2. Academic Validation
  3. Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

  • Redox Biol. 2023 Jun:62:102669. doi: 10.1016/j.redox.2023.102669.
Adelheid Weidinger 1,  Nadja Milivojev 2,  Arthur Hosmann 3,  J Catharina Duvigneau 4,  Csaba Szabo 5,  Gabor Törö 6,  Laurin Rauter 2,  Annette Vaglio-Garro 1,  Garik V Mkrtchyan 7,  Lidia Trofimova 8,  Rinat R Sharipov 9,  Alexander M Surin 10,  Irina A Krasilnikova 11,  Vsevolod G Pinelis 11,  Laszlo Tretter 12,  Rudolf Moldzio 4,  Hülya Bayır 13,  Valerian E Kagan 14,  Victoria I Bunik 15,  Andrey V Kozlov 16
Affiliations

Affiliations

  • 1 Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria.
  • 2 Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria.
  • 3 Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
  • 4 Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria.
  • 5 University of Fribourg, Section of Science and Medicine, Department of Oncology, Microbiology and Immunology, Section of Pharmacology, Fribourg, Switzerland; Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.
  • 6 Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.
  • 7 A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119234, Moscow, Russia.
  • 8 Biological Faculty, Department of Biophysics, Lomonosov Moscow State University, Moscow, Russia.
  • 9 Institute of General Pathology and Pathophysiology, Laboratory of Fundamental and Applied Problems of Pain, Moscow, Russia.
  • 10 Institute of General Pathology and Pathophysiology, Laboratory of Fundamental and Applied Problems of Pain, Moscow, Russia; National Medical Research Center of Children's Health, Russian Ministry of Health, Laboratory of Neurobiology and Brain Development, Moscow, Russia.
  • 11 National Medical Research Center of Children's Health, Russian Ministry of Health, Laboratory of Neurobiology and Brain Development, Moscow, Russia.
  • 12 Department of Biochemistry, Semmelweis University, Budapest, Hungary.
  • 13 Departments of Environmental and Occupational Health, Pharmacology and Chemical Biology, Chemistry and Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, PA, USA; Department of Critical Care Medicine, Safar Center for Resuscitation Research, Children's Neuroscience Institute, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
  • 14 Departments of Environmental and Occupational Health, Pharmacology and Chemical Biology, Chemistry and Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, PA, USA.
  • 15 A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119234, Moscow, Russia; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia; Department of Biochemistry, Sechenov University, Moscow, Russia.
  • 16 Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria. Electronic address: [email protected].
PMID: 36933393 DOI: 10.1016/j.redox.2023.102669
Abstract

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.

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