Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis.

Mona Sadeghian,Ali Rezaei Haddad,Marija Sajic,Gizem Mullali,Simon Heales,Dimitra Schiza,Kenneth J Smith,Angelina Mosley,Iain Hargreaves,Vincenzo Mastrolia,Michael R Duchen

doi:10.1038/srep33249

Abstract

Neuroinflammation can cause major neurological dysfunction, without demyelination, in both multiple sclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.

Highlights

The astrocytes showed prominent expression of the glycolytic enzyme PFK2, at the onset of neurological deficits compared with adjuvant-only controls (Fig. 7a,b): such labelling was absent in asymptomatic mice (Fig. 7c), during remission and relapse, and in naïve control mice. These data show that changes in mitochondrial and neurological function occur in parallel in EAE, suggesting a causal relationship
It is reasonable to suppose that the mitochondrial dysfunction is primary, and this accords with the presence of some mitochondrial deficits in advance of the appearance of neurological signs but worsening significantly at the onset of neurological signs
The changes in mitochondrial function were accompanied by changes in their density, morphology and transport, all of which were spatially related to the presence of inflammatory cells in inflamed lesions

Summary

Introduction

The TMRM fluorescence in partially polarised mitochondria was only decreased by 26% compared with control mice treated only with adjuvant (p < 0.01) (Fig. 2a), and only 19% of the total mass of axonal mitochondria were entirely depolarised, representing a significant improvement over animals on the first day of neurological deficit (p < 0.01) (Fig. 2b and supplementary Fig. 1c).

Results

Conclusion