Is complex II involved in the inhibition of mitochondrial respiration by N-methyl-4-phenylpyridinium cation (MMP+) and N-methyl-β-carbolines?

摘要: 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 respiration on succinate nearly to same extent [Fields, Albores, Neafsey and Collins (1992) Arch. Biochem. Biophys. 294, 539-544]. Those authors further claimed MPP+ itself also blocks through dehydrogenase, in addition its well-known effect NADH dehydrogenase (Complex I), concluded both effects may contribute development Parkinsonian symptoms. Since N-methyl-beta-carboliniums are thought be endogenous metabolites, these findings, if verified, would have important implications etiology idiopathic Parkinsonism. We re-examined observations, using mitochondria after full activation submitochondrial particles, which complexities due membrane transport not present. report following observations. (1) N-Methyl-beta-carboliniums NAD(+)-linked substrates a time-dependent manner, inhibition is potentiated by presence tetraphenylboron anion (TPB-), expected for positively charged compounds. (2) Unlike itself, however, compounds uncouplers at higher concentrations, so seen State 3 cannot assigned exclusively oxidation. (3) The oxidation mitochondria, activity enzyme expressed, 1-1.5 orders magnitude lower than via Complex I thus unlikely significantly neurotoxicity. (4) trivial, accord with previous reports from several laboratories, but contradicting findings Fields et al. (cited above). (5) In particles (via complete respiratory chain) confirmed, it differs markedly action two respects. First, enhancement TPB- very small; secondly, measured ubiquinone (Q) far lower, suggesting only target. (6) either O2 or Q incomplete, trivial absent. (7) conclude we find no basis assigning any potential biological blockade