Successful axonal regeneration is associated with intraneuronal metabolic reprogramming

Area of Science:

• Neuroscience
• Metabolic research
• Regenerative medicine

Background:

• Mammals exhibit limited central nervous system (CNS) regeneration after injury.
• Zebrafish demonstrate remarkable CNS axon regrowth capabilities.
• Mitochondrial roles in CNS regeneration are established, but metabolic pathway interplay is unclear.

Purpose of the Study:

• To investigate metabolic pathway reprogramming during zebrafish CNS axon regeneration.
• To identify key metabolic drivers supporting zebrafish axonal regrowth.
• To explore the translational potential of these pathways for mammalian CNS repair.

Main Methods:

• RNA sequencing of adult zebrafish retinal ganglion cells post-optic nerve crush injury.
• Analysis of oxidative phosphorylation, glycolysis, pentose phosphate pathway, and thioredoxin system activity.
• Functional inhibition of key metabolic pathways in zebrafish.

Main Results:

• Oxidative phosphorylation downregulated during zebrafish axonal regrowth.
• Thioredoxin antioxidant system upregulated to mitigate oxidative damage.
• Glycolysis and pentose phosphate pathway upregulated, supplying energy and NADPH.
• Metabolic signatures resemble pro-regenerative mammalian models.
• Inhibition of glycolysis and thioredoxin impairs zebrafish axon regrowth.

Conclusions:

• Metabolic reprogramming, including enhanced glycolysis and antioxidant defense, is crucial for zebrafish CNS axon regeneration.
• Targeting these metabolic pathways may promote CNS regeneration in mammals.
• Zebrafish serve as a valuable model for understanding regenerative metabolism.