Zn2+ inhibits alpha-ketoglutarate-stimulated mitochondrial respiration and the isolated alpha-ketoglutarate dehydrogenase complex.
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) = approximately 1 micrometer) was observed for respiration stimulated by alpha-ketoglutarate at concentrations 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) = approximately 6 micrometer) was less sensitive to Zn(2+), indicating the existence of a mitochondrial target for Zn(2+) upstream from bc(1) complex. Purified pig heart alpha-ketoglutarate dehydrogenase complex was strongly inhibited by Zn(2+) (K(i)(app) = 0.37 +/- 0.05 micrometer). Glutamate dehydrogenase was more resistant (K(i)(app) = 6 micrometer), malate dehydrogenase was unaffected, and succinate dehydrogenase was stimulated by Zn(2+). Zn(2+) 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 Zn(2+). Physiological free Zn(2+) may modulate hepatic mitochondrial respiration by reversible inhibition of the alpha-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.
Brown
A M
AM
Burke Medical Research Institute, White Plains, New York 10605, USA. abrown@burke.org
Kristal
B S
BS
Effron
M S
MS
Shestopalov
A I
AI
Ullucci
P A
PA
Sheu
K F
KF
Blass
J P
JP
Cooper
A J
AJ
D000818:Animals; D004579:Electron Transport / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism* / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000378:metabolism*; D051381:Rats; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D007656:Ketoglutaric Acids; D007655:Ketoglutarate Dehydrogenase Complex; D015032:Zinc