Evidence that the blockade of mitochondrial respiration by the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) involves binding at the same site as the respiratory inhibitor, rotenone.
It has been postulated that 1-methyl-4-phenylpyridinium (MPP+) blocks mitochondrial respiration by combining at the same site as rotenone, a potent inhibitor of NADH oxidation in mitochondria, known to act at the junction of NADH dehydrogenase and coenzyme Q (CoQ). The present experiments show that MPP+ and two of its analogs indeed act in a concentration dependent manner to prevent the binding of [14C]-rotenone to submitochondrial particles (ETP) and significantly decrease the inhibition of electron transport caused by rotenone. It therefore appears that MPP+ binds at the same site as rotenone or an adjacent site, supporting the hypothesis that its neurotoxic action is due to the inhibition of mitochondrial respiration.
Krueger
M J
MJ
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Singer
T P
TP
Casida
J E
JE
Ramsay
R R
RR
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D004579:Electron Transport; D066298:In Vitro Techniques; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D012402:Rotenone / Q000378:metabolism* / Q000494:pharmacology; D013367:Submitochondrial Particles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D009097:Multienzyme Complexes; D012402:Rotenone; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D015655:1-Methyl-4-phenylpyridinium