Reverse flux through cardiac NADP + -isocitrate dehydrogenase under normoxia and ischemia

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Comte, Blandine | Vincent, Geneviève | Bouchard, Bertrand | Benderdour, Mohamed | Des Rosiers, Christine

Edité par CCSD ; American Physiological Society -

International audience. Little is known about the role of mitochondrial NADP + -isocitrate dehydrogenase (NADP + -ICDH) in the heart, where this enzyme shows its highest expression and activity. We tested the hypothesis that in the heart, NADP + -ICDH operates in the reverse direction of the citric acid cycle (CAC) and thereby may contribute to the fine regulation of CAC activity (Sazanov and Jackson, FEBS Lett344: 109–116, 1994). We documented a reverse flux through this enzyme in rat hearts perfused with the medium-chain fatty acid octanoate using [U- 13 C 5 ]glutamate and mass isotopomer analysis of tissue citrate (Comte et al., J Biol Chem 272: 26117–26124, 1997). In this study, we assessed the significance of our previous finding by perfusing hearts with long-chain fatty acids and tested the effects of changes in O 2 supply. We showed that under all of these conditions citrate was enriched in an isotopomer containing five 13 C atoms. This isotopomer can only be explained by substrate flux through reversal of the NADP + -ICDH reaction, which is evaluated at 3–7% of flux through citrate synthase. Small variations in reversal fluxes induced by low-flow ischemia that mimicked hibernation occurred despite major changes in contractile function and O 2 consumption of the heart as well as citrate and succinate release rates and tissue levels. Our data show a reverse flux through NADP + -ICDH and support its hypothesized role in the fine regulation of CAC activity in the normoxic and O 2 -deprived heart.

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