Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

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Standard

Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death. / Weidinger, Adelheid; Milivojev, Nadja; Hosmann, Arthur; Duvigneau, J. Catharina; Szabo, Csaba; Törö, Gabor; Rauter, Laurin; Vaglio-Garro, Annette; Mkrtchyan, Garik V.; Trofimova, Lidia; Sharipov, Rinat R.; Surin, Alexander M.; Krasilnikova, Irina A.; Pinelis, Vsevolod G.; Tretter, Laszlo; Moldzio, Rudolf; Bayır, Hülya; Kagan, Valerian E.; Bunik, Victoria I.; Kozlov, Andrey V.

I: Redox Biology, Bind 62, 102669, 2023.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Weidinger, A, Milivojev, N, Hosmann, A, Duvigneau, JC, Szabo, C, Törö, G, Rauter, L, Vaglio-Garro, A, Mkrtchyan, GV, Trofimova, L, Sharipov, RR, Surin, AM, Krasilnikova, IA, Pinelis, VG, Tretter, L, Moldzio, R, Bayır, H, Kagan, VE, Bunik, VI & Kozlov, AV 2023, 'Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death', Redox Biology, bind 62, 102669. https://doi.org/10.1016/j.redox.2023.102669

APA

Weidinger, A., Milivojev, N., Hosmann, A., Duvigneau, J. C., Szabo, C., Törö, G., Rauter, L., Vaglio-Garro, A., Mkrtchyan, G. V., Trofimova, L., Sharipov, R. R., Surin, A. M., Krasilnikova, I. A., Pinelis, V. G., Tretter, L., Moldzio, R., Bayır, H., Kagan, V. E., Bunik, V. I., & Kozlov, A. V. (2023). Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death. Redox Biology, 62, [102669]. https://doi.org/10.1016/j.redox.2023.102669

Vancouver

Weidinger A, Milivojev N, Hosmann A, Duvigneau JC, Szabo C, Törö G o.a. Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death. Redox Biology. 2023;62. 102669. https://doi.org/10.1016/j.redox.2023.102669

Author

Weidinger, Adelheid ; Milivojev, Nadja ; Hosmann, Arthur ; Duvigneau, J. Catharina ; Szabo, Csaba ; Törö, Gabor ; Rauter, Laurin ; Vaglio-Garro, Annette ; Mkrtchyan, Garik V. ; Trofimova, Lidia ; Sharipov, Rinat R. ; Surin, Alexander M. ; Krasilnikova, Irina A. ; Pinelis, Vsevolod G. ; Tretter, Laszlo ; Moldzio, Rudolf ; Bayır, Hülya ; Kagan, Valerian E. ; Bunik, Victoria I. ; Kozlov, Andrey V. / Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death. I: Redox Biology. 2023 ; Bind 62.

Bibtex

@article{11f9d71b9a834ed1bb2510315730b158,
title = "Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death",
abstract = "Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. The aim of this study was to investigate the impact of these mechanisms on neuronal death. Patients from the neurosurgical intensive care unit suffering aneurysmal subarachnoid hemorrhage (SAH) were recruited retrospectively from a respective database. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methods including high resolution respirometry, electron spin resonance, fluorescent microscopy, kinetic determination of enzymatic activities and immunocytochemistry. We found that elevated levels of extracellular glutamate and nitric oxide (NO) metabolites correlated with poor clinical outcome in patients with SAH. In experiments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of the tricarboxylic acid (TCA) cycle, is more susceptible to the inhibition by NO than mitochondrial respiration. Inhibition of OGDHC by NO or by succinyl phosphonate (SP), a highly specific OGDHC inhibitor, caused accumulation of extracellular glutamate and neuronal death. Extracellular nitrite did not substantially contribute to this NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutary effect of TH against glutamate toxicity was confirmed in three different cell lines. Our data suggest that the loss of control over extracellular glutamate, as described here, rather than commonly assumed impaired energy metabolism, is the critical pathological manifestation of insufficient OGDHC activity, leading to neuronal death.",
author = "Adelheid Weidinger and Nadja Milivojev and Arthur Hosmann and Duvigneau, {J. Catharina} and Csaba Szabo and Gabor T{\"o}r{\"o} and Laurin Rauter and Annette Vaglio-Garro and Mkrtchyan, {Garik V.} and Lidia Trofimova and Sharipov, {Rinat R.} and Surin, {Alexander M.} and Krasilnikova, {Irina A.} and Pinelis, {Vsevolod G.} and Laszlo Tretter and Rudolf Moldzio and H{\"u}lya Bayır and Kagan, {Valerian E.} and Bunik, {Victoria I.} and Kozlov, {Andrey V.}",
note = "Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
doi = "10.1016/j.redox.2023.102669",
language = "English",
volume = "62",
journal = "Redox Biology",
issn = "2213-2317",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

AU - Weidinger, Adelheid

AU - Milivojev, Nadja

AU - Hosmann, Arthur

AU - Duvigneau, J. Catharina

AU - Szabo, Csaba

AU - Törö, Gabor

AU - Rauter, Laurin

AU - Vaglio-Garro, Annette

AU - Mkrtchyan, Garik V.

AU - Trofimova, Lidia

AU - Sharipov, Rinat R.

AU - Surin, Alexander M.

AU - Krasilnikova, Irina A.

AU - Pinelis, Vsevolod G.

AU - Tretter, Laszlo

AU - Moldzio, Rudolf

AU - Bayır, Hülya

AU - Kagan, Valerian E.

AU - Bunik, Victoria I.

AU - Kozlov, Andrey V.

N1 - Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

N2 - Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. The aim of this study was to investigate the impact of these mechanisms on neuronal death. Patients from the neurosurgical intensive care unit suffering aneurysmal subarachnoid hemorrhage (SAH) were recruited retrospectively from a respective database. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methods including high resolution respirometry, electron spin resonance, fluorescent microscopy, kinetic determination of enzymatic activities and immunocytochemistry. We found that elevated levels of extracellular glutamate and nitric oxide (NO) metabolites correlated with poor clinical outcome in patients with SAH. In experiments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of the tricarboxylic acid (TCA) cycle, is more susceptible to the inhibition by NO than mitochondrial respiration. Inhibition of OGDHC by NO or by succinyl phosphonate (SP), a highly specific OGDHC inhibitor, caused accumulation of extracellular glutamate and neuronal death. Extracellular nitrite did not substantially contribute to this NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutary effect of TH against glutamate toxicity was confirmed in three different cell lines. Our data suggest that the loss of control over extracellular glutamate, as described here, rather than commonly assumed impaired energy metabolism, is the critical pathological manifestation of insufficient OGDHC activity, leading to neuronal death.

AB - Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. The aim of this study was to investigate the impact of these mechanisms on neuronal death. Patients from the neurosurgical intensive care unit suffering aneurysmal subarachnoid hemorrhage (SAH) were recruited retrospectively from a respective database. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methods including high resolution respirometry, electron spin resonance, fluorescent microscopy, kinetic determination of enzymatic activities and immunocytochemistry. We found that elevated levels of extracellular glutamate and nitric oxide (NO) metabolites correlated with poor clinical outcome in patients with SAH. In experiments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of the tricarboxylic acid (TCA) cycle, is more susceptible to the inhibition by NO than mitochondrial respiration. Inhibition of OGDHC by NO or by succinyl phosphonate (SP), a highly specific OGDHC inhibitor, caused accumulation of extracellular glutamate and neuronal death. Extracellular nitrite did not substantially contribute to this NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutary effect of TH against glutamate toxicity was confirmed in three different cell lines. Our data suggest that the loss of control over extracellular glutamate, as described here, rather than commonly assumed impaired energy metabolism, is the critical pathological manifestation of insufficient OGDHC activity, leading to neuronal death.

U2 - 10.1016/j.redox.2023.102669

DO - 10.1016/j.redox.2023.102669

M3 - Journal article

C2 - 36933393

AN - SCOPUS:85150029515

VL - 62

JO - Redox Biology

JF - Redox Biology

SN - 2213-2317

M1 - 102669

ER -

ID: 373026731