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Cited by 19Biochemical Acid Research StudiesMetabolism and Genetic DisordersAmino Acid Enzymes and Metabolism

Exclusive neuronal detection of KGDHC-specific subunits in the adult human brain cortex despite pancellular protein lysine succinylation

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Dobolyi, Arpad, Bago, Attila, Palkovits, Miklos, Nemeria, Natalia S., Jordan, Frank, Doczi, Judit, Ambrus, Attila, Adam-Vizi, Vera +1 more·2020·Brain Structure and Function
DOI 10.1007/s00429-020-02026-5PMC PMC7046601
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Abstract

The ketoglutarate dehydrogenase complex (KGDHC) consists of three different subunits encoded by OGDH (or OGDHL), DLST, and DLD, combined in different stoichiometries. DLD subunit is shared between KGDHC and pyruvate dehydrogenase complex, branched-chain alpha-keto acid dehydrogenase complex, and the glycine cleavage system. Despite KGDHC’s implication in neurodegenerative diseases, cell-specific localization of its subunits in the adult human brain has never been investigated. Here, we show that immunoreactivity of all known isoforms of OGDHL, OGDH, and DLST was detected exclusively in neurons of surgical human cortical tissue samples identified by their morphology and visualized by double labeling with fluorescent Nissl, while being absent from glia expressing GFAP, Aldhl1, myelin basic protein, Olig2, or IBA1. In contrast, DLD immunoreactivity was evident in both neurons and glia. Specificity of anti-KGDHC subunits antisera was verified by a decrease in staining of siRNA-treated human cancer cell lines directed against the respective coding gene products; furthermore, immunoreactivity of KGDHC subunits in human fibroblasts co-localized > 99% with mitotracker orange, while western blotting of 63 post-mortem brain samples and purified recombinant proteins afforded further assurance regarding antisera monospecificity. KGDHC subunit immunoreactivity correlated with data from the Human Protein Atlas as well as RNA-Seq data from the Allen Brain Atlas corresponding to genes coding for KGDHC components. Protein lysine succinylation, however, was immunohistochemically evident in all cortical cells; this was unexpected, because this posttranslational modification requires succinyl-CoA, the product of KGDHC. In view of the fact that glia of the human brain cortex lack succinate-CoA ligase, an enzyme producing succinyl-CoA when operating in reverse, protein lysine succinylation in these cells must exclusively rely on propionate and/or ketone body metabolism or some other yet to be discovered pathway encompassing succinyl-CoA.

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  • The pathway of glutamate into the TCA cycle mainly occurs in neurons.

    “This pathway mainly occurs in neurons (Dobolyi et al., 2020; Zhong et al., 2022), and OGDHC is a limiting step in this process (Mkrtchyan et al., 2018).”

    From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Dobolyi et al., 2020

    The Results section proposes that neuronal mitochondria perform the conventional TCA cycle, while glia in the adult human cortex process glutamate through other routes. The Discussion says the apparent lack of KGDHC in human glia may prevent glutamate catabolism through the TCA cycle. This supports the neuron–glia distinction, but the source frames it as a proposal about adult human cortex, not an established general rule for all neurons. (LLM, conf=0.83)

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Authors
Dobolyi, A., Bago, A., Palkovits, M., Nemeria, N. S., Jordan, F., Doczi, J., Ambrus, A., Adam-Vizi, V., & Chinopoulos, C.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • Semmelweis University (HU)
Corresponding author
Chinopoulos, Christos
ORCID
Venue
Brain Structure and Function
Publisher
Springer Science and Business Media LLC
Published
2020-01-25
Volume
225
Issue
2
Pages
639-667
ISSN
  • 1863-2653 (ISSN-L)
  • 1863-2661
DOI
10.1007/s00429-020-02026-5
PMC
PMC7046601
OpenAlex
W3002303898
Cited by
19
References
5
Citations by year
2026: 1 · 2025: 4 · 2024: 7 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1
FWCI
0.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Structure and Function (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Semmelweis University Repository (Semmelweis University) (submittedVersion)
Funders
  • National Institutes of Health (GM050380, GM116077)
  • Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal (112230, 4300-1/2017-NKP, VEKOP 2.3.3-15-2016-00012, 2017-2.3.4-TET-RU-2017-00003, KH129567, 61822-64888-EATV)
  • Magyar Tudományos Akadémia (02001)
  • Hungarian Brain Research Program (KTIA_13_NAP-A-III/6)
  • National Research, Development and Innovation Office (2017-1.2.1-NKP-2017-00002)
  • Nemzeti Kutatási Fejlesztési és Innovációs Hivatal (FIKP 61822 64860 EATV)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
2-oxoglutarate dehydrogenase, OGDHL, DLST, DLD, neuronal localization, cerebral cortex, succinyl-CoA, glial cells, pyruvate dehydrogenase complex, post-translational modification, neurodegenerative diseases
MeSH terms
Acyl Coenzyme A, Cells, Cultured, Cerebral Cortex, Female, Humans, Ketoglutarate Dehydrogenase Complex, Lysine, Male, Neuroglia, Neurons, Protein Isoforms, Protein Subunits

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