Titel (eng)

Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

Autor*in

Adelheid Weidinger   Ludwig Boltzmann Institute for Traumatology

Andrey V. Kozlov   Ludwig Boltzmann Institute for Traumatology

Victoria I. Bunik   Lomonosov Moscow State University / Sechenov University

Valerian E. Kagan   University of Pittsburgh

Hülya Bayır   University of Pittsburgh

Rudolf Moldzio   University of Veterinary Medicine Vienna

Laszlo Tretter   Semmelweis University

Vsevolod G Pinelis

Irina A Krasilnikova

Alexander M Surin

Rinat R Sharipov

Lidia Trofimova   Lomonosov Moscow State University

Garik V Mkrtchyan   Lomonosov Moscow State University

Annette Vaglio-Garro   Ludwig Boltzmann Institute for Traumatology

Laurin Rauter   Ludwig Boltzmann Institute for Traumatology

Gabor Törö   University of Texas

Csaba Szabo   University of Fribourg / University of Texas

J. Catharina Duvigneau   University of Veterinary Medicine Vienna

Arthur Hosmann   Medical University of Vienna

Nadja Milivojev   Ludwig Boltzmann Institute for Traumatology

Verlag

Elsevier

Beschreibung (eng)

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.

Sprache des Objekts

Englisch

Datum

2023

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Nitric-Oxide; Excitotoxicity; Mitochondria; Vesicles; Pool

Mitglied in der/den Collection(s) (1)