A ubiquinone-binding site regulates the mitochondrial permeability transition pore.
We have investigated the regulation of the mitochondrial permeability transition pore (PTP) by ubiquinone analogues. We found that the Ca2+-dependent PTP opening was inhibited by ubiquinone 0 and decylubiquinone, whereas all other tested quinones (ubiquinone 5, 1,4-benzoquinone, 2-methoxy-1,4-benzoquinone, 2,3-dimethoxy-1, 4-benzoquinone, and 2,3-dimethoxy-5,6-dimethyl-1,4-benzoquinone) were ineffective. Pore inhibition was observed irrespective of the method used to induce the permeability transition (addition of Pi or atractylate, membrane depolarization, or dithiol cross-linking). Inhibition of PTP opening by decylubiquinone was comparable with that exerted by cyclosporin A, whereas ubiquinone 0 was more potent. Ubiquinone 5, which did not inhibit the PTP per se, specifically counteracted the inhibitory effect of ubiquinone 0 or decylubiquinone but not that of cyclosporin A. These findings define a ubiquinone-binding site directly involved in PTP regulation and indicate that different quinone structural features are required for binding and for stabilizing the pore in the closed conformation. At variance from all other quinones tested, decylubiquinone did not inhibit respiration. Our results define a new structural class of pore inhibitors and may open new perspectives for the pharmacological modulation of the PTP in vivo.
Fontaine
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Consiglio Nazionale delle Ricerche Unit for the Study of Biomembranes and the Laboratory of Biophysics and Membrane Biology, Department of Biomedical Sciences, University of Padova Medical School, Viale Giuseppe Colombo 3, Padova I-35121, Italy.
Ichas
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Bernardi
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D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D001278:Atractyloside / Q000494:pharmacology; D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects*; D007473:Ion Channels / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism*; D015394:Molecular Structure; D010539:Permeability / Q000187:drug effects; D018272:Porins / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology*
D001152:Arsenicals; D007473:Ion Channels; D018272:Porins; D011809:Quinones; C029341:oxophenylarsine; D014451:Ubiquinone; D001278:Atractyloside; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C060262:2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone; D016572:Cyclosporine; D002118:Calcium