Intracellular free Zn 2؉ 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 Zn 2؉ and impaired respiration might be linked, respiration of isolated rat liver mitochondria was measured after addition of Zn 2؉ . Zn 2؉ inhibition (K i app ‫؍‬ ϳ1 M) was observed for respiration stimulated by ␣-ketoglutarate at

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... rations well within the range of intracellular Zn 2؉ reported for cultured hepatocytes. The bc 1 complex is inhibited by Zn 2؉ (Link, T. A., and von Jagow, G. (1995) J. Biol. Chem. 270, 25001-25006). However, respiration stimulated by succinate (K i app ‫؍‬ ϳ6 M) was less sensitive to Zn 2؉ , indicating the existence of a mitochondrial target for Zn 2؉ upstream from bc 1 complex. Purified pig heart ␣-ketoglutarate dehydrogenase complex was strongly inhibited by Zn 2؉ (K i app ‫؍‬ 0.37 ؎ 0.05 M). Glutamate dehydrogenase was more resistant (K i app ‫؍‬ 6 M), malate dehydrogenase was unaffected, and succinate dehydrogenase was stimulated by Zn 2؉ . Zn 2؉ inhibition of ␣-ketoglutarate dehydrogenase complex required enzyme cycling and was reversed by EDTA. Reversibility was inversely related to the duration of exposure and the concentration of Zn 2؉ . Physiological free Zn 2؉ may modulate hepatic mitochondrial respiration by reversible inhibition of the ␣-ketoglutarate dehydrogenase complex. In contrast, extreme or chronic elevation of intracellular Zn 2؉ could contribute to persistent reductions in mitochondrial respiration that have been observed in Zn 2؉ -rich diseased tissues.