4.7 Article

Article Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains

期刊

ISCIENCE
卷 25, 期 2, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.isci.2022.103734

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资金

  1. Ecole Polytechnique Federale de Lausanne (EPFL)
  2. European Research Council [ERC-AdG-787702]
  3. Swiss National Science Foundation [SNSF 31003A_179435]
  4. Global Research Laboratory (GRL) National Research Foundation of Korea [NRF 2017K1A1A2013124]
  5. Accelerator prize by the United Mitochondrial Disease Foundation [PF-19-0232]
  6. Human Frontier Science Program [LT000731/2018-L]
  7. National Institute of General Medical Sciences [P41 GM108538]

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The mitochondrial unfolded protein response (UPRmt) is a potential pharmacological target for aging and age-related diseases. Through an integrative analysis of omics datasets, researchers found that activation of UPRmt through doxycycline (Dox) prolonged the lifespan of genetically divergent worm strains. The study revealed shared and strain-specific mechanisms of the beneficial effects of Dox-induced UPRmt on lifespan, involving impacts on mitochondria, defense response, and lipid metabolism.
The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different signaling layers in animals with different genetic backgrounds is lacking. Here, we applied systems approaches to investigate the effect of UPRmt induced by doxycycline (Dox) on transcriptome, proteome, and lipidome in two genetically divergent worm strains, named N2 and CB4856. From the integrated omics datasets, we found that Dox prolongs lifespan of both worm strains through shared and strain-specific mechanisms. Specifically, Dox strongly impacts mitochondria, upregulates defense response, and lipid metabolism, while decreasing triglycerides. We further validated that lipid genes acs-2/20 and fat-7/6 were required for Dox-induced UPRmt and longevity in N2 and CB4856 worms, respectively. Our data have translational value as they indicate that the beneficial effects of Dox-induced UPRmt on life span are consistent across different genetic backgrounds through different regulators.

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