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Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis

Lookup NU author(s): Jessica Zambonin, Graham Campbell, Dr Sarah Engeham, Dr Iryna Ziabreva, Emeritus Professor Doug Turnbull, Dr Don Mahad

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Abstract

Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in experimental demyelination and remyelination in vivo and in vitro are consistent with a partial amelioration of the supposed increase in energy demand of demyelinated axons by remyelination.

Publication metadata

Author(s): Zambonin JL, Zhao C, Ohno N, Campbell GR, Engeham S, Ziabreva I, Schwarz N, Lee SE, Frischer JM, Turnbull DM, Trapp BD, Lassmann H, Franklin RJM, Mahad DJ

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2011

Volume: 134

Issue: 7

Pages: 1901-1913

Print publication date: 01/07/2011

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/awr110

DOI: 10.1093/brain/awr110

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