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bioRxiv · 10.1101/2025.07.11.664440

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

Motwani, S.·Bhandari, S.·Chitkara, S.·Ujjainiya, R.·Sengupta, S.·Mukhopadhyay, A.
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Abstract

Adaptive modulation of physiological traits in response to environmental variability, particularly dietary fluctuations, is essential for organismal fitness. Such adaptability is governed by complex gene-diet interactions, yet the molecular circuits integrating microbe-derived metabolites with host metabolic and stress response pathways remain less explored. Here, we identify the conserved mechanistic target of rapamycin complex 2 (mTORC2) component, RICTOR, as a critical regulator of dietary plasticity in Caenorhabditis elegans, specifically in response to bacterially derived vitamin B12 (B12). Loss of rict-1, the C. elegans ortholog of RICTOR, confers enhanced osmotic stress tolerance and longevity on B12-rich bacterial diets. These phenotypic adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the folate-methionine cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism. The latter catalyzes the formation of succinyl-CoA, subsequently converted to succinate via the tricarboxylic acid (TCA) cycle. Elevated succinate levels were found to induce mitochondrial fragmentation, thereby activating mitophagy, an autophagic process indispensable for the increased stress resilience and longevity observed in the rict-1 mutants. Crucially, this Met-C-mitophagy axis is modulated by microbial inputs, with B12 and methionine acting as proximal dietary signals. Our findings delineate a mechanistic framework through which RICTOR restrains host sensitivity to microbial-derived metabolites, thus maintaining mitochondrial homeostasis and regulating lifespan. This work reveals a pivotal role for RICTOR in insulating host physiology from environmental nutrient-driven perturbations by modulating organellar quality control pathways.

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Motwani, S., Bhandari, S., Chitkara, S., Ujjainiya, R., Sengupta, S., Mukhopadhyay, A.. 2025-07-14. RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis. https://doi.org/10.1101/2025.07.11.664440

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