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Mitochondrial diaphorases as NAD + donors to segments of the citric acid cycle that support substrate‐level phosphorylation yielding ATP during respiratory inhibition
Author(s) -
Kiss Gergely,
Konrad Csaba,
PourGhaz Issa,
Mansour Josef J.,
Németh Béata,
Starkov Anatoly A.,
AdamVizi Vera,
Chinopoulos Christos
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-243030
Subject(s) - citric acid cycle , substrate (aquarium) , citric acid , nad+ kinase , chemistry , phosphorylation , oxidative phosphorylation , biochemistry , biology , enzyme , ecology
Substrate‐level phosphorylation mediated by succinyl‐CoA ligase in the mitochondrial matrix produces high‐energy phosphates in the absence of oxidative phosphorylation. Furthermore, when the electron transport chain is dysfunctional, provision of succinyl‐CoA by the a‐ketoglutarate dehydrogenase complex (KGDHC) is crucial for maintaining the function of succinyl‐CoA ligase yielding ATP, preventing the adenine nucleotide translocase from reversing. We addressed the source of the NAD + supply for KGDHC under anoxic conditions and inhibition of complex I. Using pharmacologic tools and specific substrates and by examining tissues from pigeon liver exhibiting no diaphorase activity, we showed that mitochondrial diaphorases in the mouse liver contribute up to 81% to the NAD + pool during respiratory inhibition. Under these conditions, KGDHC's function, essential for the provision of succinyl‐CoA to succinyl‐CoA ligase, is supported by NAD + derived from diaphorases. Through this process, diaphorases contribute to the maintenance of substrate‐level phosphorylation during respiratory inhibition, which is manifested in the forward operation of adenine nucleotide translocase. Finally, we show that reoxidation of the reducible substrates for the diaphorases is mediated by complex III of the respiratory chain.—Kiss, G., Konrad, C., Pour‐Ghaz, I., Mansour, J. J., Nemeth, B., Starkov, A A., Adam‐Vizi, V., Chinopoulos, C. Mitochondrial diaphorases as NAD + donors to segments of the citric acid cycle that support substrate‐level phosphorylation yielding ATP during respiratory inhibition. FASEB J. 28, 28–1682 (1697). www.fasebj.org