On the voltage dependence of the mitochondrial permeability transition pore. A critical appraisal

The mitochondrial permeability transition pore, a cyclosporin A-sensitive channel, can be opened by the addition of protonophoric uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) after energy-dependent accumulation of Ca2+. We have proposed that the relevant effect of FCCP on the pore is membrane depolarization, suggesting that this channel is voltage-dependent (Bernardi, P. (1992) J. Biol. Chem. 267, 8334-8339). Here, we reconsider this hypothesis in the light of recent observations suggesting that increased production of reactive oxygen species and/or direct effects of FCCP, rather than membrane depolarization, could be the actual triggers of the FCCP-dependent permeability transition. We show that although reactive oxygen species can contribute to the permeability transition, pore opening by FCCP can still be observed under strict anaerobiosis after ATP-dependent Ca2+ accumulation and that the permeability transition can be induced by the addition of valinomycin to respiring mitochondria treated with nigericin in low potassium medium. In this system, pore opening in increasing fractions of mitochondria depends on the concentration of valinomycin, i.e. on the magnitude of the potassium current that determines the extent of membrane depolarization. We conclude that the permeability transition pore is directly modulated by the membrane potential in intact isolated rat liver mitochondria.