title: Is complex II involved in the inhibition of mitochondrial respiration by N-methyl-4-phenylpyridinium cation (MMP+) and N-methyl-beta-carbolines?
abstract: It has been reported that N-methyl-beta-carbolinium analogues of the neurotoxic N-methyl-4-phenylpyridinium cation (MPP+) inhibit NADH-linked mitochondrial oxidations, as well as mitochondrial respiration on succinate nearly to the same extent [Fields, Albores, Neafsey and Collins (1992) Arch. Biochem. Biophys. 294, 539-544]. Those authors further claimed that MPP+ itself also blocks respiration through succinate dehydrogenase, in addition to its well-known effect on NADH dehydrogenase (Complex I), and concluded that both effects may contribute to the development of Parkinsonian symptoms. Since N-methyl-beta-carboliniums are thought to be endogenous metabolites, these findings, if verified, would have important implications on the etiology of idiopathic Parkinsonism. We have re-examined these observations, using mitochondria after full activation of succinate dehydrogenase, as well as submitochondrial particles, in which complexities due to membrane transport are not present. We report the following observations. (1) N-Methyl-beta-carboliniums inhibit mitochondrial respiration on NAD(+)-linked substrates in a time-dependent manner, and the inhibition is potentiated by the presence of tetraphenylboron anion (TPB-), as expected for positively charged compounds. (2) Unlike MPP+ itself, however, these compounds are uncouplers at higher concentrations, so that the effects seen in State 3 cannot be assigned exclusively to inhibition of NADH oxidation. (3) The effects on succinate oxidation in mitochondria, in which the full activity of the enzyme is expressed, are 1-1.5 orders of magnitude lower than on respiration via Complex I and are thus unlikely to contribute significantly to the neurotoxicity. (4) The effect of MPP+ on mitochondrial respiration via succinate dehydrogenase is trivial, in accord with previous reports from several laboratories, but contradicting the findings of Fields et al. (cited above). (5) In submitochondrial particles the inhibition of NADH oxidation (via the complete respiratory chain) has been confirmed, but it differs markedly from the action of MPP+ in two respects. First, the enhancement by TPB- is very small; secondly, the inhibition of NADH oxidation measured using ubiquinone (Q) analogues is far lower, suggesting that Complex I is not the only target. (6) In submitochondrial particles the inhibition of succinate oxidation by either O2 or Q analogues is incomplete, trivial or absent. (7) We thus conclude that we find no basis for assigning any potential biological effect of N-methyl-beta-carboliniums to the blockade of succinate oxidation.
authors: Molecular Biology Division, Veterans Affairs Medical Center, San Francisco, CA 94121.
authors: M J
authors: MJ
authors: Krueger
authors: A K
authors: AK
authors: Tan
authors: B A
authors: BA
authors: Ackrell
authors: T P
authors: TP
authors: Singer
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D002412:Cations; D002417:Cattle; D008745:Methylation; D008928:Mitochondria / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D013367:Submitochondrial Particles / Q000187:drug effects / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid
chemical_list: D002243:Carbolines; D002412:Cations; D013386:Succinates; D009243:NAD; D019802:Succinic Acid; D013385:Succinate Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium