Inhibition of mitochondrial succinate oxidation—Similarities and differences between N-methylated β-carbolines and MPP +

Abstract

N-Methylated β-carbolinium compounds ( N-Me-BCs), including 2- N-methyl and 2,9- N,N-dimethyl analogs, structural analogs of 1-methyl-4-phenylpyridinium (MPP +), may be endogenously bioactivated, MPP +-like toxins, capable of inducing parkinsonism. Both MPP + and selected N-Me-BCs inhibit NADH-linked mitochondrial respiration (Complex I). We now show that both also inhibit succinate-supported (Complex II) respiration, the greatest inhibition (80%) being seen for 2,9-dimethylharmanium. Complex I inhibition occurs at MPP + concentrations (IC 50 = 0.17 m m) about one order of magnitude lower than Complex II inhibition (> 1.2 m m). In contrast, Complex I and Complex II inhibition by the N-Me-BCs tested occurred at similar concentrations (I, 0.1 m m; II, 0.25 m m) and concentrations similar to Complex I inhibition by MPP +. 2,9- N,N-Dimethyl-BCs, which are the permanently charged BC analogs of MPP +, show inhibitory characteristics similar to MPP +: slow onset of inhibition, potentiation by TPB, and reversal by DNP. The fact that succinate oxidation cannot bypass the Complex II inhibition by N-Me-BCs could enhance any chronic neurotoxicity of N-Me-BCs.