The inhibition site of MPP⁺, the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine is near the Q-binding site of NADH dehydrogenase

The inhibition of NADH dehydrogenase by 1-methyl-4-phenylpyridinium (MPP⁺) leading to ATP depletion has been proposed to explain cell death in the expression of the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Electron paramagnetic resonance studies show no effect of MPP⁺ on the reduction of the iron-sulfur clusters of NADH dehydrogenase. Mitochondria inhibited by MPP⁺ were sonicated and both the NADH oxidase and the NADH-Q reductase activities were measured. NADH oxidase activity was not fully restored to control levels, but NADH-Q reductase activity was the same as that of the control. Neither succinate-oxidase nor succinate-Q reductase activities were inhibited. These data indicate that MPP⁺ interaction with NADH dehydrogenase interferes with the passage of electrons from the iron-sulfur cluster of highest potential to endogenous Q₁₀ but that the inhibition can be relieved by the addition of a small, water-soluble Q analog. Inhibition at this site is sufficient to explain the inhibition of respiration and no inhibition of other mitochondrial functions was observed.