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.
Mizuno
Y
Y
Department of Neurology, Jichi Medical School, Tochigi, Japan.
Sone
N
N
Suzuki
K
K
Saitoh
T
T
D015655:1-Methyl-4-phenylpyridinium; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002952:Citric Acid Cycle / Q000187:drug effects*; D004579:Electron Transport / Q000187:drug effects*; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D011726:Pyridinium Compounds / Q000633:toxicity*; D013347:Subcellular Fractions / Q000378:metabolism
D007476:Ionophores; D011726:Pyridinium Compounds; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; D015655:1-Methyl-4-phenylpyridinium