Drosophila CHIP protects against mitochondrial dysfunction by acting downstream of Pink1 in parallel with Parkin
Drosophila CHIP protects against mitochondrial dysfunction by acting downstream of Pink1 in parallel with Parkin
复制标题
果蝇 CHIP 通过与 Parkin 并行作用于 Pink1 下游来防止线粒体功能障碍
DOI：
10.1096/fj.201700011r
复制
发表时间：
2017-12-01
期刊：
影响因子：
4.8
通讯作者：
Duan, Ranhui
中科院分区：
文献类型：
--
作者：
Chen, Jia;Xue, Jin;Duan, Ranhui
线粒体激酶PTEN诱导的推定激酶1（PINK 1）和E3泛素连接酶Parkin在调节线粒体稳态的共同途径中起作用，从而促进帕金森病的发病机制。Hsc 70相互作用蛋白（CHIP）的羧基端作为热休克蛋白70/热休克蛋白90辅助分子伴侣介导蛋白质折叠或作为E3泛素连接酶降解靶蛋白。在这项研究中，果蝇CHIP的过表达抑制了果蝇中的一系列Pink 1突变表型，包括异常的翅膀姿势，胸部凹陷，运动缺陷，肌肉变性和多巴胺能神经元的丢失。Pink 1突变体的线粒体缺陷，如过度融合，ATP含量减少，嵴解体，被CHIP拯救，但不能拯救其连接酶死亡突变体。野生型CHIP在Parkin突变果蝇中改善了相似的表型和线粒体损伤。用空蝇突变体灭活CHIP导致线粒体缺陷，如3日龄胸部ATP含量降低，胸部线粒体DNA含量降低，60日龄线粒体形态缺陷。CHIP突变体没有加剧Pink 1突变果蝇的表型，但明显缩短了Parkin突变果蝇的寿命。这些结果表明，CHIP参与线粒体完整性，并可能与Parkin平行作用于Pink 1下游。陈杰，薛，J，阮，J.，赵，J，Tang，B.，段河，巴西-地果蝇CHIP通过与Parkin平行作用于Pink 1下游来保护线粒体功能障碍。
Mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin function in a common pathway to regulate mitochondrial homeostasis contributing to the pathogenesis of Parkinson disease. The carboxyl terminus of Hsc70-interacting protein (CHIP) acts as a heat shock protein 70/heat shock protein 90 cochaperone to mediate protein folding or as an E3 ubiquitin ligase to target proteins for degradation. In this study, overexpression of Drosophila CHIP suppressed a range of Pink1 mutant phenotypes in flies, including abnormal wing posture, thoracic indentation, locomotion defects, muscle degeneration, and loss of dopaminergic neurons. Mitochondrial defects of Pink1 mutant, such as excessive fusion, reduced ATP content, and crista disorganization, were rescued by CHIP but not its ligase-dead mutants. Similar phenotypes and mitochondrial impairment were ameliorated in Parkin mutant flies by wild-type CHIP. Inactivation of CHIP with null fly mutants resulted in mitochondrial defects, such as reduced thoracic ATP content at 3 d old, decreased thoracic mitochondrial DNA content, and defective mitochondrial morphology at 60 d old. CHIP mutants did not exacerbate the phenotypes of Pink1 mutant flies but markedly shortened the life span of Parkin mutant flies. These results indicate that CHIP is involved in mitochondrial integrity and may act downstream of Pink1 in parallel with Parkin.-Chen, J., Xue, J., Ruan, J., Zhao, J., Tang, B., Duan, R. Drosophila CHIP protects against mitochondrial dysfunction by acting downstream of Pink1 in parallel with Parkin.