Kiss 2014 FASEB J

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Kiss G, Konrad C, Pour-Ghaz I, Mansour JJ, Németh B, Starkov AA, Adam-Vizi V, Chinopoulos C (2014) Diaphorases provide NAD+ in anoxia. FASEB J 28:1682-97.

» PMID: 24391134

Kiss G, Konrad C, Pour-Ghaz I, Mansour JJ, Nemeth B, Starkov AA, Adam-Vizi V, Chinopoulos C (2014) FASEB J

Abstract: Substrate-level phosphorylation mediated by succinyl-CoA ligase in the mitochondrial matrix produces highenergy 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 maintained operation of succinyl-CoA ligase yielding ATP, preventing the adenine nucleotide translocase from reversing. Here we addressed the source of NAD+ supply for KGDHC under anoxic conditions and inhibition of complex I. Using pharmacological tools, specific substrates and by examining tissues from pigeon liver exhibiting no diaphorase activity we show that mitochondrial diaphorases in the mouse liver contributed up to 81% to the NAD+ pool during respiratory inhibition. Under these conditions, KGDHC function, essential for the provision of succinyl-CoA to succinyl-CoA ligase, is supported by NAD+ derived from diaphorases. By this, 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.

Keywords: Succinyl-CoA ligase, Adenine nucleotide translocase, DT-diaphorase, Reducing equivalent, Safranin

O2k-Network Lab: HU Budapest Chinopoulos C, HU Budapest Tretter L

Labels: MiParea: Respiration 

Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS 

HRR: Oxygraph-2k, O2k-Fluorometer, TPP