Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity
Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity
复制标题
非自主线粒体应激反应的转化调节可促进长寿。
DOI：
10.1016/j.celrep.2019.06.078
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发表时间：
2019-07-23
期刊：
影响因子：
8.8
通讯作者：
Chen, Di
中科院分区：
文献类型：
--
作者：
Lan, Jianfeng;Rollins, Jarod A.;Chen, Di
mRNA翻译减少延缓衰老，但其潜在机制仍有待探索。IGF-2（IGF-1受体）和RSKS-1（核糖体S6激酶/S6 K）的突变导致C.优雅的为了了解翻译调控在这一过程中的作用，我们进行了多聚体分析，并确定了转录调控的核糖体和细胞色素c（CYC-2.1）基因作为长寿的关键介质。cyc-2.1敲低通过激活肠道线粒体未折叠蛋白反应（UPRmt）、线粒体分裂和AMP激活激酶（AMPK）显着延长寿命。种系是cyc-2.1调节寿命的关键组织，种系特异性cyc-2.1敲低非自主激活肠道UPRmt和AMPK。此外，RNA结合蛋白GLD-1介导的生殖细胞中cyc-2.1的翻译抑制对于UPRmt的非自主激活和daf-2 rsks-1突变体的协同寿命是重要的。总而言之，这些结果说明了胰岛素样信号和S6 K在调节寿命中的非自主性线粒体应激反应机制。
Reduced mRNA translation delays aging, but the underlying mechanisms remain underexplored. Mutations in both DAF-2 (IGF-1 receptor) and RSKS-1 (ribosomal S6 kinase/S6K) cause synergistic lifespan extension in C. elegans. To understand the roles of translational regulation in this process, we performed polysomal profiling and identified translationally regulated ribosomal and cytochrome c (CYC-2.1) genes as key mediators of longevity. cyc-2.1 knockdown significantly extends lifespan by activating the intestinal mitochondrial unfolded protein response (UPRmt), mitochondrial fission, and AMP-activated kinase (AMPK). The germline serves as the key tissue for cyc-2.1 to regulate lifespan, and germline-specific cyc-2.1 knockdown non-autonomously activates intestinal UPRmt and AMPK. Furthermore, the RNA-binding protein GLD-1 -mediated translational repression of cyc-2.1 in the germline is important for the non-autonomous activation of UPRmt and synergistic longevity of the daf-2 rsks-1 mutant. Altogether, these results illustrate a translationally regulated non-autonomous mitochondrial stress response mechanism in the modulation of lifespan by insulin-like signaling and S6K.