Rotenone inhibits the mitochondrial permeability transition-induced cell death in U937 and KB cells

The permeability transition pore (PTP) is a mitochondrial inner membrane Ca 2+-sensitive channel that plays a key role in different models of cell deat h. Because functional links between the PTP and the respiratory chain compl ex I have been reported, we have investigated the effects of rotenone on PT P regulation in U937 and KB cells. We show that rotenone was more potent th an cyclosporin A at inhibiting Ca2+-induced PTP opening in digitonin-permea bilized cells energized with succinate. Consistent with PTP regulation by e lectron flux through complex I, the effect of rotenone persisted after oxid ation of pyridine nucleotides by duroquinone. tert-Butyl hydroperoxide indu ced PTP opening in intact cells (as shown by mitochondrial permeabilization to calcein and cobalt), as well as cytochrome c release and cell death. Al l these events were prevented by rotenone or cyclosporin A. These data demo nstrate that respiratory chain complex I plays a key role in PTP regulation in vivo and confirm the importance of PTP opening in the commitment to cel l death.