Studies on the toxicity of 1-methyl-4-phenylpyridinium ion (MPP+) against mitochondria of mouse brain

Effects of 1-methyl-4-phenylpyridinium ion (MPP+) on cellular respiration were studied using mitochondria prepared from mouse brains. State 3 and state 4 respiration supported by glutamate plus malate or pyruvate plus malate were significantly inhibited by 0.05 mM MPP+. On the other hand, respirations supported by succinate or alpha-glycerophosphate were not inhibited at all. Activity of mitochondrial NADH-ubiquinone oxidoreductase was significantly inhibited by MPP+. This inhibition was markedly potentiated by preincubating mitochondria with MPP+ together with glutamate plus malate. The latter observation suggested accumulation of MPP+ within the mitochondria during preincubation. When mitochondria were pretreated with an uncoupling agent such as carbonylcyanide m-chlorophenylhydrazone (CCCP) or dinitrophenol, MPP+-induced inhibition of state 3 respiration or of activity of complex I could no longer be seen. A potassium ionophore, valinomycin, showed a similar effect. Adenosine triphosphate (ATP) synthesis was also inhibited by MPP+. Among the NAD+-linked dehydrogenases in the tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase complex was significantly inhibited by MPP+. This inhibition was reversible and competitive with NAD+. Energy crisis appears to be one of the most important mechanisms of neuronal degeneration in MPTP-induced parkinsonism. Biochemical mechanisms underlying MPP+-induced inhibition of mitochondrial respiration were discussed.