Inhibition of complex I regulates the mitochondrial permeability transition through a phosphate-sensitive inhibitory site masked by cyclophilin D.
Inhibition of the mitochondrial permeability transition pore (PTP) has proved to be an effective strategy for preventing oxidative stress-induced cell death, and the pore represents a viable cellular target for drugs. Here, we report that inhibition of complex I by rotenone is more effective at PTP inhibition than cyclosporin A in tissues that express low levels of the cyclosporin A mitochondrial target, cyclophilin D; and, conversely, that tissues in which rotenone does not affect the PTP are characterized by high levels of expression of cyclophilin D and sensitivity to cyclosporin A. Consistent with a regulatory role of complex I in the PTP-inhibiting effects of rotenone, the concentrations of the latter required for PTP inhibition precisely match those required to inhibit respiration; and a similar effect is seen with the antidiabetic drug metformin, which partially inhibits complex I. Remarkably (i) genetic ablation of cyclophilin D or its displacement with cyclosporin A restored PTP inhibition by rotenone in tissues that are otherwise resistant to its effects; and (ii) rotenone did not inhibit the PTP unless phosphate was present, in striking analogy with the phosphate requirement for the inhibitory effects of cyclosporin A [Basso et al. (2008) J. Biol. Chem. 283, 26307-26311]. These results indicate that inhibition of complex I by rotenone or metformin and displacement of cyclophilin D by cyclosporin A affect the PTP through a common mechanism; and that cells can modulate their PTP response to complex I inhibition by modifying the expression of cyclophilin D, a finding that has major implications for pore modulation in vivo.
University Claude Bernard Lyon 1, Lyon, France.
Bo
B
Li
Christiane
C
Chauvin
Damien
D
De Paulis
Frédéric
F
De Oliveira
Abdallah
A
Gharib
Guillaume
G
Vial
Sandrine
S
Lablanche
Xavier
X
Leverve
Paolo
P
Bernardi
Michel
M
Ovize
Eric
E
Fontaine
D000818:Animals; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D012402:Rotenone / Q000494:pharmacology*
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D012402:Rotenone; D016572:Cyclosporine; D008687:Metformin; D021983:Cyclophilins; D042967:Electron Transport Complex I