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
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.
