Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

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

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.

Original languageEnglish
Article number102669
JournalRedox Biology
Number of pages15
Publication statusPublished - 2023
Externally publishedYes

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