Zn2+ INDUCES THE MITOCHONDRIAL PERMEABILITY TRANSITION

B.S. Kristal^1,2 and A.M. Brown
¹Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY 10605 and Department of Biochemistry, Cornell University Medical College, 1300 York Ave, New York, NY  10021
²Department of Neuroscience, Cornell University Medical College

Increased intracellular chelatable Zn2+ and induction of the mitochondrial permeability transition (PT) have both been proposed to play causative roles in ischemia-reperfusion (I/R) injury and excitotoxin-mediated cytotoxicity.  Our studies link these two changes by showing that Zn2+, in either the presence or absence of respiratory substrate (succinate), directly induces the PT in isolated rat liver mitochondria.  Zn2+ and Ca2+ act in concert at pathophysiologically relevant concentrations of both cations.  Zn2+-mediated PT induction was delayed by TPEN, a metal-specific chelator that binds Zn2+ but not Ca2+, and by the known PT inhibitors cyclosporin A and MgCl2, but only weakly by ADP.  These findings identify a probable endogenous trigger of the PT in I/R mediated cytotoxicity.

© 1999 Wadsworth Center, All Rights Reserved. Legal & Privacy Notices