Ramsay R R, Kowal A T, Johnson M K, Salach J I, Singer T P
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Arch Biochem Biophys. 1987 Dec;259(2):645-9. doi: 10.1016/0003-9861(87)90531-5.
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.
1-甲基-4-苯基吡啶鎓（MPP+）对NADH脱氢酶的抑制作用导致ATP耗竭，这被认为可以解释1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）神经毒性表达中的细胞死亡。电子顺磁共振研究表明，MPP+对NADH脱氢酶的铁硫簇还原没有影响。用MPP+抑制的线粒体进行超声处理，并测量NADH氧化酶和NADH-Q还原酶的活性。NADH氧化酶活性没有完全恢复到对照水平，但NADH-Q还原酶活性与对照相同。琥珀酸氧化酶和琥珀酸-Q还原酶活性均未受到抑制。这些数据表明，MPP+与NADH脱氢酶的相互作用会干扰电子从最高电位的铁硫簇传递到内源性Q10，但通过添加少量水溶性Q类似物可以缓解这种抑制作用。在该位点的抑制足以解释呼吸抑制，并且未观察到对其他线粒体功能的抑制。
