Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits

J Cell Biol. 2016 Jul 4;214(1):103-19. doi: 10.1083/jcb.201605101. Epub 2016 Jun 7.

Abstract

Although neuronal regeneration is a highly energy-demanding process, axonal mitochondrial transport progressively declines with maturation. Mature neurons typically fail to regenerate after injury, thus raising a fundamental question as to whether mitochondrial transport is necessary to meet enhanced metabolic requirements during regeneration. Here, we reveal that reduced mitochondrial motility and energy deficits in injured axons are intrinsic mechanisms controlling regrowth in mature neurons. Axotomy induces acute mitochondrial depolarization and ATP depletion in injured axons. Thus, mature neuron-associated increases in mitochondria-anchoring protein syntaphilin (SNPH) and decreases in mitochondrial transport cause local energy deficits. Strikingly, enhancing mitochondrial transport via genetic manipulation facilitates regenerative capacity by replenishing healthy mitochondria in injured axons, thereby rescuing energy deficits. An in vivo sciatic nerve crush study further shows that enhanced mitochondrial transport in snph knockout mice accelerates axon regeneration. Understanding deficits in mitochondrial trafficking and energy supply in injured axons of mature neurons benefits development of new strategies to stimulate axon regeneration.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Axonal Transport*
  • Axons / metabolism*
  • Axotomy
  • Cell Differentiation
  • Energy Metabolism*
  • GAP-43 Protein / metabolism
  • Growth Cones / metabolism
  • Membrane Potential, Mitochondrial
  • Membrane Proteins
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism*
  • Nerve Regeneration*
  • Nerve Tissue Proteins
  • Sciatic Nerve / metabolism
  • Stress, Physiological

Substances

  • GAP-43 Protein
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Snph protein, mouse
  • Adenosine Diphosphate
  • Adenosine Triphosphate