The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
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DOI：
10.1016/j.cub.2016.06.002
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发表时间：
2016-08-08
期刊：
影响因子：
--
通讯作者：
Haynes CM
中科院分区：
文献类型：
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作者：
Fiorese CJ;Schulz AM;Lin YF;Rosin N;Pellegrino MW;Haynes CM
线粒体功能障碍在神经退行性疾病、糖尿病、癌症和病原体感染等人类疾病以及正常衰老过程中普遍存在。细胞通过激活被称为线粒体未折叠蛋白反应（UPRmt）的保护性转录程序来感知和响应线粒体功能障碍，该程序包括促进线粒体蛋白稳态和修复缺陷细胞器的基因。在秀丽隐杆线虫中的研究表明，UPRmt受转录因子ATFS-1调控，而ATFS-1受细胞器分配调控。正常情况下，ATFS-1在线粒体内积累，但在呼吸链功能障碍、高水平ROS或线粒体蛋白折叠应激时，一定比例的ATFS-1在细胞质中积累并运输到细胞核，在那里它激活UPRmt。虽然在哺乳动物中也有类似的转录反应，但UPRmt是如何调控的仍不清楚。在这里，我们描述了一种哺乳动物转录因子ATF5，它的调控与ATFS-1相似，并诱导了类似的转录反应。ATF5的表达可以挽救atfs-1缺陷蠕虫的UPRmt信号，需要与秀丽隐杆线虫相同的UPRmt启动子元件。此外，哺乳动物细胞需要ATF5在线粒体应激期间维持线粒体活性并促进细胞器恢复。综上所述，这些数据表明，从蠕虫到哺乳动物，UPRmt的调控都是保守的。
Mitochondrial dysfunction is pervasive in human pathologies such as neurodegeneration, diabetes, cancer and pathogen infections as well as during normal aging. Cells sense and respond to mitochondrial dysfunction by activating a protective transcriptional program known as the mitochondrial unfolded protein response (UPRmt), which includes genes that promote mitochondrial protein homeostasis and the recovery of defective organelles. Work in C. elegans has shown that the UPRmt is regulated by the transcription factor ATFS-1, which is regulated by organelle partitioning. Normally, ATFS-1 accumulates within mitochondria, but during respiratory chain dysfunction, high levels of ROS or mitochondrial protein folding stress, a percentage of ATFS-1 accumulates in the cytosol and traffics to the nucleus where it activates the UPRmt. While similar transcriptional responses have been described in mammals, how the UPRmt is regulated remains unclear. Here, we describe a mammalian transcription factor, ATF5, which is regulated similarly to ATFS-1 and induces a similar transcriptional response. ATF5 expression can rescue UPRmt signaling in atfs-1-deficient worms requiring the same UPRmt promoter element identified in C. elegans. Furthermore, mammalian cells require ATF5 to maintain mitochondrial activity during mitochondrial stress and to promote organelle recovery. Combined, these data suggest that regulation of the UPRmt is conserved from worms to mammals.