Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism

Abstract

4-Phenyl-N-methylpyridinium (MPP+), the oxidation product of the neurotoxic amine MPTP, is considerably more inhibitory to the oxidation of NAD+-linked substrates in intact mitochondria in State 3 than is 4-phenylpyridine. On adding uncouplers, the inhibition by MPP+ progressively diminishes, while the effect of 4-phenylpyridine remains. This is in accord with the fact that MPP+ is rapidly concentrated in the mitochondria by an energy-dependent process, while 4-phenylpyridine seems to enter passively with the concentration gradient. Collapse of the electrical gradient after addition of uncouplers thus leaves the inhibition by 4-phenylpyridine unaffected but causes efflux of MPP+ from the mitochondria and a reversal of its inhibitory action. In isolated inner membranes the inhibition of NADH oxidation via the respiratory chain by 4-phenylpyridine is much greater than by MPP+. MPTP and 4-phenyl-N-methylpyridinone also inhibit more than MPP+, whereas N-methylpyridinium has relatively little effect. The block is not at the point of entry of electrons into the flavoprotein since the NADH-ferricyanide activity is not inhibited by MPP+ at Vmax.