The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism
The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism
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DOI：
10.1016/s0925-4439(98)00083-0
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发表时间：
1999-01-06
影响因子：
6.2
通讯作者：
Bennett, JP
中科院分区：
文献类型：
--
作者：
Cassarino, DS;Parks, JK;Bennett, JP
线粒体转换孔(MTP)在许多情况下都是细胞损伤和死亡的中介。MTP在包括活性氧物种和电子传输链抑制在内的刺激下开放。散发性帕金森病(PD)以氧化应激为特征，具体涉及电子传递链复合体I的缺陷。为了探讨MTP在PD模型中的可能作用，我们检测了复合体I抑制剂和凋亡诱导毒素N-甲基-4-苯基吡啶(MPP+)对环孢素A(CsA)敏感的线粒体肿胀和细胞色素c释放的影响。MPP+还可引起肝线粒体细胞色素c的释放。鱼藤酮是一种经典的非竞争性复合体I抑制剂，可完全抑制MPP+诱导的细胞色素c的肿胀和释放。MPP+诱导的通透性转变与一氧化氮和腺苷转运体抑制剂苍术苷协同作用，并与二硫醇残基的苯基砷氧交联剂相加。CsA、钙单一转运体抑制剂Ru红、疏水二硫试剂N-乙基马来酰亚胺、丁卡因以及自由基清除酶过氧化氢酶和超氧化物歧化酶均可阻断MPP+诱导的孔道开放和细胞色素c的释放。MPP+的神经毒性可能不仅来自它对复合体I的抑制和随后的ATP耗竭，还来自它开放MTP和释放已知的与细胞凋亡有关的线粒体因子包括钙离子和细胞色素C的能力。(C)1999 Elsevier Science B.V.保留所有权利。
The mitochondrial transition pore (MTP) is implicated as a mediator of cell injury and death in many situations. The MTP opens in response to stimuli including reactive oxygen species and inhibition of the electron transport chain. Sporadic Parkinson's disease (PD) is characterized by oxidative stress and specifically involves a defect in complex I of the electron transport chain. To explore the possible involvement of the MTP in PD models, we tested the effects of the complex I inhibitor and apoptosis-inducing toxin N-methyl-4-phenylpyridinium (MPP+) on cyclosporin A (CsA)-sensitive mitochondrial swelling and release of cytochrome c. In the presence of Ca2+ and P-i, MPP+ induced a permeability transition in both liver and brain mitochondria. MPP+ also caused release of cytochrome c from liver mitochondria. Rotenone, a classic non-competitive complex I inhibitor, completely inhibited MPP+-induced swelling and release of cytochrome c. The MPP+-induced permeability transition was synergistic with nitric oxide and the adenine nucleotide translocator inhibitor atractyloside, and additive with phenyl arsine oxide cross-linking of dithiol residues. MPP+-induced pore opening and cytochrome c release were blocked by CsA, the Ca2+ uniporter inhibitor ruthenium red, the hydrophobic disulfide reagent N-ethylmaleimide, butacaine, and the free radical scavenging enzymes catalase and superoxide dismutase. MPP+ neurotoxicity may derive from not only its inhibition of complex I and consequent ATP depletion, but also from its ability to open the MTP and to release mitochondrial factors including Ca2+ and cytochrome c known to be involved in apoptosis. (C) 1999 Elsevier Science B.V. All rights reserved.