Title (en)
Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death
Language
English
Description (en)
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.
Keywords (en)
Nitric-Oxide; Excitotoxicity; Mitochondria; Vesicles; Pool
DOI
10.1016/j.redox.2023.102669
Author of the digital object
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)
Format
application/pdf
Size
819.4 kB
Licence Selected
CC BY 4.0 International
Type of publication
Article
Name of Publication (en)
Redox Biology
Pages or Volume
15
Volume
62
Publisher
Elsevier
Publication Date
2023
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Persistent identifier
DOI
https://phaidra.vetmeduni.ac.at/o:1640
https://doi.org/10.1016/j.redox.2023.102669 - DetailsObject typePDFDocumentFormatapplication/pdfCreated01.06.2023 08:35:17
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