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 decylubiquinon e, whereas all other tested quinones (ubiquinone 5, 1,4-benzoquinone, 2-methoxy-1,4-benzoquinone, 2,3-dimethoxy-1,4-benzoquinone, and 2,3-di methoxy-5,6-dimethyl-1,8-benzoquinone) were ineffective. Pore inhibiti on was observed irrespective of the method used to induce the permeabi lity transition (addition of P-i or atractylate, membrane depolarizati on, or dithiol cross-linking). Inhibition of PTP opening by decylubiqu inone was comparable with that exerted by cyclosporin A, whereas ubiqu inone 0 was more potent. Ubiquinone 5, which did not inhibit the PTP p er se, specifically counteracted the inhibitory effect of ubiquinone 0 or decylubiquinone but not that of cyclosporin A. These findings defi ne a ubiquinone-binding site directly involved in PTP regulation and i ndicate that different quinone structural features are required for bi nding and for stabilizing the pore in the closed conformation. At vari ance from all other quinones tested, decylubiquinone did not inhibit r espiration. Our results define a new structural class of pore inhibito rs and may open new perspectives for the pharmacological modulation of the PTP in vivo.