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Am J Physiol Heart Circ Physiol 274: H467-H476, 1998;
0363-6135/98 $5.00
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Vol. 274, Issue 2, H467-H476, February 1998

Dehydrogenase regulation of metabolite oxidation and efflux from mitochondria in intact hearts

J. Michael O'Donnell1, Chris Doumen3, Kathryn F. Lanoue3, Lawrence T. White1, Xin Yu1, Nathaniel M. Alpert2, and E. Douglas Lewandowski1

1 Nuclear Magnetic Resonance Center and 2 Positron-Emission Tomography Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129; and 3 Department of Molecular and Cellular Physiology, Pennsylvania State University Medical School, Hershey, Pennsylvania 17033

To test how alpha -ketoglutarate dehydrogenase (alpha -KGDH) activity influences the balance between oxidative flux and transmitochondrial metabolite exchange, we monitored these rates in isolated mitochondria and in perfused rabbit hearts at an altered kinetics (Km) of alpha -KGDH for alpha -ketoglutarate (alpha -KG). In isolated mitochondria, relative Km dropped from 0.23 mM at pH = 7.2 to 0.10 mM at pH 6.8 (P < 0.05), and alpha -KG efflux decreased from 126 to 95 nmol · min-1 · mg-1. In intact hearts, Km was reduced with low intracellular pH, while matching control workload and respiratory rate with increased Ca2+ (pHi = 7.20, perfusate CaCl2 = 1.5 mM; pHi = 6.89, perfusate CaCl2 = 3 ± 1 mM). Sequential 13C nuclear magnetic resonance spectra from hearts oxidizing [2-13C]acetate provided tricarboxylic acid cycle flux and the exchange rate between alpha -KG and cytosolic glutamate (F1). Tricarboxylic acid cycle flux was 10 µmol · min-1 · g-1 in both groups, but F1 fell from a control of 9.3 ± 0.6 to 2.8 ± 0.4 µmol · min-1 · g-1 at low Km. The results indicate that increased activity of alpha -KGDH occurs at the expense of alpha -KG efflux during support of normal workloads.

metabolic regulation; tricarboxylic acid cycle; myocardium; nuclear magnetic resonance


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