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

J Neurol Sci. 1988 Aug;86(1):97-110. doi: 10.1016/0022-510x(88)90010-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium
  • Adenosine Triphosphate / metabolism
  • Animals
  • Brain Chemistry / drug effects*
  • Citric Acid Cycle / drug effects*
  • Electron Transport / drug effects*
  • In Vitro Techniques
  • Ionophores / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Oxidoreductases / metabolism
  • Pyridinium Compounds / toxicity*
  • Subcellular Fractions / metabolism


  • Ionophores
  • Pyridinium Compounds
  • Adenosine Triphosphate
  • Oxidoreductases
  • 1-Methyl-4-phenylpyridinium