Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease
Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease
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DOI：
10.1016/j.bbadis.2011.02.013
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发表时间：
2011-06-01
影响因子：
6.2
通讯作者：
Chakrabarti, Sasanka
中科院分区：
文献类型：
--
作者：
Jana, Sirsendu;Sinha, Maitrayee;Chakrabarti, Sasanka
研究表明，在体外长期孵育过程中，多巴胺以剂量依赖的方式诱导分离的大鼠脑线粒体膜去极化和磷酸化能力丧失，而氧自由基清除剂和金属螯合剂不能阻止这一现象。然而，多巴胺对脑线粒体的作用可被还原型谷胱甘肽和N-乙酰半胱氨酸显著阻止，并被孵育介质中存在的酪氨酸酶促进。结果提示，在这种情况下，多巴胺的苯醌氧化产物参与了线粒体的损伤。当PC12细胞暴露于不同浓度的多巴胺(100-400 mU M)长达24小时时，可观察到不同程度的线粒体生物能量功能的明显损害，并伴有细胞活力的显著丧失(近40%)，表现为细胞核的凋亡性改变以及caspase3和caspase9活性的升高，而N-乙酰半胱氨酸显著地阻止了多巴胺的这些作用。N-乙酰半胱氨酸还几乎完全阻断了多巴胺引起的PC12细胞内线粒体部分活性氧产生和藜麦蛋白加合物形成的增加，以及培养基中苯醌产物的积累。MAO-A的抑制剂Clorgyline可显著减少多巴胺诱导的PC12细胞内活性氧的形成，但对多巴胺诱导的藜麦蛋白加合物形成、线粒体功能障碍、细胞死亡和caspase激活只有轻微的保护作用。结果表明，在多巴胺的细胞毒性作用中，主要参与的是苯二酚氧化产物，而不是活性氧，线粒体损伤在后一过程中起核心作用。这些数据对帕金森氏病的发病机制有明确的影响。(C)2011爱思唯尔B.V.保留所有权利。
The study has demonstrated that dopamine induces membrane depolarization and a loss of phosphorylation capacity in dose-dependent manner in isolated rat brain mitochondria during extended in vitro incubation and the phenomena are not prevented by oxyradical scavengers or metal chelators. Dopamine effects on brain mitochondria are, however, markedly prevented by reduced glutathione and N-acetyl cysteine and promoted by tyrosinase present in the incubation medium. The results imply that quinone oxidation products of dopamine are involved in mitochondrial damage under this condition. When PC12 cells are exposed to dopamine in varying concentrations (100-400 mu M) for up to 24 h, a pronounced impairment of mitochondrial bio-energetic functions at several levels is observed along with a significant (nearly 40%) loss of cell viability with features of apoptotic nuclear changes and increased activities of caspase 3 and caspase 9 and all these effects of dopamine are remarkably prevented by N-acetyl cysteine. N-acetyl cysteine also blocks nearly completely the dopamine induced increase in reactive oxygen species production and the formation of quinoprotein adducts in mitochondrial fraction within PC12 cells and also the accumulation of quinone products in the culture medium. Clorgyline, an inhibitor of MAO-A, markedly decreases the formation of reactive oxygen species in PC12 cells upon dopamine exposure but has only mild protective actions against quinoprotein adduct formation, mitochondrial dysfunctions, cell death and caspase activation induced by dopamine. The results have indicated that quinone oxidation products and not reactive oxygen species are primarily involved in cytotoxic effects of dopamine and the mitochondrial impairment plays a central role in the latter process. The data have clear implications in the pathogenesis of Parkinson's disease. (C) 2011 Elsevier B.V. All rights reserved.