A dual effect of 1-methyl-4-phenylpyridinium (MPP(+))-analogs on the respiratory chain of bovine heart mitochondria

We examined effects of several compounds, structurally related to 1-methyl-4-phenylpyridinium (MPP(+)), on the NADH-dependent respiration of bovine heart submitochondrial particles, 1-Methyl-4-(3'-trimethylammoniophenyl)pyridinium (analog 8) as well as MPP(+) completely inhibited O-2 consumption, reduction of ubiquinone-10, and reduction of cytochrome b in a dose-dependent manner. The production of superoxide (O-2(-)) induced by MPP(+) or analog 8 was to the same extent as that by rotenone, an inhibitor of complex I of the mitochondrial respiratory chain. Rotenone had no additive effect on the maximal production of O-2(-) induced by MPP(+) or analog 8, suggesting that the production was mediated by the same way as rotenone, 1-Methyl-4-(4'-nitrophenyl) pyridinium (analog 1) induced about 20-fold more production of O-2(-) than MPP(+) and the production was additively increased by rotenone, Analog 1 only partially inhibited rotenone-sensitive O-2 consumption, Paraquat induced the production of O-2(-) as much as analog 1, Paraquat, however, did not inhibit rotenone sensitive O-2 consumption or reduction of cytochrome b, These results suggest that MPP(+) and its analogs interact with the mitochondrial respiratory chain at two sites, the substrate side of the rotenone-binding site and the rotenone-binding site. The analogs may be reduced to produce O-2(-) at the former site and inhibit the respiratory chain at the latter site. (C) 1997 Academic Press, Inc.