Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation.
Energized mouse liver mitochondria displayed the same calcium retention capacity (a sensitive measure of the propensity of the permeability transition pore (PTP) to open) irrespective of whether phosphate, arsenate, or vanadate was the permeating anion. Unexpectedly, however, phosphate was specifically required for PTP desensitization by cyclosporin A (CsA) or by genetic inactivation of cyclophilin D (CyP-D). Indeed, when phosphate was replaced by arsenate, vanadate, or bicarbonate, the inhibitory effects of CsA and of CyP-D ablation on the PTP disappeared. After loading with the same amount of Ca(2+) in the presence of arsenate or vanadate but in the absence of phosphate, the sensitivity of the PTP to a variety of inducers was identical in mitochondria from wild-type mice, CyP-D-null mice, and wild-type mice treated with CsA. These findings call for a reassessment of conclusions on the role of the PTP in cell death that are based on the effects of CsA or of CyP-D ablation.
Basso
Emy
E
Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Institute of Neuroscience, University of Padova, Viale Giuseppe Colombo 3, I-35121 Padova, Italy.
Petronilli
Valeria
V
Forte
Michael A
MA
Bernardi
Paolo
P
D000818:Animals; D000838:Anions / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism* / Q000494:pharmacology
D000838:Anions; D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; C000631446:PPIF protein, mouse; D010710:Phosphates; D016572:Cyclosporine; D021983:Cyclophilins