RICTOR regulates an interspecies crosstalk that influences longevity through a methionine cycle-mitophagy axis

Adaptive modulation of physiological traits in response to dietary fluctuations is essential for organismal fitness and is governed by complex gene-diet interactions that remain mechanistically unexplored. Here, we identify the conserved mTORC2 component RICTOR as a critical regulator of dietary plasticity in Caenorhabditis elegans. Loss of rict-1/RICTOR confers enhanced osmotic stress tolerance and longevity on vitamin B12-rich bacterial diets containing optimal methionine. These adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the one-carbon cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism which generates succinyl-CoA, and via the TCA cycle, succinate. Elevated succinate induces mitochondrial fragmentation, activating mitophagy that is indispensable for the stress resilience and longevity of rict-1 mutant worms. This host Met-C-mitophagy axis is tuned by microbial inputs, constituting an interspecies interaction. Early-life fragmentation potentiates sustained mitophagy into late adulthood, preserving tubular mitochondria as the rict-1 mutant worms age, unlike wild-type worms. Thus, RICTOR restrains host sensitivity to microbe-derived metabolite fluctuations through organellar quality control, regulating lifespan. Physiological traits are modulated in response to diet. Here the authors show that RICTOR restrains host responses to vitamin B12 in C. elegans by modulating organellar quality control and regulating lifespan.