Journal of Biological Chemistry
Volume 273, Issue 40, 2 October 1998, Pages 25734-25740
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MEMBRANES AND BIOENERGETICS
A Ubiquinone-binding Site Regulates the Mitochondrial Permeability Transition Pore*

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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.

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This work was supported by grants from the Consiglio Nazionale delle Ricerche (Dotazione Centro Biomembrane), the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (Progetto “Bioenergetica e Trasporto di Membrana”), Telethon-Italy Grant 847 (to P. B.), the Armenise Harvard Foundation, the European Economic Community Fellowship ERBFMBICT961385 (to E. F.), and the Human Frontier Science Program Organization (to F. I.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Laboratoire de Bioénergétique Fondamentale et Appliquée, Université J. Fourier, Grenoble F-38041, France.

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To whom reprint requests should be addressed: Dipartimento di Scienze Biomediche Sperimentali, Viale Giuseppe Colombo 3, Padova I-35121, Italy.