Mitochondrial hydrogen peroxide production by pyruvate dehydrogenase and α-ketoglutarate dehydrogenase in oxidative eustress and oxidative distress.

Autor: Chalifoux O; Faculty of Agricultural and Environmental Sciences, The School of Human Nutrition, McGill University, Ste.-Anne-de-Bellevue, Quebec, Canada., Faerman B; Faculty of Agricultural and Environmental Sciences, The School of Human Nutrition, McGill University, Ste.-Anne-de-Bellevue, Quebec, Canada., Mailloux RJ; Faculty of Agricultural and Environmental Sciences, The School of Human Nutrition, McGill University, Ste.-Anne-de-Bellevue, Quebec, Canada. Electronic address: ryan.mailloux@mcgill.ca.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2023 Dec; Vol. 299 (12), pp. 105399. Date of Electronic Publication: 2023 Oct 28.
DOI: 10.1016/j.jbc.2023.105399
Abstrakt: Pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) are vital entry points for monosaccharides and amino acids into the Krebs cycle and thus integral for mitochondrial bioenergetics. Both complexes produce mitochondrial hydrogen peroxide (mH 2 O 2 ) and are deactivated by electrophiles. Here, we provide an update on the role of PDH and KGDH in mitochondrial redox balance and their function in facilitating metabolic reprogramming for the propagation of oxidative eustress signals in hepatocytes and how defects in these pathways can cause liver diseases. PDH and KGDH are known to account for ∼45% of the total mH 2 O 2 formed by mitochondria and display rates of production several-fold higher than the canonical source complex I. This mH 2 O 2 can also be formed by reverse electron transfer (RET) in vivo, which has been linked to metabolic dysfunctions that occur in pathogenesis. However, the controlled emission of mH 2 O 2 from PDH and KGDH has been proposed to be fundamental for oxidative eustress signal propagation in several cellular contexts. Modification of PDH and KGDH with protein S-glutathionylation (PSSG) and S-nitrosylation (PSNO) adducts serves as a feedback inhibitor for mH 2 O 2 production in response to glutathione (GSH) pool oxidation. PSSG and PSNO adduct formation also reprogram the Krebs cycle to generate metabolites vital for interorganelle and intercellular signaling. Defects in the redox modification of PDH and KGDH cause the over generation of mH 2 O 2 , resulting in oxidative distress and metabolic dysfunction-associated fatty liver disease (MAFLD). In aggregate, PDH and KGDH are essential platforms for emitting and receiving oxidative eustress signals.
Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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