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Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal deathстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или Scopus- Авторы: 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, Hülya Bayır, Kagan Valerian E., Bunik Victoria I., Kozlov Andrey V.
- Журнал: Redox Biology
- Том: 62
- Год издания: 2023
- Первая страница: 1
- Последняя страница: 15
- Номер статьи: 102669
- DOI: 10.1016/j.redox.2023.102669
- Аннотация: Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. Theaim 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 respectivedatabase. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methodsincluding 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 ex-periments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of thetricarboxylic 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 tothis NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutaryeffect 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 criticalpathological manifestation of insufficient OGDHC activity, leading to neuronal death
- Добавил в систему: Буник-Фаренвальд Виктория-Лариса Ивановна