title: Mitochondrial swelling and microtubule depolymerization are associated with energy depletion in axon degeneration.
abstract: Although mitochondrial dysfunction is intimately related to axonal degeneration following nerve injury, the molecular mechanisms of mitochondrial swelling and its mechanistic relation to axonal degeneration are largely unknown. Previous studies have demonstrated that axonal degeneration in the injured peripheral nerves shows two morphologically distinct phases: (1) A latency period (∼24h), in which the morphology of axonal cytoskeletons seems unchanged, followed by (2) an execution period (36-48h), which shows a catastrophic granular degeneration of most axonal structures in rodent axons. In the present study, we found that, in the sciatic nerve axotomy model, energy failure and microtubule depolymerization occurred during the latency period whereas mitochondrial swelling and neurofilament degradation started in the execution period. The energy repletion with NAD or an NAD/pyruvate mixture inhibited microtubule depolymerization, mitochondrial swelling and axonal degeneration in transected sciatic nerve axons. In addition, microtubule perturbing agents enhanced axonal degeneration and mitochondrial swelling. Extracellular calcium chelation did not affect energy failure, microtubule depolymerization or mitochondrial swelling, but it did prevent neurofilament degradation. These findings suggest that an early disturbance in energy dynamics regardless of mitochondrial swelling might be a key trigger for the initiation of axonal degeneration and that extracellular calcium influx is a late effector for neurofilament degradation.
authors.affiliation: Department of Physiology, Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Park
authors.forename: S Y
authors.initials: SY
authors.lastname: Jang
authors.forename: Y K
authors.initials: YK
authors.lastname: Shin
authors.forename: H
authors.initials: H
authors.lastname: Koh
authors.forename: D J
authors.initials: DJ
authors.lastname: Suh
authors.forename: T
authors.initials: T
authors.lastname: Shinji
authors.forename: T
authors.initials: T
authors.lastname: Araki
authors.forename: H T
authors.initials: HT
authors.lastname: Park
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019771:Axotomy; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology; D012584:Sciatic Nerve / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D050257:Tubulin Modulators / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D014855:Wallerian Degeneration / Q000378:metabolism* / Q000473:pathology
chemical_list: D050257:Tubulin Modulators; D014750:Vincristine; D017239:Paclitaxel