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

• Published in: The Journal of biological chemistry 2000-05, Vol.275 (18), p.13441-13447
• Main Authors: Brown, Abraham M., Kristal, Bruce S., Effron, Michelle S., Shestopalov, Alexander I., Ullucci, Paul A., Sheu, K.-F.Rex, Blass, John P., Cooper, Arthur J.L.
• Format: Article
• Language: English
• Subjects: Animals; Electron Transport - drug effects; Enzyme Activation - drug effects; Ketoglutarate Dehydrogenase Complex - metabolism; Ketoglutaric Acids - metabolism; Ketoglutaric Acids - pharmacology; Mitochondria, Liver - metabolism; Rats; Zinc - metabolism; Zinc - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.275.18.13441

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 α-ketoglutarate at concentrations well within the range of intracellular Zn2+ reported for cultured hepatocytes. Thebc1 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 α-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 α-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 α-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.