Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death
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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.
Originalsprog | Engelsk |
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Artikelnummer | 102669 |
Tidsskrift | Redox Biology |
Vol/bind | 62 |
Antal sider | 15 |
ISSN | 2213-2317 |
DOI | |
Status | Udgivet - 2023 |
Eksternt udgivet | Ja |
Bibliografisk note
Funding Information:
The authors acknowledge Dr. Helmut Kubista and Dr. Matej Hotka for stimulating discussions and Arina E. Zgodova for technical support in culturing cortical neurons. This study was supported by Austrian Science Fund (FWF) , project #p33799 given to AVK; and by Ministry of Science and Higher Education of the Russian Federation 0520-2019-0029 to V.G.P., I.A.K., A.M.S. and a State Task FGFU-2022-0012 to R.R.S. and A.M.S; and by National Institutes of Health . NS076511 to H.B. and V.E.K.
Funding Information:
The authors acknowledge Dr. Helmut Kubista and Dr. Matej Hotka for stimulating discussions and Arina E. Zgodova for technical support in culturing cortical neurons. This study was supported by Austrian Science Fund (FWF), project #p33799 given to AVK; and by Ministry of Science and Higher Education of the Russian Federation 0520-2019-0029 to V.G.P. I.A.K. A.M.S. and a State Task FGFU-2022-0012 to R.R.S. and A.M.S; and by National Institutes of Health. NS076511 to H.B. and V.E.K.
Publisher Copyright:
© 2023 The Authors
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