Secondary inhibition of 2-ketoglutarate dehydrogenase complex by MPTP

The parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridine (MPP) acts through inhibition of complex I of the electron transport chain. Recent evidence suggests that it may also act through inhibition of 2-ketoglutarate dehydrogenase complex (KDHC). We confirmed this observation in isolated rat liver mitochondria but found that this inhibition is prevented by preincubation with the radical quencher, cysteine (Cys). KDHC is also inhibited by the NO generator S-nitroso-N-acetyl-penicillamine (SNAP) and this inhibition is similarly blocked bycysteine. MPP may inhibit KDHC secondary through a radical-mediated event rather than through directinteraction with KDHC.