Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity
Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity
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DOI：
10.1073/pnas.1310908110
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
Zhuang Jie;Ping-yuan Wang;Xinglu Huang;Xiaoyuan Chen;Ju-Gyeong Kang;P. Hwang
中科院分区：
文献类型：
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作者：
Zhuang Jie;Ping-yuan Wang;Xinglu Huang;Xiaoyuan Chen;Ju-Gyeong Kang;P. Hwang
p53是生物医学研究中研究最多的蛋白质之一，因为它在预防癌症中的重要性以及在许多生物过程中的直接或间接作用。它是一种核蛋白，对维持基因组完整性和调节基因表达至关重要。我们已经发现了一种分子机制，通过这种机制，p53易位到线粒体中，这取决于呼吸作用，并促进线粒体DNA氧化损伤的修复。p53在细胞核和线粒体区室之间的动态分配对癌症和p53在正常生理学中的许多其他基本功能具有重要意义。p53是一种重要的肿瘤抑制因子，调节线粒体呼吸，但核蛋白如何协调由两个独立基因组编码的细胞器的功能，这两个基因组都需要p53来保持其完整性，目前尚不清楚。在这里，我们报告酵母线粒体二硫键中继蛋白Mia 40（CHCHD 4）的哺乳动物同源物对于p53呼吸依赖性转运到线粒体中是必需的。在氧化应激的情况下，增加CHCHD4表达将p53分配到线粒体中并保护其基因组完整性，同时降低p53核定位和转录活性。相反，降低CHCHD4表达阻止p53的线粒体易位，同时增强其核定位和活性。因此，线粒体二硫键中继系统允许p53根据氧化代谢活性调节两个空间分离的基因组。
Significance p53 is one of the most highly studied proteins in biomedical research because of its importance in preventing cancer and its direct or indirect role in many biological processes. It is best known as a nuclear protein that is critical for maintaining genomic integrity and regulating gene expression. We have uncovered a molecular mechanism by which p53 translocates into the mitochondria, depending on respiration, and facilitates the repair of oxidative damage to mitochondrial DNA. The dynamic partitioning of p53 between the nuclear and mitochondrial compartments has important implications for cancer and the many other essential functions of p53 in normal physiology. p53, a critical tumor suppressor, regulates mitochondrial respiration, but how a nuclear protein can orchestrate the function of an organelle encoded by two separate genomes, both of which require p53 for their integrity, remains unclear. Here we report that the mammalian homolog of the yeast mitochondrial disulfide relay protein Mia40 (CHCHD4) is necessary for the respiratory-dependent translocation of p53 into the mitochondria. In the setting of oxidative stress, increased CHCHD4 expression partitions p53 into the mitochondria and protects its genomic integrity while decreasing p53 nuclear localization and transcriptional activity. Conversely, decreased CHCHD4 expression prevents the mitochondrial translocation of p53 while augmenting its nuclear localization and activity. Thus, the mitochondrial disulfide relay system allows p53 to regulate two spatially segregated genomes depending on oxidative metabolic activity.