Inhibition of ATP synthesis by 1-methyl-4-phenylpyridinium ion (MPP+) in mouse brain in vitro and in vivo.

The effects of the MPP+ ion on ATP synthesis were studied using mouse brains in vitro and in vivo. Oxidation of glutamate + malate in mitochondria estimated by polarography was significantly inhibited by MPP+, and synthesis of ATP was inhibited to approximately one-third of that of control by 0.05 mM of MPP+. Oxidation of alpha-glycerophosphate and succinate was not inhibited, and ATP was synthesized normally. In cerebral mitochondria of mice treated with 40 mg/kg of MPTP, oxidation of glutamate, pyruvate, and malate was also significantly inhibited, but ATP was synthesized in normal amounts. This inhibition was prevented by pretreatment of mice with pargyline. Our observation would give further support for the mitochondria hypothesis of the mechanism of neuronal degeneration in MPTP-induced parkinsonism.