Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans
- 1Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University
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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BibTeX
@misc{chiamkunakorn2026divergent,
title = {{Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans}},
author = {C. Chiamkunakorn and J. Poothong and K. Trakarnsanga and B. P. Braeckman and W. Suthammarak},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751667},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751667v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans
AU - C. Chiamkunakorn
AU - J. Poothong
AU - K. Trakarnsanga
AU - B. P. Braeckman
AU - W. Suthammarak
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751667
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751667v1
AB - 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.
ER -