Three classes of ubiquinone analogs regulate the mitochondrial permeability transition pore through a common site

To identify the structural features required for regulation of the mitochon drial permeability transition pore (PTP) by ubiquinone analogs (Fontaine, E ., Ichas, F., and Bernardi, P. (1998) J. Biol. Chem. 40, 25734-25740), we h ave carried out an analysis with quinone structural variants. We show that three functional classes can be defined: (i) PTP inhibitors (ubiquinone 0, decylubiquinone, ubiquinone 10, 2,3-dimethyl-6-decyl-1,4-benzoquinone, and 2,3,5-trimethyl-6-geranyl-1,4-benzoquinone); (ii) PTP inducers (2,3-dimetho xy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone and 2,5-dihydroxy-6-undecy l-1,4-benzoquinone); and (iii) PTP-inactive quinones that counteract the ef fects of both inhibitors and inducers (ubiquinone 5 and 2,3,5-trimethyl-6-( 3-hydroxyisoamyl)-1,4-benzoquinone). The structure-function correlation ind icates that minor modifications in the isoprenoid side chain can turn an in hibitor into an activator, and that the methoxy groups are not essential fo r the effects of quinones on the PTP. Since the ubiquinone analogs used in this study have a similar midpoint potential and decrease mitochondrial pro duction of reactive oxygen species to the same extent, these results suppor t the hypothesis that quinones modulate the PTP through a common binding si te rather than through oxidation-reduction reactions. Occupancy of this sit e can modulate the PTP open-closed transitions, possibly through secondary changes of the PTP Ca2+ binding affinity.