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bioRxiv · 10.64898/2026.09.15.751667

Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans

Chiamkunakorn, C.·Poothong, J.·Trakarnsanga, K.·Braeckman, B. P.·Suthammarak, W.
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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.

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Chiamkunakorn, C., Poothong, J., Trakarnsanga, K., Braeckman, B. P., Suthammarak, W.. 2026-09-17. Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans. https://doi.org/10.64898/2026.09.15.751667

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