2 MECHANISMS BY WHICH ATP DEPLETION POTENTIATES INDUCTION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION

The present and a previous study [J. W. Snyder, J. G. Pastorino, A. M. Attie, and J. L. Farber. Am. J. Physiol. 264 (Cell Physiol. 33): C709 -C714, 1993] define two mechanisms whereby ATP depletion promotes live r cell death. ATP depletion and cell death are linked by the mitochond rial permeability transition (MPT). Mitochondrial deenergization promo tes the MPT, and ATP maintains a membrane potential by reversal of ATP synthase. With an increased influx of Ca2+ induced by the ionophore A -23187, oligomycin depleted the cells of ATP without loss of the mitoc hondrial membrane potential and further elevated the intracellular Ca2 + concentration Cyclosporin A (CyA) prevented the accompanying cell ki lling. Fructose also preserved the viability of the cells. With the in creased cytosolic Ca2+ imposed by A-23187, viability is maintained by ATP-dependent processes. Upon depletion of ATP, Ca2+ homeostasis canno t be maintained, and the MPT is induced. Rotenone also depleted the ce lls of ATP, and A-23187 accelerated the loss of the mitochondrial memb rane potential occurring with rotenone alone. CyA and fructose prevent ed the cell killing with rotenone and A-23187. Oligomycin did not prev ent this action of fructose. We conclude that ATP is needed to maintai n Ca2+ homeostasis to prevent the MPT and the resultant liver cell dea th. ATP is also needed to maintain mitochondrial energization when ele ctron transport is inhibited.