MITOCHONDRIAL RESPIRATORY INHIBITION BY N-METHYLATED BETA-CARBOLINE DERIVATIVES STRUCTURALLY RESEMBLING N-METHYL-4-PHENYLPYRIDINE

Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated β-carbolines (2-MeβCs) and 2-methylated 3,4-dihydro-β-carbolines (2-MeDHβCs), which encompass the MPP+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD+-linked O2 consumption (6-min preincubations) was as follows: MPP+ = 2-methylharmine > 2-methylharmol = 2-methylharmaline >> 2-methylharmalol > 2-methylnorharman > 6-OH-2-methylharmalan >> 2-methylharman. Similar to MPP+, 2-MeDHβC/2-MeβC inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDHβC/2-MeβC inhibitory time courses, which were unlike MPP+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic β-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP+ rather than 2-MeβCs. Succinate-supported respiration was also significantly blocked by 2-MeDHβCs/2-MeβCs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD+-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDHβCs/2-MeβCs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-MeβCs.