Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury

Qi Han, Yuxiang Xie, Josue D. Ordaz, Andrew J. Huh, Ning Huang, Wei Wu, Naikui Liu, Kelly A. Chamberlain, Zu Hang Sheng, Xiao Ming Xu

Research output: Contribution to journalArticle

Abstract

Axonal regeneration in the central nervous system (CNS) is a highly energy-demanding process. Extrinsic insults and intrinsic restrictions lead to an energy crisis in injured axons, raising the question of whether recovering energy deficits facilitates regeneration. Here, we reveal that enhancing axonal mitochondrial transport by deleting syntaphilin (Snph) recovers injury-induced mitochondrial depolarization. Using three CNS injury mouse models, we demonstrate that Snph−/− mice display enhanced corticospinal tract (CST) regeneration passing through a spinal cord lesion, accelerated regrowth of monoaminergic axons across a transection gap, and increased compensatory sprouting of uninjured CST. Notably, regenerated CST axons form functional synapses and promote motor functional recovery. Administration of the bioenergetic compound creatine boosts CST regenerative capacity in Snph−/− mice. Our study provides mechanistic insights into intrinsic regeneration failure in CNS and suggests that enhancing mitochondrial transport and cellular energetics are promising strategies to promote regeneration and functional restoration after CNS injuries. By using three CNS injury mouse models, Han et al. reveal new mechanistic insights into intrinsic regenerative failure of axons in the CNS and demonstrate that enhancing mitochondrial transport and energetic metabolism represent a promising therapeutic direction to stimulate axonal regeneration and functional recovery after spinal cord injury.

Original languageEnglish (US)
Pages (from-to)623-641.e8
JournalCell Metabolism
Volume31
Issue number3
DOIs
StatePublished - Mar 3 2020

    Fingerprint

Keywords

  • CNS injury
  • axon regeneration
  • axonal transport
  • creatine
  • energy deficits
  • energy metabolism
  • mitochondria
  • spinal cord injury
  • syntaphilin

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Han, Q., Xie, Y., Ordaz, J. D., Huh, A. J., Huang, N., Wu, W., Liu, N., Chamberlain, K. A., Sheng, Z. H., & Xu, X. M. (2020). Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury. Cell Metabolism, 31(3), 623-641.e8. https://doi.org/10.1016/j.cmet.2020.02.002