Mitochondrial damage and "plugging" of transport selectively in myelinated, small-diameter axons are major early events in peripheral neuroinflammation

J Neuroinflammation. 2018 Feb 27;15(1):61. doi: 10.1186/s12974-018-1094-8.

Abstract

Background: Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory PNS and CNS diseases, resulting in pain and degeneration, but the mechanism is not known.

Methods: We used in vivo confocal microscopy to compare the effects of inflammation in experimental autoimmune neuritis (EAN), a model of Guillain-Barré syndrome (GBS), on mitochondrial function and transport in large- and small-diameter axons. We have compared mitochondrial function and transport in vivo in (i) healthy axons, (ii) axons affected by experimental autoimmune neuritis, and (iii) axons in which mitochondria were focally damaged by laser induced photo-toxicity.

Results: Mitochondria affected by inflammation or laser damage became depolarized, fragmented, and immobile. Importantly, the loss of functional mitochondria was accompanied by an increase in the number of mitochondria transported towards, and into, the damaged area, perhaps compensating for loss of ATP and allowing buffering of the likely excessive Ca2+ concentration. In large-diameter axons, healthy mitochondria were found to move into the damaged area bypassing the dysfunctional mitochondria, re-populating the damaged segment of the axon. However, in small-diameter axons, the depolarized mitochondria appeared to "plug" the axon, obstructing, sometimes completely, the incoming (mainly anterograde) transport of mitochondria. Over time (~ 2 h), the transported, functional mitochondria accumulated at the obstruction, and the distal part of the small-diameter axons became depleted of functional mitochondria.

Conclusions: The data show that neuroinflammation, in common with photo-toxic damage, induces depolarization and fragmentation of axonal mitochondria, which remain immobile at the site of damage. The damaged, immobile mitochondria can "plug" myelinated, small-diameter axons so that successful mitochondrial transport is prevented, depleting the distal axon of functioning mitochondria. Our observations may explain the selective vulnerability of small-diameter axons to dysfunction and degeneration in a number of neurodegenerative and neuroinflammatory disorders.

Keywords: Confocal imaging; Experimental autoimmune neuritis (EAN); In vivo; Mitochondrial; Neuropathy; Pain; Phototoxic damage; Small axons.

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / pathology
  • Biological Transport / physiology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Nerve Fibers, Myelinated / metabolism*
  • Nerve Fibers, Myelinated / pathology
  • Neuritis, Autoimmune, Experimental / metabolism*
  • Neuritis, Autoimmune, Experimental / pathology
  • Peripheral Nerves / metabolism*
  • Peripheral Nerves / pathology