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

Arwen W. Gao; Gaby El Alam; Amélia Lalou; Terytty Yang Li; Marte Molenaars; Yunyun Zhu; Katherine A. Overmyer; Evgenia Shishkova; Kevin Hof; Maroun Bou Sleiman; Riekelt H. Houtkooper; Joshua J. Coon; Johan Auwerx

iScience (Feb 2022)

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

Arwen W. Gao,
Gaby El Alam,
Amélia Lalou,
Terytty Yang Li,
Marte Molenaars,
Yunyun Zhu,
Katherine A. Overmyer,
Evgenia Shishkova,
Kevin Hof,
Maroun Bou Sleiman,
Riekelt H. Houtkooper,
Joshua J. Coon,
Johan Auwerx

Affiliations

Arwen W. Gao: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Gaby El Alam: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Amélia Lalou: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Terytty Yang Li: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Marte Molenaars: Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 Amsterdam, AZ, the Netherlands
Yunyun Zhu: Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53506, USA
Katherine A. Overmyer: National Center for Quantitative Biology of Complex Systems, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53515, USA; Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53506, USA
Evgenia Shishkova: National Center for Quantitative Biology of Complex Systems, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53515, USA
Kevin Hof: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Maroun Bou Sleiman: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Riekelt H. Houtkooper: Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 Amsterdam, AZ, the Netherlands
Joshua J. Coon: National Center for Quantitative Biology of Complex Systems, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53515, USA; Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53506, USA; Department of Chemistry, University of Wisconsin, Madison, WI 53506, USA
Johan Auwerx: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Corresponding author

Journal volume & issue: Vol. 25, no. 2
p. 103734

Abstract

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Summary: 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 lifespan are consistent across different genetic backgrounds through different regulators.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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