Ramsay R R, Salach J I, Dadgar J, Singer T P
Biochem Biophys Res Commun. 1986 Feb 26;135(1):269-75. doi: 10.1016/0006-291x(86)90972-1.
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.
神经毒性胺MPTP的氧化产物4-苯基-N-甲基吡啶鎓（MPP⁺），在状态3下对完整线粒体中NAD⁺连接底物氧化的抑制作用比4-苯基吡啶强得多。加入解偶联剂后，MPP⁺的抑制作用逐渐减弱，而4-苯基吡啶的作用依然存在。这与以下事实相符：MPP⁺通过能量依赖过程迅速在线粒体中浓缩，而4-苯基吡啶似乎是顺着浓度梯度被动进入。加入解偶联剂后跨膜电位梯度崩溃，因此4-苯基吡啶的抑制作用不受影响，但导致MPP⁺从线粒体中流出并逆转其抑制作用。在分离的内膜中，4-苯基吡啶通过呼吸链对NADH氧化的抑制作用比MPP⁺大得多。MPTP和4-苯基-N-甲基吡啶酮的抑制作用也比MPP⁺强，而N-甲基吡啶鎓的作用相对较小。该阻断作用并非发生在电子进入黄素蛋白的位点，因为在最大反应速度时MPP⁺并不抑制NADH-铁氰化物活性。
