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 O2consumption, 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−2induced 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−2than MPP+and the production was additively increased by rotenone. Analog 1 only partially inhibited rotenone-sensitive O2consumption. Paraquat induced the production of O−2as much as analog 1. Paraquat, however, did not inhibit rotenone-sensitive O2consumption 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−2at the former site and inhibit the respiratory chain at the latter site.