality as high as 70%. The pathophysiology of this kidney failure</br>was previously believed to be secondary to decreased global renal perfusion causing hypoxia-induced injury. However, new research suggests this paradigm is overly simplistic, and injury is now considered multifactorial in origin. Mechanisms that contribute to kidney injury mainly include inflammation, alterations in microvascular renal blood flow and changes in bioenergetics.</br></br>To study the mechanism of oxygen regulation in acute kidney injury during sepsis, we developed a sepsis-induced ''in vitro'' model using proximal tubular epithelial cells (HK-2) exposed to a bacterial endotoxin (lipopolysaccharide, LPS). Our first investigation, by using both high-resolution respirometry and electron spin resonance spectroscopy, showed that HK-2 cells exhibit a decreased oxygen consumption rate when treated with LPS. Surprisingly,this cellular respiration alteration persists even after the stress factor is removed. We suggested that this irreversible decrease in renal oxygen consumption after LPS challenge is related to a pathologic metabolic down-regulation such as a lack of oxygen utilization by cells for ATP production. In the long term, this metabolic disturbance leads cells to a predominantly</br>apoptotic death. cells to a predominantly apoptotic death.)
• Li 2022 Mol Med  + (Acute kidney injury (AKI) is still a criti … Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive.</br></br>We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine ''in vivo'' with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. ''In vitro'' experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration.</br></br>We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity.</br></br>Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.ing pharmacologic approach to prevent AKI.)
• Zhang 2019 Biochem Biophys Res Commun  + (Acute liver injury seriously endangers hum … Acute liver injury seriously endangers human health. Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has antioxidative effects in addition to being widely used in the treatment of type 2 diabetes and was reported to ameliorate liver diseases. The aim of this study was to evaluate the hepatoprotective effects of liraglutide on carbon tetrachloride (CCl4)-induced acute liver injury in mice and to investigate the mechanisms involved in this protective effect. Male BALB/c mice were pre-treated with liraglutide (200 μg/kg/day) by hypodermic injection for 3 days before a 0.1% (v/v) CCl4 (10 ml/kg, dissolved in olive oil) intraperitoneal injection, or post-treated with liraglutide once immediately after a CCl4 intraperitoneal injection. The experimental data showed that liraglutide treatment significantly decreased the serum ALT and AST levels and ameliorated the liver histopathological changes induced by CCl4. In addition, liraglutide pre-treatment dramatically increased the number of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and significantly reduced hepatocyte apoptosis after CCl4 treatment. As a consequence, liraglutide pre-treatment significantly prevented CCl4-induced malondialdehyde (MDA) production and increased the activity of the antioxidant superoxide dismutase (SOD) enzyme. In addition, liraglutide pre-treatment significantly ameliorated mitochondrial respiratory functions and ultrastructural features. Furthermore, liraglutide pre-treatment enhances the activation of the NRF2/HO-1 signaling pathway. In summary, liraglutide protects against CCl4-induced acute liver injury by protecting mitochondrial functions and inhibiting oxidative stress, which may partly involve the activation of NRF2/HO-1 signaling pathway.</br></br><small>Copyright © 2019 Elsevier Inc. All rights reserved.</small> 2019 Elsevier Inc. All rights reserved.</small>)

• Canevarolo 2017 Thesis  + (Acute lymphoblastic leukemia (ALL) is the … Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, accounting for 25% of all cancers in this age group. One of the chemotherapeutics used in the therapy of ALL (and autoimmune diseases such as rheumatoid arthritis) is methotrexate (MTX), a folic acid antagonist (antifolate). As a chemotherapeutic agent, MTX´s mechanism of action is primarily attributed to the inhibition of the dihydrophate reductase enzyme, which synthesizes tetrahydrofolate from dihydrofolate – a key step in the ''de novo'' synthesis of purine nucleotides used in cell division. In rheumatoid arthritis, lower doses of MTX inhibit the 5-aminoimidazole-4-ribonucleotide-carboxamide formyltransferase (ATIC) enzyme, which culminates in the production of high levels of adenosine, a potent anti-inflammatory. However, recent works continue to present previously unknown mechanisms and effects through which MTX acts within the cell, attesting that MTX´s mechanisms of action appear to be as multiple as complex. Using several techniques of molecular biology, this work sought to expand the existing knowledge of the action of MTX in ALL. For this purpose, several</br>biological parameters were measured under or without MTX treatment in a panel of 13 ALL</br>cell lines. Proliferation tests, metabolic studies, drug synergism, quantification of cellular</br>respiration and the production of reactive oxygen species (ROS) were performed, as well as</br>the measurement of the activation of the NF-κB signaling pathway. Resistance of the MTX</br>strains within 48 h of treatment (but not 96 h) was related to the proliferation rate of the cells.</br>Treatment with MTX altered the concentration of 28 intracellular metabolites, highlights for a</br>consistent increase in glycine concentration. Intracellular concentrations of asparagine,</br>guanosine and glutathione – including the expression of genes from glutathione pathway –</br>were associated with MTX resistance. Supplementation of the culture medium with Nacetylcysteine,</br>a precursor metabolite of glutathione, promoted proliferation and resistance to</br>MTX; however, cell treatment with piperlongumine or hydrogen peroxide, two glutathione</br>scavengers and ROS promoters, did not potentiate the effect of MTX. MTX induced ROS in</br>ALL after 6 h of treatment with low fold change, though. Paradoxically, higher ROS</br>production was found in cell lines with high MTX resistance and intracellular glutathione.</br>The oxygen uptake of the cell lines was not associated with MTX resistance and a preliminary</br>test showed that MTX did not alter cellular respiration. MTX activated the transcription factor</br>NF-κB in some ALL cell lines and, interestingly, the activation of this transcription factor by</br>tumor necrosis factor alpha (TNF-α) was positively correlated with the resistance of leukemic</br>lines to MTX. A wide bibliographic review allowed both the integration of the obtained</br>results to the most current knowledge on the subject, and the identification of new paths to be</br>explored in future stages.new paths to be explored in future stages.)
• Warren 2017 Metabolism  + (Acute metabolic demands that promote exces … Acute metabolic demands that promote excessive and/or prolonged reactive oxygen species production may stimulate changes in mitochondrial oxidative capacity.</br></br>To assess changes in skeletal muscle H₂O₂ production, mitochondrial function, and expression of genes at the mRNA and protein levels regulating energy metabolism and mitochondrial dynamics following a hyperinsulinemic-euglycemic clamp in a cohort of 11 healthy premenopausal women.</br></br>Skeletal muscle biopsies of the vastus lateralis were taken at baseline and immediately following the conclusion of a hyperinsulinemic-euglycemic clamp. Mitochondrial production of H₂O₂ was quantified fluorometrically and mitochondrial oxidation supported by pyruvate, malate, and succinate (PMS) or palmitoyl carnitine and malate (PCM) was measured by high-resolution respirometry in permeabilized muscle fiber bundles. mRNA and protein levels were assessed by real time PCR and Western blotting.</br></br>H₂O₂ emission increased following the clamp (P<0.05). Coupled respiration (State 3) supported by PMS and the respiratory control ratio (index of mitochondrial coupling) for both PMS and PCM were lower following the clamp (P<0.05). IRS1 mRNA decreased, whereas PGC1α and GLUT4 mRNA increased following the clamp (P≤0.05). PGC1α, IRS1, and phosphorylated AKT protein levels were higher after the clamp compared to baseline (P<0.05).</br></br>This study demonstrated that acute hyperinsulinemia induced H₂O₂ production and a concurrent decrease in coupling of mitochondrial respiration with ATP production in a cohort of healthy premenopausal women. Future studies should determine if this uncoupling ameliorates peripheral oxidative damage, and if this mechanism is impaired in diseases associated with chronic oxidative stress.</br></br>Copyright © 2017 Elsevier Inc. All rights reserved.amage, and if this mechanism is impaired in diseases associated with chronic oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.)
• Bailey 2001 High Alt Med Biol  + (Acute mountain sickness; prophylactic bene … Acute mountain sickness; prophylactic benefits of Free-radical-mediated damage to the blood-brain barrier may be implicated in the pathophysiology of acute mountain sickness (AMS). To indirectly examine this, we conducted a randomized double-blind placebo-controlled trial to assess the potentially prophylactic benefits of enteral antioxidant vitamin supplementation during ascent to high altitude. Eighteen subjects aged 35 +/- 10 years old were randomly assigned double-blind to either an antioxidant (n = 9) or placebo group (n = 9). The antioxidant group ingested 4 capsules/day(-1) (2 after breakfast/2 after evening meal) that each contained 250 mg of L-ascorbic acid, 100 IU of dl-a-tocopherol acetate and 150 mg of alpha-lipoic acid. The placebo group ingested 4 capsules of identical external appearance, taste, and smell. Supplementation was enforced for 3 weeks at sea level and during a 10-day ascent to Mt. Everest base camp (approximately 5,180 m). Antioxidant supplementation resulted in a comparatively lower Lake Louise AMS score at high altitude relative to the placebo group (2.8 +/- 0.8 points versus 4.0 +/- 0.4 points, P = 0.036), higher resting arterial oxygen saturation (89 +/- 5% versus 85 +/- 5%, P = 0.042), and total caloric intake (13.2 +/- 0.6 MJ/day(-1) versus 10.1 +/- 0.7 MJ/day(-1), P = 0.001); the latter is attributable to a lower satiety rating following a standardized meal. These findings indicate that the exogenous provision of water and lipid-soluble antioxidant vitamins at the prescribed doses is an apparently safe and potentially effective intervention that can attenuate AMS and improve the physiological profile of mountaineers at high altitude. profile of mountaineers at high altitude.)
• Fisher-Wellman 2023 Cancers (Basel)  + (Acute myelogenous leukemia (AML), the most … Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and glycosylation has been shown to be an element in chemotherapy-resistant AML, a problem considering the crucial role ceramide plays in eliciting apoptosis. Herein we employed agents that block ceramide clearance to determine if such a "reset" would be of therapeutic benefit. SACLAC was utilized to limit ceramide hydrolysis, and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) was used to block the glycosylation route. The SACLAC D-threo-PDMP inhibitor combination was synergistically cytotoxic in drug-resistant, P-glycoprotein-expressing (P-gp) AML but not in wt, P-gp-poor cells. Interestingly, P-gp antagonists that can limit ceramide glycosylation via depression of glucosylceramide transit also synergized with SACLAC, suggesting a paradoxical role for P-gp in the implementation of cell death. Mechanistically, cell death was accompanied by a complete drop in ceramide glycosylation, concomitant, striking increases in all molecular species of ceramide, diminished sphingosine 1-phosphate levels, resounding declines in mitochondrial respiratory kinetics, altered Akt, pGSK-3β, and Mcl-1 expression, and caspase activation. Although ceramide was generated in wt cells upon inhibitor exposure, mitochondrial respiration was not corrupted, suggestive of mitochondrial vulnerability in the drug-resistant phenotype, a potential therapeutic avenue. The inhibitor regimen showed efficacy in an ''in vivo'' model and in primary AML cells from patients. These results support the implementation of SL enzyme targeting to limit ceramide clearance as a therapeutic strategy in chemotherapy-resistant AML, inclusive of a novel indication for the use of P-gp antagonists.ndication for the use of P-gp antagonists.)
• Peng 2022 Front Oncol  + (Acute myeloid leukemia (AML) is a heteroge … Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by multiple cytogenetic and molecular abnormalities, with a very poor prognosis. Current treatments for AML often fail to eliminate leukemic stem cells (LSCs), which perpetuate the disease. LSCs exhibit a unique metabolic profile, especially dependent on oxidative phosphorylation (OXPHOS) for energy production. Whereas, normal hematopoietic stem cells (HSCs) and leukemic blasts rely on glycolysis for adenosine triphosphate (ATP) production. Thus, understanding the regulation of OXPHOS in LSCs may offer effective targets for developing clinical therapies in AML. This review summarizes these studies with a focus on the regulation of the electron transport chain (ETC) and tricarboxylic acid (TCA) cycle in OXPHOS and discusses potential therapies for eliminating LSCs. potential therapies for eliminating LSCs.)
• Jayasankar 2022 ACS Omega  + (Acute myeloid leukemia (AML) is an aggress … Acute myeloid leukemia (AML) is an aggressive blood cancer with limited effective chemotherapy options and negative patient outcomes. Food-derived molecules such as avocatin B (Avo B), a fatty-acid oxidation (FAO) inhibitor, are promising novel therapeutics. The roots of the Curcuma amada plants have been historically used in traditional medicine, but isolated bioactive compounds have seldom been studied. Here, we report that 2,4,6-trihydroxy-3,5-diprenyldihydrochalcone (M1), a bioactive from C. Amada, possesses novel anticancer activity. This in vitro study investigated the antileukemia properties of M1 and its effects on mitochondrial metabolism. In combination with Avo B, M1 synergistically reduced AML cell line viability and patient-derived clonogenic growth with no effect on normal peripheral blood stem cells. Mechanistically, M1 alone inhibited mitochondria complex I, while the M1/Avo B combination inhibited FAO by 60 %, a process essential to the synergy. These results identified a novel food-derived bioactive and its potential as a novel chemotherapeutic for AML.ntial as a novel chemotherapeutic for AML.)
• Maeda 2020 J Cell Mol Med  + (Acute myocardial infarction is a leading c … Acute myocardial infarction is a leading cause of death among single organ diseases. Despite successful reperfusion therapy, ischaemia reperfusion injury (IRI) can induce oxidative stress (OS), cardiomyocyte apoptosis, autophagy and release of inflammatory cytokines, resulting in increased infarct size. In IRI, mitochondrial dysfunction is a key factor, which involves the production of reactive oxygen species, activation of inflammatory signalling cascades or innate immune responses, and apoptosis. Therefore, intercellular mitochondrial transfer could be considered as a promising treatment strategy for ischaemic heart disease. However, low transfer efficiency is a challenge in clinical settings. We previously reported uptake of isolated exogenous mitochondria into cultured cells through co-incubation, mediated by macropinocytosis. Here, we report the use of transactivator of transcription dextran complexes (TAT-dextran) to enhance cellular uptake of exogenous mitochondria and improve the protective effect of mitochondrial replenishment in neonatal rat cardiomyocytes (NRCMs) against OS. TAT-dextran-modified mitochondria (TAT-Mito) showed a significantly higher level of cellular uptake. Mitochondrial transfer into NRCMs resulted in anti-apoptotic capability and prevented the suppression of oxidative phosphorylation in mitochondria after OS. Furthermore, TAT-Mito significantly reduced the apoptotic rates of cardiomyocytes after OS, compared to simple mitochondrial transfer. These results indicate the potential of mitochondrial replenishment therapy in OS-induced myocardial IRI.</br></br><small>© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.</small>ular Medicine and John Wiley & Sons Ltd.</small>)
• Roy 2016 Free Radic Biol Med  + (Acute myocardial infarction leads to an in … Acute myocardial infarction leads to an increase in oxidative stress and lipid peroxidation. 4(RS)-4-F4t-Neuroprostane (4-F4t-NeuroP) is a mediator produced by non-enzymatic free radical peroxidation of the cardioprotective polyunsaturated fatty acid, docosahexaenoic acid (DHA). In this study, we investigated whether intra-cardiac delivery of 4-F4t-NeuroP (0.03mg/kg) prior to occlusion (ischemia) prevents and protects rat myocardium from reperfusion damages. Using a rat model of ischemic-reperfusion (I/R), we showed that intra-cardiac infusion of 4-F4t-NeuroP significantly decreased infarct size following reperfusion (-27%) and also reduced ventricular arrhythmia score considerably during reperfusion (-41%). Most notably, 4-F4t-NeuroP decreased ventricular tachycardia and post-reperfusion lengthening of QT interval. The evaluation of the mitochondrial homeostasis indicates a limitation of mitochondrial swelling in response to Ca²⁺ by decreasing the mitochondrial permeability transition pore opening and increasing mitochondria membrane potential. On the other hand, mitochondrial respiration measured by oxygraphy, and mitochondrial ROS production measured with MitoSox red® were unchanged. We found decreased cytochrome ''c'' release and caspase 3 activity, indicating that 4-F4t-NeuroP prevented reperfusion damages and reduced apoptosis. In conclusion, 4-F4t-NeuroP derived from DHA was able to protect I/R cardiac injuries by regulating the mitochondrial homeostasis.</br></br>Copyright © 2016 Elsevier Inc. All rights reserved.. Copyright © 2016 Elsevier Inc. All rights reserved.)
• Ohsawa 2007 Nat Med  + (Acute oxidative stress induced by ischemia … Acute oxidative stress induced by ischemia-reperfusion or inflammation causes serious damage to tissues, and persistent oxidative stress is accepted as one of the causes of many common diseases including cancer. We show here that hydrogen (H₂) has potential as an antioxidant in preventive and therapeutic applications. We induced acute oxidative stress in cultured cells by three independent methods. H₂ selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H₂ did not react with other ROS, which possess physiological roles. We used an acute rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion. The inhalation of H₂ gas markedly suppressed brain injury by buffering the effects of oxidative stress. Thus H₂ can be used as an effective antioxidant therapy; owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.)
• Mikami 2019 Can J Physiol Pharmacol  + (Acute physical exercise increases reactive … Acute physical exercise increases reactive oxygen species in skeletal muscle, leading to tissue damage and fatigue. Molecular hydrogen (H2) acts as a therapeutic antioxidant directly or indirectly by inducing antioxidative enzymes. Here, we examined the effects of drinking H2 water (H2-infused water) on psychometric fatigue and endurance capacity in a randomized, double-blind, placebo-controlled fashion. In Experiment 1, all participants drank only placebo water in the first cycle ergometer exercise session, and for comparison they drank either H2 water or placebo water 30 min before exercise in the second examination. In these healthy non-trained participants (''N'' = 99), psychometric fatigue judged by visual analogue scales was significantly decreased in the H2 group after mild exercise. When each group was divided into 2 subgroups, the subgroup with higher visual analogue scale values was more sensitive to the effect of H2. In Experiment 2, trained participants (''N'' = 60) were subjected to moderate exercise by cycle ergometer in a similar way as in Experiment 1, but exercise was performed 10 min after drinking H2 water. Endurance and fatigue were significantly improved in the H2 group as judged by maximal oxygen consumption and Borg's scale, respectively. Taken together, drinking H2 water just before exercise exhibited anti-fatigue and endurance effects.ibited anti-fatigue and endurance effects.)
• Hoppel 2015 Abstract MiP2015  + (Acute strenuous exercise is linked to seve … Acute strenuous exercise is linked to severe inflammatory responses [1,2], alterations of mitochondrial function of human skeletal muscle and increased oxidative stress [3]. Due to the invasive nature of muscle biopsies, minimally-invasive alternatives to study mitochondrial function in tissues such as blood cells are gaining significance. Mitochondrial function in human platelets and lymphocytes has been characterized in various disease states. Importantly, respiratory capacity of human PBMCs was linked to physical fitness [4], supporting the concept that mitochondrial function in human blood cells can be used as a systemic mitochondrial marker. In this study we investigated the influence of completion of an ultramarathon on mitochondrial respiration in human platelets.</br></br>After informed consent, 10 male recreational athletes (mean age: 39.9 yrs; BMI 24.9 kg2/m) who participated in a competition over 67 km and approximately 4,500 m ascent, were included in the study. Baseline (PRE) measurements were performed on the day before the competition and follow-up sampling was performed within 15 min after finishing the race (POST) by sampling whole blood. To address potential effects of recovery, a third time point was selected 24 h after finishing (REC). Evaluation of mitochondrial respiration was conducted in freshly purified human platelets by the use of six Oroboros Oxygraph-2k operating in parallel. ROUTINE respiration (R), Complex I-linked LEAK and OXPHOS capacity (CI), and CI&II-linked OXPHOS and ET capacity were determined in a single SUIT protocol. Additionally, neutrophils, monocytes and lymphocytes (inflammatory response), creatine kinase (CK; muscular damage) and plasma markers of oxidative damage and repair were quantified at baseline and after the race.</br></br>Absolute concentrations of all leukocyte subgroups and serum creatine kinase were changed significantly after the race. No significant changes were found in respiratory substrate control ratios CI/CI&II and CII/CI&II, neither when comparing PRE and POST, nor between POST and recovery. However, the ROUTINE coupling control ratio, R/E (ROUTINE respiration of intact cells, R, divided by uncoupler-stimulated electron transfer-pathway capacity, E) was increased significantly (+25,4% PRE vs. POST; +9,5% PRE vs. REC; ''p''<0.05), indicating the influence of massive physical strain and time of recovery on human platelet metabolism. We found a significant (''p''<0,05) relationship between BMI and CI/CI&II ratio, whereas age and training time per week were without significant effects on platelet metabolism.er week were without significant effects on platelet metabolism.)
• Datzmann 2019 J Neurosurg  + (Acute subdural hematoma (ASDH) is a leadin … Acute subdural hematoma (ASDH) is a leading entity in brain injury. Rodent models mostly lack standard intensive care, while large animal models frequently are only short term. Therefore, the authors developed a long-term, resuscitated porcine model of ASDH-induced brain injury and report their findings.</br></br>Anesthetized, mechanically ventilated, and instrumented pigs with human-like coagulation underwent subdural injection of 20 mL of autologous blood and subsequent observation for 54 hours. Continuous bilateral multimodal brain monitoring (intracranial pressure [ICP], cerebral perfusion pressure [CPP], partial pressure of oxygen in brain tissue [PbtO₂], and brain temperature) was combined with intermittent neurological assessment (veterinary modified Glasgow Coma Scale [MGCS]), microdialysis, and measurement of plasma protein S100β, GFAP, neuron-specific enolase [NSE], nitrite+nitrate, and isoprostanes. Fluid resuscitation and continuous intravenous norepinephrine were targeted to maintain CPP at pre-ASDH levels. Immediately postmortem, the brains were taken for macroscopic and histological evaluation, immunohistochemical analysis for nitrotyrosine formation, albumin extravasation, NADPH oxidase 2 (NOX2) and GFAP expression, and quantification of tissue mitochondrial respiration.</br></br>Nine of 11 pigs survived the complete observation period. While ICP significantly increased after ASDH induction, CPP, PbtO₂, and the MGCS score remained unaffected. Blood S100β levels significantly fell over time, whereas GFAP, NSE, nitrite+nitrate, and isoprostane concentrations were unaltered. Immunohistochemistry showed nitrotyrosine formation, albumin extravasation, NOX2 expression, fibrillary astrogliosis, and microglial activation.</br></br>The authors describe a clinically relevant, long-term, resuscitated porcine model of ASDH-induced brain injury. Despite the morphological injury, maintaining CPP and PbtO₂ prevented serious neurological dysfunction. This model is suitable for studying therapeutic interventions during hemorrhage-induced acute brain injury with standard brain-targeted intensive care.rrhage-induced acute brain injury with standard brain-targeted intensive care.)
• Krumschnabel 2004 Aquat Toxicol  + (Acute toxic effects of hexavalent chromium … Acute toxic effects of hexavalent chromium [Cr(VI)], a widely recognised carcinogenic, mutagenic and redox active metal, were investigated in isolated hepatocytes of goldfish (Carassius auratus). Exposure to 250 microM Cr(VI) induced a significant decrease of cell viability from 94% in controls to 88% and 84% after 30 min and 4 h of exposure, respectively. Cr-toxicity was associated with a concentration-dependent stimulation of the formation of reactive oxygen species (ROS). As one potential source of ROS formation we identified the lysosomal Fe(2+) pool, since the ferric ion chelator deferoxamin inhibited ROS formation by approximately 15%. Lysosomal membranes remained nevertheless intact during Cr-exposure, as determined from neutral red retention in this compartment. Another significant source of ROS appear to be the mitochondria, where a presumably uncoupled increase of respiration by 20-30% was triggered by the metal. Inhibition of mitochondrial respiration by cyanide caused an approximately 40% decrease of Cr-induced ROS-formation, whereas the uncoupling agent carbonyl cyanide m-chlorophenyl hydrazine was without effect. Cellular Ca(2+) homeostasis was not disturbed by Cr(VI) and thus played no role in this scenario. Overall, our data show that Cr(VI) is acutely toxic to goldfish hepatocytes, and its toxicity is associated with the induction of radical stress, presumably involving lysosomes and mitochondria as important sources of ROS formation.ria as important sources of ROS formation.)
• Isola 2022 Abstract Bioblast  + (Acutely exposure to low oxygen concentrati … Acutely exposure to low oxygen concentrations, impairs the capability to perform muscular workout. On the other hand, repeated and prolonged exposure to low PO2 may improve physical performance due to a progressive adaptation of the body. This is mainly due to enhanced hemoglobin and red blood cells content, and decreased sympathetic autonomic nervous system input. These changes were evaluated in a number of chronic hypoxia studies [1-2], whereas acute hypoxia outcomes are still unknown.</br></br>This study investigates on acute hypoxia and normoxia impact on cardiac and brain mitochondrial bioenergetics and the possible occurrence of different gender responses.</br></br>We used male and female Wistar rats that had been trained for 5 weeks, 1h/day, on a treadmill set at 35 cm/s. The day of the experiment they were allowed to run on the treadmill for 30 minutes in hypoxia (at the same oxygen concentration of an altitude of 4000 mt.) or in normoxia. After euthanasia, we removed the brain and the heart and isolated brain mitochondria, subsarcolemmal (SSM) and interfibrillar (IFM) heart mitochondria [3]. Mitochondrial bioenergetics was assessed by Clark-type electrode, testing for oxidative phosphorylation (OXPHOS): complex I (glutamate plus malate), complex II (rotenone plus succinate), complex III (rotenone plus durohydroquinone), complex IV (rotenone plus tetramethyl-p-phenylenediamine and ascorbate), Palmitoyl CoA as lipid substrate and adding at the end of the assay dinitrophenol (DNP) to test uncoupled respiration with these substrates.</br></br>After acute hypoxia, brain male mitochondria showed an increase of uncoupled respiration at complex II and IV, whereas female mitochondria displayed no significant difference compared to controls.</br></br>In heart male IFM mitochondria, following acute hypoxia, ADP/O decreased at complex I and II, compared with controls. Furthermore, in the same complexes data showed an increase of respiratory control ratio, but only complex I resulted statistically significant. These data suggest that hypoxia induced a mild uncoupling of IFM.</br></br>Among female heart mitochondria, SSM only showed a decrease in state 3 of complex II after acute hypoxia.</br></br>In conclusion, in both genders cardiac and brain mitochondrial bioenergetics change after athletic training in acute hypoxia.</br></br>It seems that in female cardiac mitochondria hypoxia induced an impairment of complex II activity, while in male heart mitochondria the result need further investigation as it could be linked to a reported increased activity of ATPase under hypoxia [4] or a defective OXPHOS with a possible enhanced ROS production.</br></br>In male brain mitochondria the increased of uncoupled respiration might be linked to a better efficiency of electron transfer system (ETS). Future studies will need to verify these results.</br><small></br># Horscroft JA, Kotwica AO, Laner V, West JA, Hennis PJ, Levett DZH, Howard DJ, Fernandez BO, Burgess SL, Ament Z, Gilbert-Kawai ET, Vercueil A, Landis BD, Mitchell K, Mythen MG, Branco C, Johnson RS, Feelisch M, Montgomery HE, Griffin JL, Grocott MPW, Gnaiger E, Martin DS, Murray AJ (2017) Metabolic basis to Sherpa altitude adaptation. https://doi.org/10.1073/pnas.1700527114</br># Levett DZ, Radford EJ, Menassa DA, Graber EF, Morash AJ, Hoppeler H, Clarke K, Martin DS, Ferguson-Smith AC, Montgomery HE, Grocott MP, Murray AJ; Caudwell Xtreme Everest Research Group (2012) Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. https://doi.org/10.1096/fj.11-197772</br># Palmer JW, Tandler B, Hoppel CL (1977) Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. https://www.jbc.org/article/S0021-9258(19)75283-1/pdf</br># Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Takafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y, Takashima S (2014) Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation. https://doi.org/10.1073/pnas.1318547111</br></small>https://doi.org/10.1073/pnas.1318547111 </small>)
• Fisher-Wellman 2019 Cell Rep  + (Acyl CoA metabolites derived from the cata … Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ∼15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics.</br></br><small>Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.</small>ished by Elsevier Inc. All rights reserved.</small>)
• Rajkumar 2018 Metabolism  + (Acyl-CoA Synthetase Long Chain 5 (ACSL5) g … Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated with ''ACSL5'' mRNA expression and response to lifestyle interventions. However, the mechanistic understanding of the increased response in T allele carriers is lacking. Study objectives were to investigate the effect of rs2419621 genotype and ACSL5 human protein isoforms on fatty acid oxidation and respiration.</br></br>Human ACSL5 overexpression in C2C12 mouse myoblasts was conducted to measure ¹⁴C palmitic acid oxidation and protein isoform localization ''in vitro''. ¹⁴C palmitic acid oxidation studies and Western blot analysis of ACSL5 proteins were carried out in ''rectus abdominis'' primary myotubes from 5 rs2419621 T allele carriers and 4 non-carriers. In addition, mitochondrial high-resolution respirometry was conducted on ''vastus lateralis'' muscle biopsies from 4 rs2419621 T allele carriers and 4 non-carriers. Multiple linear regression analysis was conducted to test the association between rs2419621 genotype and respiratory quotient related pre- and post-lifestyle intervention measurements in postmenopausal women with overweight or obesity.</br></br>In comparison to rs2419621 non-carriers, T allele carriers displayed higher levels of i) 683aa ACSL5 isoform, localized mainly in the mitochondria, playing a greater role in fatty acid oxidation in comparison to the 739aa protein isoform ii) ''in vitro'' CO₂ production in ''rectus abdominis'' primary myotubes iii) ''in vivo'' fatty acid oxidation and lower carbohydrate oxidation post-intervention iv) ''ex vivo'' complex I and II tissue respiration in ''vastus lateralis'' muscle.</br></br>These results support the conclusion that rs2419621 T allele carriers, are more responsive to lifestyle interventions partly due to an increase in the short ACSL5 protein isoform, increasing cellular, tissue and whole-body fatty acid utilization. With the increasing effort to develop personalized medicine to combat obesity, our findings provide additional insight into genotypes that can significantly affect whole body metabolism and response to lifestyle interventions.</br></br>Copyright © 2018 Elsevier Inc. All rights reserved. lifestyle interventions. Copyright © 2018 Elsevier Inc. All rights reserved.)
• Dambrova 2022 Abstract Bioblast  + (Acylcarnitines are esters of L-carnitine t … Acylcarnitines are esters of L-carnitine that emerge from the energy metabolism pathways of fatty acids in mitochondria and peroxisomes [1]. Depending on the length of the acyl chain, acylcarnitines can be grouped as short-, medium-, long- and very long-chain acylcarnitines. Metabolomic profiling assays that investigate disease and nutrition states often include measurements of different acylcarnitines. This has resulted in increased interest regarding the consequences of elevated/decreased levels of plasma acylcarnitine concentrations and the mechanisms associated with these changes.</br></br>Altered acylcarnitine metabolome is characteristic for certain inborn errors of fatty acid metabolism, as well as cardiovascular, metabolic and neurological diseases, and some forms of cancer. Acylcarnitines are considered as biomarkers for such diseases and pathological conditions as insulin resistance, heart failure and fatty acid oxidation metabolism-related inherited diseases. Long-chain acylcarnitines accumulate under conditions of insufficient mitochondrial functionality and can reach tissue levels that can affect enzyme and ion channel activities and impact energy metabolism pathways and cellular homeostasis. These detrimental processes directly impact mitochondrial physiology and can exaggerate arrhythmia, insulin insufficiency, neurodegenerative and neuropsychiatric conditions.</br></br>Dietary and pharmacological means can be used to regulate synthesis and transport pathways of acylcarnitines and thus counteract the detrimental effects of their accumulation or reverse deficits. The most abundant acylcarnitines, acetylcarnitine and propionylcarnitine, are used as food supplements to tackle neurological and cardiovascular conditions.</br></br>Better understanding of biochemical and molecular mechanisms behind increased/decreased acylcarnitine levels and their physiological and pathological roles forms basis for therapeutic target selection and preclinical drug discovery in future and also explains off-target effects of some clinically used drugs.</br><small></br># Dambrova M et al (2022) Acylcarnitines: nomenclature, biomarkers, therapeutic potential, drug targets and clinical trials. Pharmacol Rev 74:1-50 (in press).</br></small>ials. Pharmacol Rev 74:1-50 (in press). </small>)
• Dambrova 2022 Pharmacol Rev  + (Acylcarnitines are fatty acid metabolites … Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.larification of their physiological roles.)
• Ojuka 2015 Abstract MiPschool Cape Town 2015  + (Acylcarnitines when converted to acyl –CoA … Acylcarnitines when converted to acyl –CoA in the mitochondrial matrix</br>are a major source of ATP after oxidation. Their oxidation process,</br>termed β-oxidation, runs through four sequential enzymes namely:</br>acyl-CoA dehydrogenase, 2-enoyl-CoA hydratase, L-3-hydroxyacyl-</br>CoA dehydrogenase, and 3-ketoacyl-CoA thiolase [1]. Acyl-CoA</br>dehydrogenases transfer single electrons to electron transferring</br>flavoprotein (ETF) [2] which donates electrons directly to the ubiquinone</br>(Q) pool in the mitochondrial inner membrane. Hydroxyacyl-CoA</br>dehydrogenase transfers electrons to NAD+ and the reduced NADH</br>is oxidized by complex I. The end product of β-oxidation, acetyl-CoA,</br>condenses with oxaloacetate to form citrate which is oxidized by the</br>Krebs cycle. Oxidation of fatty acylcarnitines therefore contributes to</br>OXPHOS and ATP production by donating electrons at various points of</br>the electron transfer-pathway.</br></br>To assess oxidation of acylcarnitines under various experimental</br>conditions, scientist often measure oxygen consumption in isolated</br>mitochondria, permeabilized cells, or tissues in an oxygraph using</br>a variety of substrate combinations including palmatoylcarnitine in</br>combination with carnitine or malate. Use of palmatoylcarnitine alone</br>yields low oxygen flux rates and is not responsive to ADP, oligomycin</br>or uncouplers. These observations are attributed to a low CoA/</br>palmatoylCoA ratio which inactivates 3-ketoacyl-CoA thiolase and slows</br>down or stops β-oxidation. Use of palmatoylcarnitine in combination with</br>carnitine or malate increase State 2 respiration (oxygen consumption</br>with substrate without addition of ADP) and are responsive to ADP,</br>oligomycin and uncouples -- but to different degrees. The increase in</br>oxygen flux rates after ADP or uncoupler addition is explained by the</br>increased CoA/palmatoylCoA ratio which favours β-oxidation. The</br>differences in response to ADP and uncoupler is probably due the fact</br>that oxidation of palmitoylcarnitine in the presence of carnitine transfers</br>electrons to the ETS without involving the Krebs cycle whereas oxidation</br>of palmitoylcarnitine and malate does [3].of palmitoylcarnitine and malate does [3].)
• Kang 2017 Mol Cell  + (Acylglycerol kinase (AGK) is a mitochondri … Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins. Mitochondria isolated from Sengers syndrome patient cells and tissues show a destabilized TIM22 complex and defects in the biogenesis of carrier substrates. Consistent with this phenotype, we observe perturbations in the tricarboxylic acid (TCA) cycle in cells lacking AGK. Our identification of AGK as a bona fide subunit of TIM22 provides an exciting and unexpected link between mitochondrial protein import and Sengers syndrome.drial protein import and Sengers syndrome.)
• Gak 2015 Biochim Biophys Acta  + (Adaptability to stress is a fundamental pr … Adaptability to stress is a fundamental prerequisite for survival. Mitochondria are a key component of the stress response in all cells. For steroid-hormones-producing cells, including also Leydig cells of testes, the mitochondria are a key control point for the steroid biosynthesis and regulation. However, the mitochondrial biogenesis in steroidogenic cells has never been explored. Here we show that increased mitochondrial biogenesis is the adaptive response of testosterone-producing Leydig cells from stressed rats. All markers of mitochondrial biogenesis together with transcription factors and related kinases are up-regulated in Leydig cells from rats exposed to repeated psychophysical stress. This is followed with increased mitochondrial mass. The expression of PGC1, master regulator of mitochondrial biogenesis and integrator of environmental signals, is stimulated by cAMP-PRKA, cGMP, and β-adrenergic receptors. Accordingly, stress-triggered mitochondrial biogenesis represents an adaptive mechanism and does not only correlate with but also is an essential for testosterone production, being both events depend on the same regulators. Here we propose that all events induced by acute stress, the most common stress in human society, provoke adaptive response of testosterone-producing Leydig cells and activate PGC1, a protein required to make new mitochondria but also protector against the oxidative damage. Given the importance of mitochondria for steroid hormones production and stress response, as well as the role of steroid hormones in stress response and metabolic syndrome, we anticipate our result to be a starting point for more investigations since stress is a constant factor in life and has become one of the most significant health problems in modern societies.</br></br>Copyright © 2015 Elsevier B.V. All rights reserved. © 2015 Elsevier B.V. All rights reserved.)
• Mantilla 2017 PLOS Pathog  + (Adaptation to different nutritional enviro … Adaptation to different nutritional environments is essential for life cycle completion by all ''Trypanosoma brucei'' sub-species. In the tsetse fly vector, L-proline is among the most abundant amino acids and is mainly used by the fly for lactation and to fuel flight muscle. The procyclic (insect) stage of ''T. b. brucei'' uses L-proline as its main carbon source, relying on an efficient catabolic pathway to convert it to glutamate, and then to succinate, acetate and alanine as the main secreted end products. Here we investigated the essentiality of an undisrupted proline catabolic pathway in ''T. b. brucei'' by studying mitochondrial Δ1-pyrroline-5-carboxylate dehydrogenase (TbP5CDH), which catalyzes the irreversible conversion of gamma-glutamate semialdehyde (γGS) into L-glutamate and NADH. In addition, we provided evidence for the absence of a functional proline biosynthetic pathway. TbP5CDH expression is developmentally regulated in the insect stages of the parasite, but absent in bloodstream forms grown ''in vitro''. RNAi down-regulation of TbP5CDH severely affected the growth of procyclic trypanosomes ''in vitro'' in the absence of glucose, and altered the metabolic flux when proline was the sole carbon source. Furthermore, TbP5CDH knocked-down cells exhibited alterations in the mitochondrial inner membrane potential (ΔΨm), respiratory control ratio and ATP production. Also, changes in the proline-glutamate oxidative capacity slightly affected the surface expression of the major surface glycoprotein EP-procyclin. In the tsetse, TbP5CDH knocked-down cells were impaired and thus unable to colonize the fly's midgut, probably due to the lack of glucose between bloodmeals. Altogether, our data show that the regulated expression of the proline metabolism pathway in ''T. b. brucei'' allows this parasite to adapt to the nutritional environment of the tsetse midgut.ritional environment of the tsetse midgut.)
• Ter Veld 2005 FEBS J  + (Adaptations of the kinetic properties of m … Adaptations of the kinetic properties of mitochondria in striated muscle lacking cytosolic (M) and/or mitochondrial (mt) creatine kinase (CK) isoforms in comparison to wild-type (WT) were investigated ''in vitro''. Intact mitochondria were isolated from heart and gastrocnemius muscle of WT and single- and double CK-knock-out mice strains (cytosolic (M-CK^–/–), mitochondrial (mt-CK^–/–) and double knock-out (mtM-CK^–/–), respectively). Maximal ADP-stimulated oxygen consumption flux (State3 Vmax; nmol O2·mg mitochondrial protein^–1·min^–1) and ADP affinity (inline image; µm) were determined by respirometry. State 3 Vmax and inline image of M-CK^–/– and mtIM-CK^–/– gastrocnemius mitochondria were twofold higher than those of WT, but were unchanged for mt-CK^–/–. For mutant cardiac mitochondria, only the inline image of mitochondria isolated from the mtM-CK^–/– phenotype was different (i.e. twofold higher) than that of WT. The implications of these adaptations for striated muscle function were explored by constructing force-flow relations of skeletal muscle respiration. It was found that the identified shift in affinity towards higher ADP concentrations in mtM-CK^–/– muscle genotypes may contribute to linear mitochondrial control of the reduced cytosolic ATP free energy potentials in these phenotypes.lt;sup>–/–</sup> muscle genotypes may contribute to linear mitochondrial control of the reduced cytosolic ATP free energy potentials in these phenotypes.)
• Dogan 2014 Cell Metab  + (Adaptive stress responses activated upon m … Adaptive stress responses activated upon mitochondrial dysfunction are assumed to arise in order to counteract respiratory chain deficiency. Here, we demonstrate that loss of DARS2 (mitochondrial aspartyl-tRNA synthetase) leads to the activation of various stress responses in a tissue-specific manner independently of respiratory chain deficiency. DARS2 depletion in heart and skeletal muscle leads to the severe deregulation of mitochondrial protein synthesis followed by a strong respiratory chain deficit in both tissues, yet the activation of adaptive responses is observed predominantly in cardiomyocytes. We show that the impairment of mitochondrial proteostasis in the heart activates the expression of mitokine FGF21, which acts as a signal for cell-autonomous and systemic metabolic changes. Conversely, skeletal muscle has an intrinsic mechanism relying on the slow turnover of mitochondrial transcripts and higher proteostatic buffering capacity. Our results show that mitochondrial dysfunction is sensed independently of respiratory chain deficiency, questioning the current view on the role of stress responses in mitochondrial diseases.</br></br><small>Copyright © 2014 Elsevier Inc. All rights reserved.</small> 2014 Elsevier Inc. All rights reserved.</small>)
• Puigserver 1998 Cell  + (Adaptive thermogenesis is an important com … Adaptive thermogenesis is an important component of energy homeostasis and a metabolic defense against obesity. We have cloned a novel transcriptional coactivator of nuclear receptors, termed PGC-1, from a brown fat cDNA library. PGC-1 mRNA expression is dramatically elevated upon cold exposure of mice in both brown fat and skeletal muscle, key thermogenic tissues. PGC-1 greatly increases the transcriptional activity of PPARgamma and the thyroid hormone receptor on the uncoupling protein (UCP-1) promoter. Ectopic expression of PGC-1 in white adipose cells activates expression of UCP-1 and key mitochondrial enzymes of the respiratory chain, and increases the cellular content of mitochondrial DNA. These results indicate that PGC-1 plays a key role in linking nuclear receptors to the transcriptional program of adaptive thermogenesis.ptional program of adaptive thermogenesis.)