Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c.
Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c.
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DOI：
10.1038/ncomms15500
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发表时间：
2017-06-07
影响因子：
16.6
通讯作者：
Hattori N
中科院分区：
文献类型：
--
作者：
Meng H;Yamashita C;Shiba-Fukushima K;Inoshita T;Funayama M;Sato S;Hatta T;Natsume T;Umitsu M;Takagi J;Imai Y;Hattori N
在一些帕金森病（PD）病例中已发现CHCHD 2突变。为了了解CHCHD 2的生理和病理作用，我们操纵了CHCHD 2在果蝇和哺乳动物细胞中的表达。果蝇中CHCHD 2的丢失导致线粒体中基质结构异常和氧呼吸受损，导致氧化应激、多巴胺能神经元丢失和随年龄增长的运动功能障碍。这些PD相关表型通过翻译抑制剂4 E-BP的过表达和通过引入人CHCHD 2而不是其PD相关突变体来拯救。在果蝇中，CHCHD 2被各种线粒体应激上调，包括线粒体基因组的不稳定和未折叠蛋白应激。CHCHD 2与Bax抑制剂-1超家族成员MICS 1一起沿着与细胞色素c结合，并调节细胞死亡信号传导，表明CHCHD 2在响应线粒体应激的氧化磷酸化和细胞死亡中动态调节细胞色素c的功能。CHCHD 2的突变与帕金森病有关。在本文中，作者研究了CHCHD 2在果蝇和哺乳动物细胞中的生理和病理作用，发现它通过稳定细胞色素c来调节线粒体呼吸。
Mutations in CHCHD2 have been identified in some Parkinson's disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of the translation inhibitor 4E-BP and by the introduction of human CHCHD2 but not its PD-associated mutants. CHCHD2 is upregulated by various mitochondrial stresses, including the destabilization of mitochondrial genomes and unfolded protein stress, in Drosophila. CHCHD2 binds to cytochrome c along with a member of the Bax inhibitor-1 superfamily, MICS1, and modulated cell death signalling, suggesting that CHCHD2 dynamically regulates the functions of cytochrome c in both oxidative phosphorylation and cell death in response to mitochondrial stress. Mutations in CHCHD2 are associated with Parkinson's disease. Here the authors investigate the physiological and pathological roles of CHCHD2 in Drosophila and mammalian cells, and find that it regulates mitochondrial respiration through stabilizing cytochrome c.