Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria.
Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria.
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DOI：
10.1016/s0021-9258(19)57434-8
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发表时间：
1986-06
期刊：
影响因子：
--
通讯作者：
R. Ramsay;T. Singer
中科院分区：
文献类型：
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作者：
R. Ramsay;T. Singer
1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 是某些批次非法海洛因替代品中的杂质，已知会导致吸毒者和灵长类动物出现帕金森病症状和黑质纹状体细胞变性。神经毒性取决于脑细胞中的单胺氧化酶将 MPTP 氧化为二氢吡啶鎓形式，后者进一步氧化为 N-甲基-4-苯基吡啶鎓 (MPP+)，即 4 电子氧化产物。后者被广泛认为是造成神经元破坏的化合物，并且内膜的 NADH 脱氢酶被认为是其目标。然而，这种酶仅在非常高浓度的 MPP+ 下才会受到抑制，而 MPTP 处理的动物黑质纹状体细胞中 MPP+ 的稳态浓度要低几个数量级。现在，通过发现线粒体中 MPP+ 的供能摄取系统，该悖论已得到解决，该系统可以在微摩尔外部浓度下将线粒体中的 MPP+ 快速浓缩至非常高的浓度。该过程取决于膜的电梯度，Km 约为 5 mM，并被呼吸抑制剂和解偶联剂完全阻断。
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an impurity in certain batches of illicit heroin substitutes, is known to cause parkinsonian symptoms and degeneration of the nigrostriatal cells in drug abusers and primates. Neurotoxicity depends on oxidation of MPTP by monoamine oxidase in brain cells to the dihydropyridinium form, which is further oxidized to N-methyl-4-phenylpyridinium (MPP+), the 4-electron oxidation product. The latter is widely believed to be the compound responsible for neuronal destruction and the NADH dehydrogenase of the inner membrane has been postulated to be its target. This enzyme is inhibited, however, only at very high concentrations of MPP+, while the steady-state concentration of MPP+ in the nigrostriatal cells of MPTP-treated animals is several orders of magnitude lower. This paradox has now been resolved by the discovery of an energized uptake system for MPP+ in mitochondria which rapidly concentrates MPP+ to very high concentrations in the mitochondria at micromolar external concentrations. The process is dependent on the electrical gradient of the membrane, has a Km of about 5 mM, and is completely blocked by respiratory inhibitors and uncouplers.