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Cell Rep. 2019 Jul 23;28(4):1050-1062.e6. doi: 10.1016/j.celrep.2019.06.078.

Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Institute for Brain Sciences, Nanjing University, 12 Xuefu Rd, Pukou, Nanjing, Jiangsu 210061, China.
2
MDI Biological Laboratory, 159 Old Bar Harbor Rd., Salisbury Cove, ME 04672, USA.
3
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA. Electronic address: pkapahi@buckinstitute.org.
4
MDI Biological Laboratory, 159 Old Bar Harbor Rd., Salisbury Cove, ME 04672, USA. Electronic address: arogers@mdibl.org.
5
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Institute for Brain Sciences, Nanjing University, 12 Xuefu Rd, Pukou, Nanjing, Jiangsu 210061, China. Electronic address: chendi@nju.edu.cn.

Abstract

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.

KEYWORDS:

AMPK; C. elegans; UPR(mt); aging; daf-2 rsks-1; germline; mRNA translation

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