Inhibition of mitochondrial respiration by analogues of the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium: Structural requirements for accumulation-dependent enhanced inhibitory potency on intact mitochondria

Abstract

Analogues of 1-methyl-4-phenylpyridinium (MPP +), the neurotoxic metabolite of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, were evaluated for inhibition of respiration in intact mitochondria (M w) and in electron transport particles (ETP). MPP + exhibits relatively weak inhibitory activity in ETP, but potent inhibition in M w occurs on account of its energy-dependent accumulation inside mitochondria. The permeant anion tetraphenylborate potentiates the inhibition in both M w and ETP. Replacement of the 4-phenyl ring of MPP + by a variety of aromatic and nonaromatic rings, and of the N-methylpyridinium group by other cationic aromatic heterocycles, preserves the inhibitory patterns seen for MPP +. The general observation of enhanced inhibitory potency in M w for all these permanently charged cations is consistent with our contention that energy-dependent accumulation inside mitochondria represents a passive Nernstian concentration in response to the transmembrane electrochemical gradient. Nonetheless, the magnitude of the inhibitory potentiation seen in M w relative to ETP varies widely with structure. In particular, less lipophilic analogues, especially those bearing a localized, rather than resonance-stabilized, permanent positive charge, exhibit similar inhibitory activity to MPP + in ETP, but the inhibition in M w is not comparably enhanced. For these same analogues, the inhibitory activity in ETP is only weakly potentiated by tetraphenylborate. Since succinate was found to completely reverse the respiratory inhibition in M w induced by all types of MPP + analogues investigated, a common site 1 inhibition appears to be involved; thus the different inhibitory patterns observed must be due to structural factors governing membrane transport and distribution properties.