Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation

文献类型： 外文期刊

第一作者： Wu, Yongshu

作者： Wu, Yongshu;Yang, Yang;Qin, Xiaodong;Zhang, Zhixiong;Ullah, Munib;Li, Yanmin;Zhang, Zhidong

作者机构：

关键词： Mitochondrial unfolded protein response; eIF2 alpha phosphorylation; Heme-regulated inhibitor; Mitochondrial proteostasis

期刊名称：CELLULAR SIGNALLING （ 影响因子：3.7； 五年影响因子：4.2 ）

ISSN： 0898-6568

年卷期： 2024 年 123 卷

页码：

收录情况： SCI

摘要： The mitochondrial unfolded protein response (UPRmt) mt ) is triggered through eIF2 alpha phosphorylation in mammals. However, the mechanisms of UPRmt mt activation and the influence of eIF2 alpha phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt mt is a rapid and specific stress response that occurs through pharmacological induction of eIF2 alpha phosphorylation, along with the phosphorylation of eIF2 alpha, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2 alpha phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. mt . Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt mt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interaction with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2 alpha phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt mt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, mt , including its implications for human disease and pathobiology.

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