Zn2+ inhibits alpha-ketoglutarate-stimulated mitochondrial respiration andthe isolated alpha-ketoglutarate dehydrogenase complex

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 co nditions. To test whether elevated Zn2+ and impaired respiration might be l inked, respiration of isolated rat liver mitochondria was measured after ad dition of Zn2+. Zn2+ inhibition (K-i(app) = similar to 1 mu M) was observed for respiration stimulated by alpha-ketoglutarate at concentrations well w ithin the range of intracellular Zn2+ reported for cultured hepatocytes, Th e be, complex is inhibited by Zn2+ (Link, T, A, and von Jagow, G, (1995) J. Biol. Chem, 270, 25001-25006), However, respiration stimulated by succinat e (K-i(app) = similar to 6 mu M) was less sensitive to Zn2+, indicating the existence of a mitochondrial target for Zn2+ upstream from bc(1) complex. Purified pig heart cu-ketoglutarate dehydrogenase complex was strongly inhi bited by Zn2+ (K-i(app) = 0 37 +/- 0.05 mu M). Glutamate dehydrogenase was more resistant (K-i(app) = 6 mu M), malate dehydrogenase was unaffected, an d succinate dehydrogenase was stimulated by Zn2+, Zn2+ inhibition of alpha- ketoglutarate dehydrogenase complex required enzyme cycling and was reverse d 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-ketoglutar ate dehydrogenase complex. In contrast, extreme or chronic elevation of int racellular Zn2+ could contribute to persistent reductions in mitochondrial respiration that have been observed in Zn2+-rich diseased tissues.