{
  "abstract": "Mild reductions in mitochondrial electron transport chain (ETC) capacity paradoxically extend organismal lifespan, a conserved phenomenon termed mitohormesis. While the mitochondrial unfolded protein response (UPRmt) 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 Caenorhabditis elegans, we demonstrate that targeted RNAi knockdown of Complex I (nuo-6) and Complex IV (cco-1) subunits activates fundamentally divergent downstream pathways. Both structural defects robustly induce the UPRmt, yet lifespan extension from Complex I impairment highly dependent on the UPRmt 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 - a Complex I inhibitor and AMPK activator - further exposed complex-specific vulnerabilities: metformin markedly suppressed the longevity phenotype of nuo-6;aak-2 mutants, whereas in cco-1;aak-2 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "C. Chiamkunakorn"
    },
    {
      "name": "J. Poothong"
    },
    {
      "name": "K. Trakarnsanga"
    },
    {
      "name": "B. P. Braeckman"
    },
    {
      "affs": [
        0
      ],
      "name": "W. Suthammarak"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cvnk26nkxre7f.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.15.751667",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.15.751667v1.full",
  "id": "cvnk26nkxre7f",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.15.751667v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cell biology"
    ],
    [
      "openalex",
      "1302|Genetics, Aging, and Longevity in Model Organisms"
    ]
  ],
  "openalex": "W7213460363",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.15.751667v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-15",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cvnk26nkxre7f.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:49Z",
      "native_id": "10.64898/2026.09.15.751667",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.15.751667v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans",
  "title_text": "Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:49Z",
  "url": "https://research.draconitic.com/paper/cvnk26nkxre7f",
  "venue": "bioRxiv",
  "versions": []
}