Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.
Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.
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DOI：
10.1126/science.1223560
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发表时间：
2012-08-03
期刊：
影响因子：
--
通讯作者：
Haynes CM
中科院分区：
文献类型：
--
作者：
Nargund AM;Pellegrino MW;Fiorese CJ;Baker BM;Haynes CM
为了更好地理解对线粒体功能障碍的反应，我们研究了与应激相关的激活转录因子-1（ATFS-1）感知线粒体应激并在线粒体未折叠蛋白反应（UPRmt）期间与细胞核通信的机制。我们发现，调控的关键点是ATFS-1的线粒体输入效率。除了核定位序列外，ATFS-1还具有氨基末端线粒体靶向序列，这对于UPRmt抑制是必需的。通常，ATFS-1被输入线粒体并降解。然而，在线粒体应激期间，输入效率降低，允许一定百分比的ATFS-1在细胞质中积累并运输到细胞核。我们的研究结果表明，细胞通过ATFS-1监测线粒体输入效率，以协调线粒体功能障碍的水平与保护性转录反应。
To better understand the response to mitochondrial dysfunction, we examined the mechanism by which Activating Transcription Factor associated with Stress-1 (ATFS-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPRmt). We found that the key point of regulation was the mitochondrial import efficiency of ATFS-1. In addition to a nuclear localization sequence, ATFS-1 has an amino-terminal mitochondrial targeting sequence, which was essential for UPRmt repression. Normally, ATFS-1 is imported into mitochondria and degraded. However, during mitochondrial stress, import efficiency was reduced allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus. Our results show that cells monitor mitochondrial import efficiency via ATFS-1 to coordinate the level of mitochondrial dysfunction with the protective transcriptional response.
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