phaidra.vetmeduni.ac.at o:1640 DOI 10.1016/j.redox.2023.102669 Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death 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. eng Nitric-Oxide; Excitotoxicity; Mitochondria; Vesicles; Pool 2023-06-01T08:46:13.868Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Weidinger;Adelheid; FN:Adelheid Weidinger END:VCARD BEGIN:VCARD VERSION:3.0 N:Kozlov;Andrey V.; FN:Andrey V. Kozlov END:VCARD BEGIN:VCARD VERSION:3.0 N:Bunik;Victoria I.; FN:Victoria I. Bunik END:VCARD BEGIN:VCARD VERSION:3.0 N:Kagan;Valerian E.; FN:Valerian E. Kagan END:VCARD BEGIN:VCARD VERSION:3.0 N:Bayır;Hülya; FN:Hülya Bayır END:VCARD BEGIN:VCARD VERSION:3.0 N:Moldzio;Rudolf; FN:Rudolf Moldzio X-ORCID:https://orcid.org/0000-0002-1597-8402 END:VCARD BEGIN:VCARD VERSION:3.0 N:Tretter;Laszlo; FN:Laszlo Tretter END:VCARD BEGIN:VCARD VERSION:3.0 N:Pinelis;Vsevolod G; FN:Vsevolod G Pinelis END:VCARD BEGIN:VCARD VERSION:3.0 N:Krasilnikova;Irina A; FN:Irina A Krasilnikova END:VCARD BEGIN:VCARD VERSION:3.0 N:Surin;Alexander M; FN:Alexander M Surin END:VCARD BEGIN:VCARD VERSION:3.0 N:Sharipov;Rinat R; FN:Rinat R Sharipov END:VCARD BEGIN:VCARD VERSION:3.0 N:Trofimova;Lidia; FN:Lidia Trofimova END:VCARD BEGIN:VCARD VERSION:3.0 N:Mkrtchyan;Garik V; FN:Garik V Mkrtchyan END:VCARD BEGIN:VCARD VERSION:3.0 N:Vaglio-Garro;Annette; FN:Annette Vaglio-Garro END:VCARD BEGIN:VCARD VERSION:3.0 N:Rauter;Laurin; FN:Laurin Rauter END:VCARD BEGIN:VCARD VERSION:3.0 N:Törö;Gabor; FN:Gabor Törö END:VCARD BEGIN:VCARD VERSION:3.0 N:Szabo;Csaba; FN:Csaba Szabo END:VCARD BEGIN:VCARD VERSION:3.0 N:Duvigneau;J. Catharina; FN:J. Catharina Duvigneau END:VCARD BEGIN:VCARD VERSION:3.0 N:Hosmann;Arthur; FN:Arthur Hosmann END:VCARD BEGIN:VCARD VERSION:3.0 N:Milivojev;Nadja; FN:Nadja Milivojev END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 839039 https://phaidra.vetmeduni.ac.at/o:1640 https://phaidra.vetmeduni.ac.at/api/object/o:1640/thumbnail LOMv1.0 discipline