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 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 rotenone-sensitive 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 rotenone-binding 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.
Hasegawa
E
E
Department of Biochemistry, Kyushu University School of Medicine, Fukuoka, Japan.
Kang
D
D
Sakamoto
K
K
Mitsumoto
A
A
Nagano
T
T
Minakami
S
S
Takeshige
K
K
D000818:Animals; D002417:Cattle; D003573:Cytochrome b Group / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects*; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D013367:Submitochondrial Particles / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
D003573:Cytochrome b Group; D011726:Pyridinium Compounds; D009243:NAD; D013481:Superoxides; D014451:Ubiquinone; C026560:1-(4-methoxyphenyl)pyridinium; C025204:Ubiquinone Q2