{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:15:13Z","timestamp":1785402913198,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,12]]},"group-title":"Genetics","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01h531d29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of\n                  <jats:italic>fmo-2<\/jats:italic>\n                  in the long lifespan of genetic mitochondrial mutants in\n                  <jats:italic>C. elegans<\/jats:italic>\n                  . We found that\n                  <jats:italic>fmo-2<\/jats:italic>\n                  , but not other\n                  <jats:italic>fmo<\/jats:italic>\n                  genes, are specifically upregulated in the long-lived mitochondrial mutants\n                  <jats:italic>clk-1, isp-1<\/jats:italic>\n                  and\n                  <jats:italic>nuo-6<\/jats:italic>\n                  . Disruption of\n                  <jats:italic>fmo-2<\/jats:italic>\n                  through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that\n                  <jats:italic>fmo-2<\/jats:italic>\n                  is required for lifespan extension in these worms. Moreover, signaling molecules that have been shown to be involved in upregulation of\n                  <jats:italic>fmo-2<\/jats:italic>\n                  are also required for the long life of\n                  <jats:italic>clk-1, isp-1<\/jats:italic>\n                  and\n                  <jats:italic>nuo-6<\/jats:italic>\n                  mutants including HLH-30, NHR-49 and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in\n                  <jats:italic>clk-1<\/jats:italic>\n                  mutants on the expression of\n                  <jats:italic>fmo-2<\/jats:italic>\n                  . We found that in all cases, genes required for\n                  <jats:italic>clk-1<\/jats:italic>\n                  longevity are also required for the upregulation of\n                  <jats:italic>fmo-2<\/jats:italic>\n                  in\n                  <jats:italic>clk-1<\/jats:italic>\n                  worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.\n                <\/jats:p>","DOI":"10.64898\/2026.02.10.705198","type":"posted-content","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:15:15Z","timestamp":1770898515000},"source":"Crossref","is-referenced-by-count":0,"title":["Mild Mitochondrial Impairment Activates Overlapping Longevity Pathways Converging on the Flavin-Containing Monooxygenase FMO-2"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8376-9605","authenticated-orcid":false,"given":"Jeremy M","family":"Van Raamsdonk","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada"},{"name":"Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada"},{"name":"Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026021413250466000_2026.02.10.705198v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1173507"},{"key":"2026021413250466000_2026.02.10.705198v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006348"},{"key":"2026021413250466000_2026.02.10.705198v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2010.10.057"},{"issue":"1","key":"2026021413250466000_2026.02.10.705198v1.4","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s12915-018-0615-3","article-title":"Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways","volume":"16","year":"2018","journal-title":"BMC biology"},{"key":"2026021413250466000_2026.02.10.705198v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac9257"},{"key":"2026021413250466000_2026.02.10.705198v1.6","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1038\/ncomms3267","article-title":"The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans","volume":"4","year":"2013","journal-title":"Nature communications"},{"issue":"3","key":"2026021413250466000_2026.02.10.705198v1.7","doi-asserted-by":"crossref","first-page":"e1006695","DOI":"10.1371\/journal.pgen.1006695","article-title":"Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans","volume":"13","year":"2017","journal-title":"PLoS Genet"},{"key":"2026021413250466000_2026.02.10.705198v1.8","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12743"},{"issue":"1","key":"2026021413250466000_2026.02.10.705198v1.9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12964-025-02567-4","article-title":"Bacterial exopolysaccharides mediate activation of flavin-containing monooxygenase 2 to extend lifespan in Caenorhabditis elegans","volume":"24","year":"2025","journal-title":"Cell Commun Signal"},{"key":"2026021413250466000_2026.02.10.705198v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2016.08.008"},{"key":"2026021413250466000_2026.02.10.705198v1.11","doi-asserted-by":"crossref","unstructured":"Soo SK , Traa A , Rudich PD , Mistry M , & Van Raamsdonk JM (2021) Activation of mitochondrial unfolded protein response protects against multiple exogenous stressors. 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