Enhanced number and activity of mitochondria in multiple sclerosis lesions

Abstract

Mitochondrial dysfunction has been implicated in the development and progression of multiple sclerosis (MS) lesions. Mitochondrial alterations might occur as a response to demyelination and inflammation, since demyelination leads to an increased energy demand in axons and could thereby affect the number, distribution and activity of mitochondria. We have studied the expression of mitochondrial proteins and mitochondrial enzyme activity in active demyelinating and chronic inactive MS lesions. Mitochondrial protein expression and enzyme activity in active and chronic inactive MS lesions was investigated using (immuno)histochemical and biochemical techniques. The number of mitochondria and their co-localization with axons and astrocytes within MS lesions and adjacent normal-appearing white matter (NAWM) was quantitatively assessed. In both active and inactive lesions we observed an increase in mitochondrial protein expression as well as a significant increase in the number of mitochondria. Mitochondrial density in axons and astrocytes was significantly enhanced in active lesions compared to adjacent NAWM, whereas a trend was observed in inactive lesions. Complex IV activity was strikingly up-regulated in MS lesions compared to control white matter and, to a lesser extent, NAWM. Finally, we demonstrated increased immunoreactivity of the mitochondrial stress protein mtHSP70 in MS lesions, particularly in astrocytes and axons. Our data indicate the occurrence of severe mitochondrial alterations in MS lesions, which coincides with enhanced mitochondrial oxidative stress. Together, these findings support a mechanism whereby enhanced density of mitochondria in MS lesions might contribute to the formation of free radicals and subsequent tissue damage.

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

“…Studies of postmortem multiple sclerosis brains have described increased mitochondria volume in axons that are likely to be demyelinated for years or decades (14,42). We establish here that increased axonal mitochondrial volume occurs within days (slice cultures) or weeks (mice) of demyelination, and that this increase is caused by increased sizes of mitochondrial stationary sites.…”

“…The cuprizone dose used in the present study does not cause changes in mitochondrial structure in CNS axons. Although we cannot rule out cuprizone-induced changes in mitochondrial function, increased mitochondrial size/volume in demyelinated axons has been reported in multiple studies regardless of the cause of demyelination (14,17,(40)(41)(42). The mitochondrial changes described following cuprizone-induced demyelination in vivo were also found following lysolecithin-induced demyelination in vitro.…”

The molecular basis of neurodegeneration in multiple sclerosis

“…Profound mitochondrial disturbances have been found in MS lesions by microarray based gene expression analysis [26,27], by immunohistochemistry, biochemical analysis and by electron microscopy [26,79,112]. In acute and active lesions first changes in mitochondria are reflected by a dominant loss of immunoreactivity of cytochrome C oxidase (COX1) and loss of the respective complex IV activity of the mitochondrial respiratory chain [79].…”

White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

“…These spontaneous improvements may reflect either restored mitochondrial activity or a compensatory increase in the number of mitochondria. Histopathological studies found increased numbers of mitochondria and an upregulation of mitochondrial cytochrome C oxidase (complex IV) in axons in both chronic lesions and normal appearing white matter of MS subjects (Mahad et al, 2009;Witte et al, 2009). …”