Mitochondrial hydrogen peroxide production by pyruvate dehydrogenase and α-ketoglutarate dehydrogenase in oxidative eustress and oxidative distress.
J Biol Chem
; 299(12): 105399, 2023 Dec.
Article
em En
| MEDLINE
| ID: mdl-37898400
ABSTRACT
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 (mH2O2) 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 â¼45% of the total mH2O2 formed by mitochondria and display rates of production several-fold higher than the canonical source complex I. This mH2O2 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 mH2O2 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 mH2O2 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 mH2O2, 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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Complexo Piruvato Desidrogenase
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Mitocôndrias Hepáticas
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Hepatócitos
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Peróxido de Hidrogênio
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Complexo Cetoglutarato Desidrogenase
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article