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Methionine cycle in C. elegans serotonergic neurons regulates diet-dependent behaviour and longevity through neuron-gut signaling

Sabnam Sahin Rahman, Shreya Bhattacharjee, Simran Motwani, Govind Prakash, Rajat Ujjainiya, Shivani Chitkara, Tripti Nair, Rachamadugu Sai Keerthana, Shantanu Sengupta and Arnab Mukhopadhyay ()
Additional contact information
Sabnam Sahin Rahman: Aruna Asaf Ali Marg
Shreya Bhattacharjee: Aruna Asaf Ali Marg
Simran Motwani: Aruna Asaf Ali Marg
Govind Prakash: Aruna Asaf Ali Marg
Rajat Ujjainiya: CSIR-Institute of Genomics and Integrative Biology
Shivani Chitkara: Academy of Scientific and Innovative Research (AcSIR)
Tripti Nair: Aruna Asaf Ali Marg
Rachamadugu Sai Keerthana: Aruna Asaf Ali Marg
Shantanu Sengupta: CSIR-Institute of Genomics and Integrative Biology
Arnab Mukhopadhyay: Aruna Asaf Ali Marg

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The folate and methionine cycles (Met-C) are regulated by vitamin B12 (B12), obtained exclusively from diet and microbiota. Met-C supports amino acid, nucleotide, and lipid biosynthesis and provides one-carbon moieties for methylation reactions. While B12 deficiency and polymorphisms in Met-C genes are clinically attributed to neurological and metabolic disorders, less is known about their cell-non-autonomous regulation of systemic physiological processes. Using a B12-sensitive Caenorhabditis elegans mutant, we show that the neuronal Met-C responds to differential B12 content in diet to regulate p38-MAPK activation in the intestine, thereby modulating cytoprotective gene expression, osmotic stress tolerance, behaviour and longevity. Mechanistically, our data suggest that B12-driven changes in the metabolic flux through the Met-C in the mutant’s serotonergic neurons increase serotonin biosynthesis. Serotonin activates its receptor, MOD-1, in the post-synaptic interneurons, which then secretes the neuropeptide FLR-2. FLR-2 binding to its intestinal receptor, FSHR-1, induces the phase transition of the SARM domain protein TIR-1, thereby activating the p38-MAPK pathway. Together, we reveal a dynamic neuron-gut signalling axis that helps an organism modulate life history traits based on the status of neuronal Met-C, determined by B12 availability in its diet.

Date: 2025
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DOI: 10.1038/s41467-025-60475-0

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