The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform
Christos Chinopoulos - One of the best experts on this subject based on the ideXlab platform.
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Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer.
Frontiers in nutrition, 2020Co-Authors: Thomas N. Seyfried, Purna Mukherjee, Miriam Kalamian, Mehmet Salih Iyikesici, Abdul Kadir Slocum, Jean-pierre Spinosa, Christos ChinopoulosAbstract:Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative Phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level Phosphorylation (fermentation) than on oxidative Phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level Phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.
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The Effect of 2-Ketobutyrate on Mitochondrial Substrate-Level Phosphorylation
Neurochemical Research, 2019Co-Authors: Dora Ravasz, Christos ChinopoulosAbstract:The reaction catalyzed by succinate-CoA ligase in the mitochondrial matrix yields a high-energy phosphate when operating towards hydrolysis of the thioester bond of succinyl-CoA, known as mitochondrial Substrate-Level Phosphorylation (mSLP). The catabolism of several metabolites converge to succinyl-CoA but through different biochemical pathways. Among them, threonine, serine and methionine catabolize to succinyl-CoA through the common intermediate, 2-ketobutyrate. During the course of this pathway 2-ketobutyrate will become succinyl-CoA through propionyl-CoA catabolism, obligatorily passing through an ATP-consuming step substantiated by propionyl-CoA carboxylase. Here, by recording the directionality of the adenine nucleotide translocase while measuring membrane potential we tested the hypothesis that catabolism of 2-ketobutyrate negates mSLP due to the ATP-consuming propionyl-CoA carboxylase step in rotenone-treated, isolated mouse liver and brain mitochondria. 2-Ketobutyrate produced a less negative membrane potential compared to NADH or FADH_2-linked substrates, which was sensitive to inhibition by rotenone, atpenin and arsenate, implying the involvement of complex I, complex II and a dehydrogenase—most likely branched chain keto-acid dehydrogenase, respectively. Co-addition of 2-ketobutyrate with NADH- or FADH_2-linked substrates yielded no greater membrane potential than in the presence of substrates alone. However, in the presence of NADH-linked substrates, 2-ketobutyrate prevented mSLP in a dose-dependent manner. Our results imply that despite that 2-ketobutyrate leads to succinyl-CoA formation, obligatory metabolism through propionyl-CoA carboxylase associated with ATP expenditure abolishes mSLP. The provision of metabolites converging to 2-ketobutyrate may be a useful way for manipulating mSLP without using pharmacological or genetic tools.
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Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis.
ASN neuro, 2018Co-Authors: Christos Chinopoulos, Thomas N. SeyfriedAbstract:Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers. Ultrastructural and biochemical evidence shows that GBM cells exhibit mitochondrial abnormalities ...
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OXPHOS Defects Due to mtDNA Mutations: Glutamine to the Rescue!
Cell metabolism, 2018Co-Authors: Christos ChinopoulosAbstract:Mutations in mtDNA associated with OXPHOS defects preclude energy harnessing by OXPHOS. The work of Chen et al. (2018) is previewed, reporting flux pathways of glutamine catabolism in mtDNA mutant cells yielding high-energy phosphates through Substrate-Level Phosphorylation and the influence exerted by the severity of OXPHOS impairment.
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Reduction of 2-methoxy-1,4-naphtoquinone by mitochondrially-localized Nqo1 yielding NAD+ supports Substrate-Level Phosphorylation during respiratory inhibition.
Biochimica et biophysica acta. Bioenergetics, 2018Co-Authors: Dora Ravasz, Gergely Kacso, Viktoria Fodor, Kata Horvath, Veronika Ádám-vizi, Christos ChinopoulosAbstract:Abstract Provision of NAD+ for oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA by the ketoglutarate dehydrogenase complex (KGDHC) is critical for maintained operation of succinyl-CoA ligase yielding high-energy phosphates, a process known as mitochondrial Substrate-Level Phosphorylation (mSLP). We have shown previously that when NADH oxidation by complex I is inhibited by rotenone or anoxia, mitochondrial diaphorases yield NAD+, provided that suitable quinones are present (Kiss G et al., FASEB J 2014, 28:1682). This allows for KGDHC reaction to proceed and as an extension of this, mSLP. NAD(P)H quinone oxidoreductase 1 (NQO1) is an enzyme exhibiting diaphorase activity. Here, by using Nqo1−/− and WT littermate mice we show that in rotenone-treated, isolated liver mitochondria 2-methoxy-1,4-naphtoquinone (MNQ) is preferentially reduced by matrix Nqo1 yielding NAD+ to KGDHC, supporting mSLP. This process was sensitive to inhibition by specific diaphorase inhibitors. Reduction of idebenone and its analogues MRQ-20 and MRQ-56, menadione, mitoquinone and duroquinone were unaffected by genetic disruption of the Nqo1 gene. The results allow for the conclusions that i) MNQ is a Nqo1-preferred substrate, and ii) in the presence of suitable quinones, mitochondrially-localized diaphorases other than Nqo1 support NADH oxidation when complex I is inhibited. Our work confirms that complex I bypass can occur by quinones reduced by intramitochondrial diaphorases oxidizing NADH, ultimately supporting mSLP. Finally, it may help to elucidate structure-activity relationships of redox-active quinones with diaphorase enzymes.
Thomas N. Seyfried - One of the best experts on this subject based on the ideXlab platform.
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Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer.
Frontiers in nutrition, 2020Co-Authors: Thomas N. Seyfried, Purna Mukherjee, Miriam Kalamian, Mehmet Salih Iyikesici, Abdul Kadir Slocum, Jean-pierre Spinosa, Christos ChinopoulosAbstract:Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative Phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level Phosphorylation (fermentation) than on oxidative Phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level Phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.
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Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis.
ASN neuro, 2018Co-Authors: Christos Chinopoulos, Thomas N. SeyfriedAbstract:Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers. Ultrastructural and biochemical evidence shows that GBM cells exhibit mitochondrial abnormalities ...
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Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis
SAGE Publishing, 2018Co-Authors: Christos Chinopoulos, Thomas N. SeyfriedAbstract:Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers. Ultrastructural and biochemical evidence shows that GBM cells exhibit mitochondrial abnormalities incompatible with energy production through oxidative Phosphorylation (OxPhos). Under such conditions, the mitochondrial F0-F1 ATP synthase operates in reverse at the expense of ATP hydrolysis to maintain a moderate membrane potential. Moreover, expression of the dimeric M2 isoform of pyruvate kinase in GBM results in diminished ATP output, precluding a significant ATP production from glycolysis. If ATP synthesis through both glycolysis and OxPhos was impeded, then where would GBM cells obtain high-energy phosphates for growth and invasion? Literature is reviewed suggesting that the succinate-CoA ligase reaction in the tricarboxylic acid cycle can substantiate sufficient ATP through mitochondrial Substrate-Level Phosphorylation (mSLP) to maintain GBM growth when OxPhos is impaired. Production of high-energy phosphates would be supported by glutaminolysis—a hallmark of GBM metabolism—through the sequential conversion of glutamine → glutamate → alpha-ketoglutarate → succinyl CoA → succinate. Equally important, provision of ATP through mSLP would maintain the adenine nucleotide translocase in forward mode , thus preventing the reverse-operating F0-F1 ATP synthase from depleting cytosolic ATP reserves. Because glucose and glutamine are the primary fuels driving the rapid growth of GBM and most tumors for that matter, simultaneous restriction of these two substrates or inhibition of mSLP should diminish cancer viability, growth, and invasion
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abstract 53 krebs cycle substrate level Phosphorylation drives metastatic cancer cells
Cancer Research, 2010Co-Authors: Laura M Shelton, Cheryl L Strelko, Mary F Roberts, Thomas N. SeyfriedAbstract:Many metastatic cancers are derived from compromised respiration in tissue cells of myeloid origin (e.g., macrophages), which use glutamine as a major energy substrate. Although impaired respiration can render tumor cells dependent on glycolysis for energy in the presence of oxygen (Warburg effect), it has not been determined if glutamine alone could provide enough energy (ATP) through substrate level Phosphorylation in the TCA (Krebs) cycle to maintain tumor cell viability. Using a bioluminescent-based ATP assay, we determined the viability of metastatic mouse VM-M3 tumor cells grown in serum free medium in the presence of glucose alone (25 mM), glutamine alone (4 mM), or in glucose + glutamine. The VM-M3 cells could not survive on glucose alone, but could survive in glutamine alone indicating an absolute requirement for glutamine in these metastatic tumor cells. Glucose + glutamine acted synergistically in providing growth and viability. Lactic acid production was 10-fold lower in the cells grown in glutamine alone than in glucose alone. Glutamine could also maintain viability in the absence of glucose and in the presence of the F1 ATPase inhibitor oligomycin. Glutamine could not maintain viability in the presence of the TCA cycle enzyme inhibitor, 3-Nitropropionic acid. NMR analysis indicated that glutamine metabolism via the TCA cycle was active resulting in accumulation of both succinate and aspartate. The data indicate that glutamine can provide ATP for viability in the metastatic VM-M3 cells through Krebs cycle Phosphorylation in the absence of energy from either glycolysis or oxidative Phosphorylation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 53.
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Cancer as a metabolic disease
Nutrition & Metabolism, 2010Co-Authors: Thomas N. Seyfried, Laura M SheltonAbstract:Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative Phosphorylation, most cancer cells become heavily dependent on substrate level Phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.
Michael Berger - One of the best experts on this subject based on the ideXlab platform.
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Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix Substrate-Level Phosphorylation arrest
eLife, 2020Co-Authors: Amijai Saragovi, Ori Toker, Eliran Arbib, Ibrahim Omar, Eyal Gottlieb, Ifat Abramovich, Michael BergerAbstract:Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions, including chronic obstructive pulmonary disease (COPD), and is associated with increased susceptibility to viral infections. However, the influence of SOR on T cell immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial-biogenesis in activated mouse CD8+ T cells. We find that low oxygen level diminishes CD8+ T cell anti-viral response in vivo. We reveal that respiratory restriction inhibits ATP-dependent matrix processes that are critical for mitochondrial-biogenesis. This respiratory restriction-mediated effect could be rescued by TCA cycle re-stimulation, which yielded increased mitochondrial matrix-localized ATP via Substrate-Level Phosphorylation. Finally, we demonstrate that the hypoxia-arrested CD8+ T cell anti-viral response could be rescued in vivo through brief exposure to atmospheric oxygen pressure. Overall, these findings elucidate the detrimental effect of hypoxia on mitochondrial-biogenesis in activated CD8+ T cells, and suggest a new approach for reducing viral infections in COPD.
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Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix Substrate-Level Phosphorylation arrest
2020Co-Authors: Michael Berger, Amijai Saragovi, Ifat Abramovitch, Ori Toker, Eliran Arbib, Ibrahim Omar, Eyal GottliebAbstract:Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions including chronic obstructive pulmonary disease (COPD). However, the influence of SOR on T cell protective immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells. We find that low oxygen diminishes CD8+ T cell viral response in vivo. Using genetic and pharmacological models, we demonstrate that respiratory restriction inhibits ATP dependent matrix processes, all critical for mitochondrial biogenesis. The effect mediated by respiratory restriction could be rescued by TCA cycle re-stimulation, which led to increased mitochondrial matrix localized ATP via Substrate-Level Phosphorylation. Finally, we demonstrate that short exposure to atmospheric oxygen pressure rescues the CD8+ viral response under systemic oxygen restriction in vivo. Our findings reveal the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells and provide a new approach for reducing viral infections in COPD.
Gergely Kiss - One of the best experts on this subject based on the ideXlab platform.
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abolition of mitochondrial substrate level Phosphorylation by itaconic acid produced by lps induced irg1 expression in cells of murine macrophage lineage
The FASEB Journal, 2016Co-Authors: Beata Nemeth, Gergely Kiss, Dora Ravasz, Judit Doczi, Gergely Kacso, Daniel Adams, Daniel Csete, Adam M Nagy, Gergo Horvath, Laszlo TretterAbstract:Itaconate is a nonamino organic acid exhibiting antimicrobial effects. It has been recently identified in cells of macrophage lineage as a product of an enzyme encoded by immunoresponsive gene 1 (Irg1), acting on the citric acid cycle intermediate cis-aconitate. In mitochondria, itaconate can be converted by succinate-coenzyme A (CoA) ligase to itaconyl-CoA at the expense of ATP (or GTP), and is also a weak competitive inhibitor of complex II. Here, we investigated specific bioenergetic effects of increased itaconate production mediated by LPS-induced stimulation of Irg1 in murine bone marrow-derived macrophages (BMDM) and RAW-264.7 cells. In rotenone-treated macrophage cells, stimulation by LPS led to impairment in Substrate-Level Phosphorylation (SLP) of in situ mitochondria, deduced by a reversal in the directionality of the adenine nucleotide translocase operation. In RAW-264.7 cells, the LPS-induced impairment in SLP was reversed by short-interfering RNA(siRNA)-but not scrambled siRNA-treatment directed against Irg1. LPS dose-dependently inhibited oxygen consumption rates (61-91%) and elevated glycolysis rates (>21%) in BMDM but not RAW-264.7 cells, studied under various metabolic conditions. In isolated mouse liver mitochondria treated with rotenone, itaconate dose-dependently (0.5-2 mM) reversed the operation of adenine nucleotide translocase, implying impairment in SLP, an effect that was partially mimicked by malonate. However, malonate yielded greater ADP-induced depolarizations (3-19%) than itaconate. We postulate that itaconate abolishes SLP due to 1) a "CoA trap" in the form of itaconyl-CoA that negatively affects the upstream supply of succinyl-CoA from the α-ketoglutarate dehydrogenase complex; 2) depletion of ATP (or GTP), which are required for the thioesterification by succinate-CoA ligase; and 3) inhibition of complex II leading to a buildup of succinate which shifts succinate-CoA ligase equilibrium toward ATP (or GTP) utilization. Our results support the notion that Irg1-expressing cells of macrophage lineage lose the capacity of mitochondrial SLP for producing itaconate during mounting of an immune defense.
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Abolition of mitochondrial substrate‐level Phosphorylation by itaconic acid produced by LPS‐induced Irg1 expression in cells of murine macrophage lineage
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015Co-Authors: Beata Nemeth, Gergely Kiss, Dora Ravasz, Judit Doczi, Gergely Kacso, Daniel Adams, Daniel Csete, Adam M Nagy, Gergo Horvath, Laszlo TretterAbstract:Itaconate is a nonamino organic acid exhibiting antimicrobial effects. It has been recently identified in cells of macrophage lineage as a product of an enzyme encoded by immunoresponsive gene 1 (Irg1), acting on the citric acid cycle intermediate cis-aconitate. In mitochondria, itaconate can be converted by succinate-coenzyme A (CoA) ligase to itaconyl-CoA at the expense of ATP (or GTP), and is also a weak competitive inhibitor of complex II. Here, we investigated specific bioenergetic effects of increased itaconate production mediated by LPS-induced stimulation of Irg1 in murine bone marrow-derived macrophages (BMDM) and RAW-264.7 cells. In rotenone-treated macrophage cells, stimulation by LPS led to impairment in Substrate-Level Phosphorylation (SLP) of in situ mitochondria, deduced by a reversal in the directionality of the adenine nucleotide translocase operation. In RAW-264.7 cells, the LPS-induced impairment in SLP was reversed by short-interfering RNA(siRNA)-but not scrambled siRNA-treatment directed against Irg1. LPS dose-dependently inhibited oxygen consumption rates (61-91%) and elevated glycolysis rates (>21%) in BMDM but not RAW-264.7 cells, studied under various metabolic conditions. In isolated mouse liver mitochondria treated with rotenone, itaconate dose-dependently (0.5-2 mM) reversed the operation of adenine nucleotide translocase, implying impairment in SLP, an effect that was partially mimicked by malonate. However, malonate yielded greater ADP-induced depolarizations (3-19%) than itaconate. We postulate that itaconate abolishes SLP due to 1) a "CoA trap" in the form of itaconyl-CoA that negatively affects the upstream supply of succinyl-CoA from the α-ketoglutarate dehydrogenase complex; 2) depletion of ATP (or GTP), which are required for the thioesterification by succinate-CoA ligase; and 3) inhibition of complex II leading to a buildup of succinate which shifts succinate-CoA ligase equilibrium toward ATP (or GTP) utilization. Our results support the notion that Irg1-expressing cells of macrophage lineage lose the capacity of mitochondrial SLP for producing itaconate during mounting of an immune defense.
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mitochondrial diaphorases as nad donors to segments of the citric acid cycle that support substrate level Phosphorylation yielding atp during respiratory inhibition
The FASEB Journal, 2014Co-Authors: Gergely Kiss, Csaba Konrad, Issa Pourghaz, Josef Mansou, Eata Nemeth, Anatoly A Starkov, Vera Adamvizi, Christos ChinopoulosAbstract:Substrate-Level Phosphorylation mediated by succinyl-CoA ligase in the mitochondrial matrix produces high-energy phosphates in the absence of oxidative Phosphorylation. Furthermore, when the electron transport chain is dysfunctional, provision of succinyl-CoA by the α-ketoglutarate dehydrogenase complex (KGDHC) is crucial for maintaining the function of succinyl-CoA ligase yielding ATP, preventing the adenine nucleotide translocase from reversing. We addressed the source of the NAD+ supply for KGDHC under anoxic conditions and inhibition of complex I. Using pharmacologic tools and specific substrates and by examining tissues from pigeon liver exhibiting no diaphorase activity, we showed that mitochondrial diaphorases in the mouse liver contribute up to 81% to the NAD+ pool during respiratory inhibition. Under these conditions, KGDHC's function, essential for the provision of succinyl-CoA to succinyl-CoA ligase, is supported by NAD+ derived from diaphorases. Through this process, diaphorases contribute to the maintenance of Substrate-Level Phosphorylation during respiratory inhibition, which is manifested in the forward operation of adenine nucleotide translocase. Finally, we show that reoxidation of the reducible substrates for the diaphorases is mediated by complex III of the respiratory chain.—Kiss, G., Konrad, C., Pour-Ghaz, I., Mansour, J. J., Nemeth, B., Starkov, A. A., Adam-Vizi, V., Chinopoulos, C. Mitochondrial diaphorases as NAD+ donors to segments of the citric acid cycle that support Substrate-Level Phosphorylation yielding ATP during respiratory inhibition.
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the negative impact of α ketoglutarate dehydrogenase complex deficiency on matrix substrate level Phosphorylation
The FASEB Journal, 2013Co-Authors: Gergely Kiss, Csaba Konrad, Anatoly A Starkov, Judit Doczi, Hibiki Kawamata, Giovanni Manfredi, Steven F Zhang, Gary E Gibson, Flint M Beal, Vera AdamviziAbstract:A decline in α-ketoglutarate dehydrogenase complex (KGDHC) activity has been associated with neurodegeneration. Provision of succinyl-CoA by KGDHC is essential for generation of matrix ATP (or GTP) by Substrate-Level Phosphorylation catalyzed by succinyl-CoA ligase. Here, we demonstrate ATP consumption in respiration-impaired isolated and in situ neuronal somal mitochondria from transgenic mice with a deficiency of either dihydrolipoyl succinyltransferase (DLST) or dihydrolipoyl dehydrogenase (DLD) that exhibit a 20–48% decrease in KGDHC activity. Import of ATP into the mitochondrial matrix of transgenic mice was attributed to a shift in the reversal potential of the adenine nucleotide translocase toward more negative values due to diminished matrix Substrate-Level Phosphorylation, which causes the translocase to reverse prematurely. Immunoreactivity of all three subunits of succinyl-CoA ligase and maximal enzymatic activity were unaffected in transgenic mice as compared to wild-type littermates. Therefor...
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forward operation of adenine nucleotide translocase during f0f1 atpase reversal critical role of matrix substrate level Phosphorylation
The FASEB Journal, 2010Co-Authors: Christos Chinopoulos, Gergely Kiss, Csaba Konrad, Judit Doczi, Akos A Gerencser, Miklos Mandi, Katalin Mathe, Beata Torocsik, Lilla Turiak, Szilvia VajdaAbstract:In pathological conditions, F(0)F(1)-ATPase hydrolyzes ATP in an attempt to maintain mitochondrial membrane potential. Using thermodynamic assumptions and computer modeling, we established that mitochondrial membrane potential can be more negative than the reversal potential of the adenine nucleotide translocase (ANT) but more positive than that of the F(0)F(1)-ATPase. Experiments on isolated mitochondria demonstrated that, when the electron transport chain is compromised, the F(0)F(1)-ATPase reverses, and the membrane potential is maintained as long as matrix Substrate-Level Phosphorylation is functional, without a concomitant reversal of the ANT. Consistently, no cytosolic ATP consumption was observed using plasmalemmal K(ATP) channels as cytosolic ATP biosensors in cultured neurons, in which their in situ mitochondria were compromised by respiratory chain inhibitors. This finding was further corroborated by quantitative measurements of mitochondrial membrane potential, oxygen consumption, and extracellular acidification rates, indicating nonreversal of ANT of compromised in situ neuronal and astrocytic mitochondria; and by bioluminescence ATP measurements in COS-7 cells transfected with cytosolic- or nuclear-targeted luciferases and treated with mitochondrial respiratory chain inhibitors in the presence of glycolytic plus mitochondrial vs. only mitochondrial substrates. Our findings imply the possibility of a rescue mechanism that is protecting against cytosolic/nuclear ATP depletion under pathological conditions involving impaired respiration. This mechanism comes into play when mitochondria respire on substrates that support matrix Substrate-Level Phosphorylation.
Amijai Saragovi - One of the best experts on this subject based on the ideXlab platform.
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Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix Substrate-Level Phosphorylation arrest
eLife, 2020Co-Authors: Amijai Saragovi, Ori Toker, Eliran Arbib, Ibrahim Omar, Eyal Gottlieb, Ifat Abramovich, Michael BergerAbstract:Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions, including chronic obstructive pulmonary disease (COPD), and is associated with increased susceptibility to viral infections. However, the influence of SOR on T cell immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial-biogenesis in activated mouse CD8+ T cells. We find that low oxygen level diminishes CD8+ T cell anti-viral response in vivo. We reveal that respiratory restriction inhibits ATP-dependent matrix processes that are critical for mitochondrial-biogenesis. This respiratory restriction-mediated effect could be rescued by TCA cycle re-stimulation, which yielded increased mitochondrial matrix-localized ATP via Substrate-Level Phosphorylation. Finally, we demonstrate that the hypoxia-arrested CD8+ T cell anti-viral response could be rescued in vivo through brief exposure to atmospheric oxygen pressure. Overall, these findings elucidate the detrimental effect of hypoxia on mitochondrial-biogenesis in activated CD8+ T cells, and suggest a new approach for reducing viral infections in COPD.
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Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix Substrate-Level Phosphorylation arrest
2020Co-Authors: Michael Berger, Amijai Saragovi, Ifat Abramovitch, Ori Toker, Eliran Arbib, Ibrahim Omar, Eyal GottliebAbstract:Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions including chronic obstructive pulmonary disease (COPD). However, the influence of SOR on T cell protective immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells. We find that low oxygen diminishes CD8+ T cell viral response in vivo. Using genetic and pharmacological models, we demonstrate that respiratory restriction inhibits ATP dependent matrix processes, all critical for mitochondrial biogenesis. The effect mediated by respiratory restriction could be rescued by TCA cycle re-stimulation, which led to increased mitochondrial matrix localized ATP via Substrate-Level Phosphorylation. Finally, we demonstrate that short exposure to atmospheric oxygen pressure rescues the CD8+ viral response under systemic oxygen restriction in vivo. Our findings reveal the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells and provide a new approach for reducing viral infections in COPD.
