Abstract
BackgroundSmall-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.MethodsWe 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.ResultsMitochondria 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.ConclusionsThe 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.
Highlights
Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory Peripheral nervous system (PNS) and Central nervous system (CNS) diseases, resulting in pain and degeneration, but the mechanism is not known
Inflammation at the onset of experimental autoimmune neuritis (EAN) reduces the number of transported mitochondria in peripheral nerve axons, but not their velocity To investigate the mechanisms of inflammatory damage to peripheral nerve axons and axonal mitochondria, we immunized mito-S Cyan fluorescent protein (CFP)+ mice with peripheral nerve myelin, and Mycobacterium tuberculosis and pertussis toxin as adjuvants
As increased mitochondrial fission has been associated with mitochondrial dysfunction in neurodegenerative diseases [13,14,15], we examined whether axonal mitochondria maintained their mitochondrial membrane potential (Fig. 2a–b′)
Summary
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. Severe ascending muscle weakness, caused by dysfunction of peripheral motor fibers, is the best recognized and the most dramatic sign of the disease. Sensory symptoms have been underemphasized [2], but recent studies reveal that these are clinically relevant [3,4,5] and prevalent, with paresthesia being reported by 75% [2] of patients and pain by 89% [6]. A prospective multi-center study conducted 2 years after disease onset identified sensory impairment in over half of the patient population [11], while another study reported that sensory deficits persist in the legs of 66% of patients between 3 and 6 years after the onset of GBS [12]
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