Successful axonal regeneration is driven by evolutionarily conserved metabolic reprogramming

Unlike mammals, zebrafish can regrow axons after injury and restore circuit function in the central nervous system (CNS). Mitochondria have been identified as key players in this process, but how different metabolic pathways work together to sustain regeneration remains unclear. Using RNA sequencing of adult zebrafish retinal ganglion cells after optic nerve crush injury, we found that oxidative phosphorylation is downregulated during axonal regrowth. Simultaneously, the thioredoxin antioxidant system was upregulated, likely to limit oxidative damage. Additionally, we observed an integrated upregulation of glycolysis and the pentose phosphate pathway during the initial regrowth phases, possibly to provide energy and supplying NADPH for biosynthesis and antioxidant responses. We show that this metabolic reprogramming is evolutionarily conserved, as a comparable one occurs in the pro-regenerative mammalian Pten and Socs3 co-deletion model. Inhibiting glycolysis and thioredoxin in zebrafish impairs axonal regrowth, suggesting that targeting these pathways could enhance CNS regeneration in mammals.