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 O2 consumption, reduction of ubiquinone-10, and reduction of cytochrome b in a dose-dependent manner. The production of superoxide (O2) 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 O2 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 O2 than MPP+ and the production was additively increased by rotenone. Analog 1 only partially inhibited rotenonesensitive O2 consumption. Paraquat induced the production of O2 as much as analog 1. Paraquat, however, did not inhibit rotenone-sensitive O2 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 rotenonebinding site and the rotenone-binding site. The analogs may be reduced to produce O2 at the former site and inhibit the respiratory chain at the latter site.
All Science Journal Classification (ASJC) codes
- Molecular Biology