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bioRxiv · 10.1101/2023.03.05.531166

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

Yadav, D. K.·Chang, A. C.·Gabel, C. V.
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Abstract

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 {beta}-N-acetylglucosamine (O-GlcNAc), 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 mutation of the O-GlcNAc transferase (ogt-1) increases regenerative outgrowth. Performing in vivo laser axotomy and measuring subsequent regeneration of individual neurons in C. elegans, we find that the ogt-1 mutation 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 the ogt-1 mutation, in the genes involved in glycolysis, OCM, TSP and ATP metabolism. Strikingly, the beneficial effects of the ogt-1 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 ogt-1 animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/531166v1_ufig1.gif" ALT="Figure UFIG"> View larger version (19K): org.highwire.dtl.DTLVardef@7da18eorg.highwire.dtl.DTLVardef@1f997d6org.highwire.dtl.DTLVardef@15fa337org.highwire.dtl.DTLVardef@1d476bd_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOAbstarct Figure.C_FLOATNO Metabolic pathways involved in the enhanced neuronal regeneration in ogt-1 animalsThe green highlighted pathway illustrates the metabolic rewiring in ogt-1 mutant animals supporting enhanced axonal regeneration of injured neurons in vivo. C_FIG

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Yadav, D. K., Chang, A. C., Gabel, C. V.. 2023-03-06. O-GlcNAc Signaling Increases Neuron Regeneration Through One-Carbon Metabolism in Caenorhabditis elegans. https://doi.org/10.1101/2023.03.05.531166

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