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 death. Because functional links between the PTP and the respiratory chain complex I have been reported, we have investigated the effects of rotenone on PTP regulation in U937 and KB cells. We show that rotenone was more potent than cyclosporin A at inhibiting Ca(2+)-induced PTP opening in digitonin-permeabilized cells energized with succinate. Consistent with PTP regulation by electron flux through complex I, the effect of rotenone persisted after oxidation of pyridine nucleotides by duroquinone. tert-butyl hydroperoxide induced PTP opening in intact cells (as shown by mitochondrial permeabilization to calcein and cobalt), as well as cytochrome c release and cell death. All these events were prevented by rotenone or cyclosporin A. These data demonstrate 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 cell death.
Chauvin
C
C
Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, 38041 Grenoble, France.
De Oliveira
F
F
Ronot
X
X
Mousseau
M
M
Leverve
X
X
Fontaine
E
E
D016923:Cell Death / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D003574:Cytochrome c Group / Q000378:metabolism; D006801:Humans; D007624:KB Cells; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D012402:Rotenone / Q000494:pharmacology*; D020298:U937 Cells; D014475:Uncoupling Agents / Q000494:pharmacology*
D003574:Cytochrome c Group; D014475:Uncoupling Agents; D012402:Rotenone