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J Biol Chem, Vol. 275, Issue 18, 13441-13447, May 5, 2000

Zn2+ Inhibits alpha -Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated alpha -Ketoglutarate Dehydrogenase Complex*

Abraham M. BrownDagger §, Bruce S. KristalDagger §||, Michelle S. EffronDagger , Alexander I. ShestopalovDagger , Paul A. Ullucci**, K.-F. Rex SheuDagger ||dagger , John P. BlassDagger ||Dagger Dagger , and Arthur J. L. CooperDagger §||

From the Dagger  Burke Medical Research Institute, White Plains, New York 10605, the Departments of § Biochemistry, || Neurology and Neuroscience, and Dagger Dagger  Medicine, Weill Medical College of Cornell University, New York, New York 10021 and ** ESA, Inc., Chelmsford, Massachusetts 01824

Intracellular free Zn2+ is elevated in a variety of pathological conditions, including ischemia-reperfusion injury and Alzheimer's disease. Impairment of mitochondrial respiration is also associated with these pathological conditions. To test whether elevated Zn2+ and impaired respiration might be linked, respiration of isolated rat liver mitochondria was measured after addition of Zn2+. Zn2+ inhibition (Kiapp = ~1 µM) was observed for respiration stimulated by alpha -ketoglutarate at concentrations well within the range of intracellular Zn2+ reported for cultured hepatocytes. The bc1 complex is inhibited by Zn2+ (Link, T. A., and von Jagow, G. (1995) J. Biol. Chem. 270, 25001-25006). However, respiration stimulated by succinate (Kiapp = ~6 µM) was less sensitive to Zn2+, indicating the existence of a mitochondrial target for Zn2+ upstream from bc1 complex. Purified pig heart alpha -ketoglutarate dehydrogenase complex was strongly inhibited by Zn2+ (Kiapp = 0.37 ± 0.05 µM). Glutamate dehydrogenase was more resistant (Kiapp = 6 µM), malate dehydrogenase was unaffected, and succinate dehydrogenase was stimulated by Zn2+. Zn2+ inhibition of alpha -ketoglutarate dehydrogenase complex required enzyme cycling and was reversed by EDTA. Reversibility was inversely related to the duration of exposure and the concentration of Zn2+. Physiological free Zn2+ may modulate hepatic mitochondrial respiration by reversible inhibition of the alpha -ketoglutarate dehydrogenase complex. In contrast, extreme or chronic elevation of intracellular Zn2+ could contribute to persistent reductions in mitochondrial respiration that have been observed in Zn2+-rich diseased tissues.

* This work was supported by National Institutes of Health (NIH)/NINDS Grant NS38741 (to A. M. B.). Pilot support was provided from Leadership and Excellence Award in Alzheimer's Disease AG09014 NIH/NIA (to J. P. B.) and the Winifred Masterson Burke Relief Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dementia Research Service, Burke Medical Research Inst., 785 Mamaroneck Ave., White Plains, NY 10605. Tel.: 914-597-2361; Fax: 914-597-2757; E-mail: abrown@burke.org.

dagger Deceased March 2, 1999.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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