O-GlcNAc Signaling Increases Neuron Regeneration Through One-Carbon Metabolism inCaenorhabditis elegans

Abstract

AbstractCellular 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), a ubiquitous post-translational modification that acts as a cellular nutrient sensor, can significantly enhancein vivoneuron regeneration. Here we define the specific metabolic pathway by which mutation of the O-GlcNAc transferase (ogt-1)increases regenerative outgrowth. Performingin vivolaser axotomy and measuring subsequent regeneration of individual neurons inC. elegans, we find that theogt-1mutation increases regeneration by diverting the metabolic flux of enhanced glycolysis towards one carbon metabolism (OCM) and the downstream transsulfuration metabolic pathway (TSP). These effects are abrogated by genetic and/or pharmacological disruption of OCM or the serine synthesis pathway (SSP) that links 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 theogt-1mutation, in the genes involved in glycolysis, OCM, TSP and ATP metabolism. Strikingly, the beneficial effects of theogt-1mutation 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 inogt-1animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury.Abstarct Figure.Metabolic pathways involved in the enhanced neuronal regeneration inogt-1animals:The green highlighted pathway illustrates the metabolic rewiring inogt-1mutant animals supporting enhanced axonal regeneration of injured neuronsin vivo.