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Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity
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Jul 23 2019
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Source: Cell Rep. 28(4):1050-1062.e6
[PDF-1.84 MB]
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Alternative Title:Cell Rep
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Description: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 (UPR|), 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 UPR| 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 UPR| 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.
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Pubmed ID:31340143
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Pubmed Central ID:PMC6684276
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Funding:R01 AG045835/NIA NIH HHS/National Institute on Aging/United States ; R21 AG056743/NIA NIH HHS/National Institute on Aging/United States ; P40 OD010440/ODCDC CDC HHS/Office of the Director/United States ; R21 AG053066/NIA NIH HHS/National Institute on Aging/United States ; P20 GM104318/NIGMS NIH HHS/National Institute of General Medical Sciences/United States ; ... More +
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Volume:28
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Issue:4
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