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.
Ramsay
R R
RR
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Kowal
A T
AT
Johnson
M K
MK
Salach
J I
JI
Singer
T P
TP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001665:Binding Sites; D003579:Cytochrome Reductases / Q000037:antagonists & inhibitors*; D004578:Electron Spin Resonance Spectroscopy; D042963:Electron Transport Complex II; D005260:Female; D008930:Mitochondria, Liver / Q000201:enzymology; D009097:Multienzyme Complexes / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011808:Quinone Reductases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013385:Succinate Dehydrogenase / Q000378:metabolism
D009097:Multienzyme Complexes; D011725:Pyridines; D011726:Pyridinium Compounds; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D003579:Cytochrome Reductases; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D009245:NADH Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium