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Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

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Weidinger, Adelheid, Milivojev, Nadja, Hosmann, Arthur, Duvigneau, J. Catharina, Szabo, Csaba, Törö, Gabor, Rauter, Laurin, Vaglio-Garro, Annette +12 more·2023·Redox Biology
DOI 10.1016/j.redox.2023.102669PMC PMC10031542
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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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  • Endogenous NO serves as a posttranslational regulator of OGDHC and may affect toxic effects of glutamate.

    “Previous studies have shown that elevated levels of glutamate may upregulate the activity of OGDHC and that endogenous NO serves as a posttranslational regulator of OGDHC and may affect toxic effects of glutamate (Weidinger et al., 2023).”

    From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Weidinger et al., 2023

    The Results (page unavailable) report that glutamate treatment increased OGDHC activity and that NO inhibited it and increased glutamate-induced cell damage. The Discussion (page unavailable) links increased NO production to reduced OGDHC activity and toxic extracellular glutamate. Our copy does not establish that NO acts through a posttranslational modification of OGDHC, so that specific characterization is unsupported. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In primary neuronal cultures, glutamate toxicity primarily targets neurons, causing a marked reduction in tyrosine hydroxylase-positive neurons and neurite degeneration.

    “In primary neuronal cultures, it has been shown that glutamate toxicity primarily targets neurons, as evidenced by a marked reduction in the number of tyrosine hydroxylase-positive neurons together with neurite degeneration (Weidinger et al., 2023).”

    From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Weidinger et al., 2023

    The Results (Fig. 6; page not provided) report that glutamate reduced the number of tyrosine hydroxylase-positive neurons and shortened their neurites in primary murine mesencephalic cultures. The paper does not establish that glutamate primarily targets neurons rather than other cell types; that comparative part of the claim is unsupported. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Elevated levels of glutamate may upregulate the activity of OGDHC.

    “Previous studies have shown that elevated levels of glutamate may upregulate the activity of OGDHC and that endogenous NO serves as a posttranslational regulator of OGDHC and may affect toxic effects of glutamate (Weidinger et al., 2023).”

    From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Weidinger et al., 2023

  • Restoration of OGDHC activity attenuated glutamate-induced Ca2+ accumulation and neuronal cell death.

    “In a previous study, restoration of the mitochondrial enzyme complex oxoglutarate dehydrogenase complex (OGDHC) activity attenuated glutamate-induced Ca2+ accumulation and neuronal cell death (Weidinger et al., 2023), supporting a mechanistic link between glutamate metabolism, excitotoxic Ca2+ signaling, and neuronal survival.”

    From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Weidinger et al., 2023

  • Memantine, an NMDA receptor antagonist, protected neuronal primary cells from glutamate-induced death.

    “It has been shown that memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, protected neuronal primary cells from glutamate-induced death (Weidinger et al., 2023).”

    From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Weidinger et al., 2023

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Authors
Weidinger, A., Milivojev, N., Hosmann, A., Duvigneau, J. C., Szabo, C., Törö, G., Rauter, L., Vaglio-Garro, A., Mkrtchyan, G. V., Trofimova, L., Sharipov, R. R., Surin, A. M., Krasilnikova, I. A., Pinelis, V. G., Tretter, L., Moldzio, R., Bayır, H., Kagan, V. E., Bunik, V. I., & Kozlov, A. V.
Affiliations
  • Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA (AT)
  • Medical University of Vienna (AT)
  • University of Veterinary Medicine Vienna (AT)
  • Lomonosov Moscow State University (RU)
  • Research Institute of General Pathology and Pathophysiology, the Russian Academy of Medical Sciences (RU)
  • Ministry of Health of the Russian Federation (RU)
  • University of Pittsburgh (US)
  • Sechenov University (RU)
Corresponding author
Kozlov, Andrey V.
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2023-06
Volume
62
Pages
102669
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2023.102669
PMC
PMC10031542
OpenAlex
W4323928491
Cited by
45
References
6
Citations by year
2026: 11 · 2025: 15 · 2024: 14 · 2023: 5
FWCI
4.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Austrian Science Fund (33799)
  • National Institutes of Health (NS076511)
  • Ministry of Education and Science of the Russian Federation (FGFU-2022-0012, 0520-2019-0029)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
Keywords
2-oxoglutarate dehydrogenase, glutamate excitotoxicity, neuronal cell death, aneurysmal subarachnoid hemorrhage, nitric oxide, thiamine, mitochondrial respiration, TCA cycle, neuroinflammation, mitochondrial dysfunction, calcium influx, neurosurgical intensive care
MeSH terms
Animals, Cytoplasm, Ketoglutarate Dehydrogenase Complex, Mitochondria, Nitric Oxide, Retrospective Studies, Thiamine, Glutamic Acid, Rats

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