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Articles in PresS, published online ahead of print June 6, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00287.2002
Submitted on April 2, 2002
Accepted on May 30, 2002
1 Biochemistry & Nutrition, University of Montreal, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: christine.des.rosiers{at}umontreal.ca.
Little is known about the role of mitochondrial NADP+-isocitrate dehydrogenase in the heart, where this enzyme shows its highest expression and activity. We tested the hypothesis that in the heart, NADP+-isocitrate dehydrogenase operates in the reverse direction of the citric acid cycle and, thereby, may contribute to the fine regulation of citric acid cycle activity (Sazanov and Jackson, FEBS lett 344: 109-116, 1994). We documented a reverse flux through this enzyme in rat hearts perfused with the medium chain fatty acid octanoate using [U-13C5]glutamate and mass isotopomer analysis of tissue citrate (Comte et al. J Biol Chem 272: 26117-26124, 1997). In the present study, we assessed the physiological significance of our previous finding by perfusing hearts with long chain fatty acids. In addition, we tested the effects of changes in oxygen supply. We showed that under all these conditions, citrate was enriched in an isotopomer containing five 13C. This isotopomer can only be explained by substrate flux through reversal of the NADP+-isocitrate dehydrogenase reaction, which is evaluated at 3 to 7% of flux through citrate synthase. Small variations in reversal fluxes induced by low-flow ischemia, which mimicked hibernation, occurred in spite of major changes in the heart's contractile function, oxygen consumption, as well as release rates and tissue levels of citrate and succinate. Our data, which show a reverse flux through NADP+-isocitrate dehydrogenase, support its hypothesized role in the fine regulation of citric acid cycle activity in the normoxic and oxygen-deprived heart.
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