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Diabetes 54:944-951, 2005
© 2005 by the American Diabetes Association, Inc.

Modular Kinetic Analysis of the Adenine Nucleotide Translocator–Mediated Effects of Palmitoyl-CoA on the Oxidative Phosphorylation in Isolated Rat Liver Mitochondria

Jolita Ciapaite1, Gerco Van Eikenhorst1, Stephan J.L. Bakker2, Michaela Diamant3, Robert J. Heine3, Marijke J. Wagner1, Hans V. Westerhoff1, and Klaas Krab1

1 Department of Molecular Cell Physiology, Institute for Molecular Cell Biology, BioCenter Amsterdam, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, the Netherlands
2 Department of Internal Medicine, University Hospital Groningen, Groningen, the Netherlands
3 Department of Endocrinology, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, the Netherlands

To test whether long-chain fatty acyl-CoA esters link obesity with type 2 diabetes through inhibition of the mitochondrial adenine nucleotide translocator, we applied a system-biology approach, dual modular kinetic analysis, with mitochondrial membrane potential ({Delta}{psi}) and the fraction of matrix ATP as intermediates. We found that 5 µmol/l palmitoyl-CoA inhibited adenine nucleotide translocator, without direct effect on other components of oxidative phosphorylation. Indirect effects depended on how oxidative phosphorylation was regulated. When the electron donor and phosphate acceptor were in excess, and the mitochondrial "work" flux was allowed to vary, palmitoyl-CoA decreased phosphorylation flux by 38% and the fraction of ATP in the medium by 39%. {Delta}{psi} increased by 15 mV, and the fraction of matrix ATP increased by 46%. Palmitoyl-CoA had a stronger effect when the flux through the mitochondrial electron transfer chain was maintained constant: {Delta}{psi} increased by 27 mV, and the fraction of matrix ATP increased 2.6 times. When oxidative phosphorylation flux was kept constant by adjusting the rate using hexokinase, {Delta}{psi} and the fraction of ATP were not affected. Palmitoyl-CoA increased the extramitochondrial AMP concentration significantly. The effects of palmitoyl-CoA in our model system support the proposed mechanism linking obesity and type 2 diabetes through an effect on adenine nucleotide translocator.

Address correspondence and reprint requests to Klaas Krab, Department of Molecular Cell Physiology, Institute for Molecular Cell Biology, BioCenter Amsterdam, Faculty of EarthLife Sciences, Vrije Universiteit, De Boelelaan 1085, NL-1081 HV Amsterdam, the Netherlands. E-mail: klaas{at}bio.vu.nl


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Copyright © 2005 by the American Diabetes Association.