O-GlcNAc signaling increases neuron regeneration through one-carbon metabolism in Caenorhabditis elegans

• Published in: eLife 2024-02, Vol.13
• Main Authors: Yadav, Dilip Kumar, Chang, Andrew C, Grooms, Noa W F, Chung, Samuel H, Gabel, Christopher V
• Format: Article
• Language: English
• Subjects: Animals; Axotomy; Caenorhabditis elegans; Carbon; cell metabolism; Gene expression; Genetic transcription; Glycolysis; Kinases; Lasers; Metabolic pathways; Metabolism; Metabolites; Methionine; Mutation; N-Acetylglucosamine; Nematodes; neuron regeneration; Neurons; one-carbon metabolism; Physiological aspects; Post-translation; Post-translational modification; Regeneration; RNA; RNA sequencing; Sensors; Signal transduction; Vitamin B12; Worms
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.86478

Cellular metabolism plays an essential role in the regrowth and regeneration of a neuron following physical injury. Yet, our knowledge of the specific metabolic pathways that are beneficial to neuron regeneration remains sparse. Previously, we have shown that modulation of O-linked β-N-acetylglucosamine (O-GlcNAc) signaling, a ubiquitous post-translational modification that acts as a cellular nutrient sensor, can significantly enhance in vivo neuron regeneration. Here, we define the specific metabolic pathway by which O-GlcNAc transferase ( ) loss of function mediates increased regenerative outgrowth. Performing in vivo laser axotomy and measuring subsequent regeneration of individual neurons in , we find that glycolysis, serine synthesis pathway (SSP), one-carbon metabolism (OCM), and the downstream transsulfuration metabolic pathway (TSP) are all essential in this process. The regenerative effects of mutation are abrogated by genetic and/or pharmacological disruption of OCM and the SSP linking OCM to glycolysis. Testing downstream branches of this pathway, we find that enhanced regeneration is dependent only on the vitamin B12 independent shunt pathway. These results are further supported by RNA sequencing that reveals dramatic transcriptional changes by the mutation, in the genes involved in glycolysis, OCM, TSP, and ATP metabolism. Strikingly, the beneficial effects of the mutation can be recapitulated by simple metabolic supplementation of the OCM metabolite methionine in wild-type animals. Taken together, these data unearth the metabolic pathways involved in the increased regenerative capacity of a damaged neuron in animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury.