Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans
Year: 2026
Type: preprint
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 (UPR mt ) 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 UPR mt , yet lifespan extension from Complex I impairment highly dependent on the UPR mt 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.
Institutions: Siriraj Hospital, Mahidol University, Ghent University
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
Awards: G827607322, G8628795943
OpenAlex ID: W7213460363