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- Title
Mitochondrial diaphorases as NAD<sup>+</sup> donors to segments of the citric acid cycle that support substrate-level phosphorylation yielding ATP during respiratory inhibition.
- Authors
Kiss, Gergely; Konrad, Csaba; Pour-Ghaz, Issa; Mansour, Josef J.; Németh, Beata; Starkov, Anatoly A.; Adam-Vizi, Vera; Chinopoulos, Christos
- Abstract
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 α-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., Németh, 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.
- Subjects
MITOCHONDRIA; NAD (Coenzyme); ADENOSINE triphosphate; KREBS cycle; BIOCHEMICAL substrates; PHOSPHORYLATION; SUCCINYL-CoA synthetase
- Publication
FASEB Journal, 2014, Vol 28, Issue 4, p1682
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.13-243030