Mitochondrial dysfunction induced by knockdown of mortalin is rescued by Parkin
Mitochondrial dysfunction induced by knockdown of mortalin is rescued by Parkin
复制标题
DOI：
10.1016/j.bbrc.2011.05.116
复制
发表时间：
2011-06-24
影响因子：
3.1
通讯作者：
Liu, Wen
中科院分区：
文献类型：
--
作者：
Yang, Hui;Zhou, Xiaoping;Liu, Wen
帕金森氏基因突变是常染色体隐性帕金森氏病(PD)最常见的病因。作为一种e3泛素连接酶，Parkin与线粒体动力学和线粒体自噬有关。Mortalin是一种分子伴侣，主要位于线粒体中，在线粒体中起维持线粒体稳态和对抗氧化应激损伤的作用。在PD患者受影响的脑区观察到mortalin的表达水平降低。Mortalin还与多种pd相关蛋白相互作用，在帮助天然蛋白重折叠和将蛋白质导入线粒体基质中起着不可或缺的作用。因此，本研究的主要目的是研究mortalin敲低引起的线粒体功能障碍，并测试Parkin过表达是否可以挽救这种影响。我们发现，在h2o2诱导的应激条件下，慢病毒介导的HeLa细胞中mortalin的敲低导致线粒体膜电位的崩溃，活性氧的异常积累和线粒体形态的明显改变。值得注意的是，帕金过表达挽救了这些线粒体异常。在表达Parkin的HeLa细胞中，用羰基氰化3-氯苯基腙（CCCP）处理内源性mortalin和野生型Parkin时，检测到它们的免疫共沉淀。综上所述，我们认为mortalin表达水平的相对降低及其与Parkin相互作用的减弱可能会影响其在线粒体功能中的作用。(C) 2011爱思唯尔公司版权所有。
Mutations in the parkin gene are the most common cause of autosomal recessive Parkinson's disease (PD). As an E3-ubiquitin ligase, Parkin is associated with mitochondrial dynamics and mitophagy. Mortalin, a molecular chaperone, is located primarily in mitochondria, where it functions to maintain mitochondrial homeostasis and antagonize oxidative stress injury. A reduced expression level of mortalin has been observed in the affected brain regions of PD patients. Mortalin also interacts with a variety of PD-related proteins and plays an indispensible role in helping native protein refolding and importing proteins into the mitochondrial matrix. Thus, the main aims of the present study were to investigate mitochondrial dysfunction induced by knockdown of mortalin and to test whether Parkin overexpression could rescue this effect. We found that lentivirus-mediated knockdown of mortalin in HeLa cells resulted in a collapse of mitochondrial membrane potential, an abnormal accumulation of reactive oxygen species and apparent alterations in mitochondrial morphology under H2O2-induced stress conditions. Remarkably, Parkin overexpression rescued these mitochondrial abnormalities. In HeLa cells expressing Parkin, co-immunoprecipitation of endogenous mortalin and wild-type Parkin was detected when they were treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In conclusion, we indicate that the relatively decreased mortalin expression level and its impaired interaction with Parkin could affect its roles in mitochondrial function. (C) 2011 Elsevier Inc. All rights reserved.