Enhanced oxidative stress resilience in C. elegans acox-1.1 mutants through CTL-3 and proteasomal regulation.

Oxidative stress is a primary driver of aging, necessitating robust cellular adaptation mechanisms. While peroxisomal β-oxidation and proteasomal degradation are known to influence stress responses, their functional crosstalk remains elusive. In this study, we show that C. elegans acox-1.1 mutants, despite having a shortened lifespan under normal conditions, exhibit a paradoxical resistance to mild chronic oxidative stress (1 mM paraquat, PQ) compared to wild-type worms. This PQ-induced resistance in acox-1.1 mutants was independent of the canonical SKN-1 pathway but required the peroxisomal catalase CTL-3. RNA-mediated knockdown of ctl-3 largely abolished the stress resistance of acox-1.1 mutants, leading to rapid mortality. Proteomic and biochemical analyses revealed that acox-1.1 mutants possess reduced levels of PAS-5, a core 20S proteasome subunit, resulting in impaired proteasomal assembly and accumulation of ubiquitinated (Ub) substrates under basal conditions. Intriguingly, exposure to 1 mM PQ significantly reduced the Ub-smear in acox-1.1 mutants, suggesting a metabolic shift where the cell prioritizes ROS scavenging over ATP-dependent protein degradation. Under oxidative stress, acox-1.1 mutants bypass defective proteasomal machinery and redirect energy toward CTL-3-mediated antioxidant defense. This study identified a peroxisomal adaptation mechanism whereby reduced proteasome complexity, coupled with enhanced ROS-regulatory machinery, confers survival advantages under specific oxidative challenges.