{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:10Z","timestamp":1792790350444,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,17]]},"group-title":"Cell Biology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"The National Research Council of Thailand (NRCT) and Mahidol University","award":["NRCT5-RSA63015-20"],"award-info":[{"award-number":["NRCT5-RSA63015-20"]}],"id":[{"id":"https:\/\/ror.org\/01znkr924","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mild reductions in mitochondrial electron transport chain (ETC) capacity paradoxically extend organismal lifespan, a conserved phenomenon termed mitohormesis. While the mitochondrial unfolded protein response (UPR\n                  <jats:sup>mt<\/jats:sup>\n                  ) and AMP-activated protein kinase (AMPK) are both established regulators of this process, whether distinct mitochondrial lesions converge on a single, unified survival mechanism remains unclear. By systematically dissecting the genetic architectures governing longevity in\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  , we demonstrate that targeted RNAi knockdown of Complex I (\n                  <jats:italic>nuo-6<\/jats:italic>\n                  ) and Complex IV (\n                  <jats:italic>cco-1<\/jats:italic>\n                  ) subunits activates fundamentally divergent downstream pathways. Both structural defects robustly induce the UPR\n                  <jats:sup>mt<\/jats:sup>\n                  , yet lifespan extension from Complex I impairment highly dependent on the UPR\n                  <jats:sup>mt<\/jats:sup>\n                  master regulator ATFS-1 while bypassing the AMPK ortholog AAK-2. Conversely, Complex IV-mediated longevity operates independent of ATFS-1 but requires AAK-2-driven metabolic reprogramming. Pharmacological intervention with metformin\u2014a Complex I inhibitor and AMPK activator\u2014further exposed complex-specific vulnerabilities: metformin markedly suppressed the longevity phenotype of\n                  <jats:italic>nuo-6;aak-2<\/jats:italic>\n                  mutants, whereas in\n                  <jats:italic>cco-1;aak-2<\/jats:italic>\n                  animals it produced a trend toward lifespan extension that appeared independent of AAK-2. Together, these findings challenge the view of mitohormesis as a uniform response, revealing instead that cells engage specialized, molecularly tailored retrograde signaling networks to govern lifespan and respond to pharmacological interventions.\n                <\/jats:p>","DOI":"10.64898\/2026.09.15.751667","type":"posted-content","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:25:25Z","timestamp":1789640725000},"source":"Crossref","is-referenced-by-count":0,"title":["Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient\n                  <i>C. elegans<\/i>"],"prefix":"10.64898","author":[{"given":"Chutipong","family":"Chiamkunakorn","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juthakorn","family":"Poothong","sequence":"additional","affiliation":[{"name":"Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kongtana","family":"Trakarnsanga","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0085-8264","authenticated-orcid":false,"given":"Bart P.","family":"Braeckman","sequence":"additional","affiliation":[{"name":"Department of Biology, Ghent University, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2471-9696","authenticated-orcid":false,"given":"Wichit","family":"Suthammarak","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 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