INDUCTION OF A PERMEABILITY TRANSITION IN RAT-KIDNEY MITOCHONDRIA BY PENTACHLOROBUTADIENYL CYSTEINE - A BETA-LYASE-INDEPENDENT PROCESS

A Ca2+-dependent inner mitochondrial membrane permeability transition is induced by a number of agents, an effect which is thought to cause cytotoxicity. This transition involves formation of a pore allowing th e passage of solutes of up to 1500 Da; it is blocked by cyclosporine A and Ca2+ chelating agents, The mitochondrial nephrotoxicant S-(1,2,3, 4,4-pentachlorobutadienyl)-L-cysteine (PCBC) caused collapse of the mi tochondrial membrane potential, Ca2+-independent oxidation of pyridine nucleotides and release of accumulated Ca2+ in isolated rat kidney mi tochondria, three hallmarks of the permeability transition. These effe cts were blocked by cyclosporine A and by ethylene glycol bis(beta-ami noethyl ether) tetraacetic acid (EGTA), Furthermore, EGTA was capable of reversing the collapse of the membrane potential. These data indica te that PCBC induced an inner membrane permeability transition, Intere stingly, addition of aminoxyacetic acid, a beta-lyase inhibitor, did n ot prevent the permeability transition, and a nonmetabolizable analog of PCBC, S-(1,2,3,4,4-pentachlorobutadienyl)-L-alpha-methyl cysteine, induced the permeability transition, Thus PCBC may act to induce the p ermeability transition through a mechanism that does not require metab olism by a beta-lyase. Since metabolism by a beta-lyase is required fo r PCBC toxicity, it is not clear that the permeability transition is i nvolved in cysteine conjugate-mediated renal cell injury. (C) 1996 Aca demic Press, Inc.