Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition.

Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Apart from the proteostasis response, whether and how other mechanisms contribute to lifespan extension upon mitochondrial translation inhibition is underexplored. Using multi-omics and functional in vivo screening, we identified the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as essential for mitochondrial translation inhibition-induced longevity. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition while mitochondrial unfolded protein response activation is unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Additionally, we discovered that sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the “immuno-metabolic stress responses” in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses. N2 worms were synchronized and treated with RNAi bacteria ( HT115, mrps-5, C32E8.9, mrps-5 + C32E8.9 ) from the L1 stage. Day 5 adult animals were harvested by washing three times with M9 buffer and two times with water before being snap-frozen in liquid nitrogen. ~1000 worms for each sample. 6 replicates per condition.