CHCHD4 (MIA40) and the mitochondrial disulfide relay system.
CHCHD4 (MIA40) and the mitochondrial disulfide relay system.
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DOI：
10.1042/bst20190232
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发表时间：
2021-02-26
影响因子：
3.9
通讯作者：
Ashcroft M
中科院分区：
文献类型：
--
作者：
Al-Habib H;Ashcroft M
线粒体是正常细胞生理学的关键，因为它们在多种细胞功能和过程中发挥关键作用，包括呼吸和生物能量和生物合成途径的调节，以及调节细胞信号传导和转录网络。以这种方式，线粒体是细胞的稳态机制的核心，并且因此线粒体功能障碍是包括线粒体疾病和癌症在内的多种疾病的病理学基础。线粒体输入途径和靶向机制提供了将数百种对细胞器的许多功能至关重要的核编码线粒体蛋白转运到线粒体中的手段。一种这样的输入途径是线粒体膜间隙（IMS）内的高度进化保守的二硫键中继系统（DRS），由此蛋白质经历一种形式的氧化依赖性蛋白质输入。DRS的一个中心组分是含有氧化还原酶卷曲螺旋螺旋（CHCH）结构域的蛋白4（CHCHD4，也称为MIA40），是酵母Mia40的人类同源物。在这里，我们总结了我们对CHCHD4和DRS在生理学和疾病中的作用的理解的最新进展，特别关注CHCHD4在调节细胞对低氧（缺氧）和癌症代谢的反应中的重要性。
Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the regulation of bioenergetic and biosynthetic pathways, as well as regulating cellular signalling and transcriptional networks. In this way, mitochondria are central to the cell's homeostatic machinery, and as such mitochondrial dysfunction underlies the pathology of a diverse range of diseases including mitochondrial disease and cancer. Mitochondrial import pathways and targeting mechanisms provide the means to transport into mitochondria the hundreds of nuclear-encoded mitochondrial proteins that are critical for the organelle's many functions. One such import pathway is the highly evolutionarily conserved disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS), whereby proteins undergo a form of oxidation-dependent protein import. A central component of the DRS is the oxidoreductase coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein 4 (CHCHD4, also known as MIA40), the human homologue of yeast Mia40. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating the cellular response to low oxygen (hypoxia) and metabolism in cancer.