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

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.

Mitochondria-Division Inhibitor 1 Protects Against Amyloid-β induced Mitochondrial Fragmentation and Synaptic Damage in Alzheimer’s Disease

“…Findings from our study may have implications for other neurological diseases, such as Huntington’s [50–53], Parkinson’s [54–56], multiple sclerosis [57], and ALS [58], in which excessive mitochondrial fragmentation is present.…”

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…In neuroinflammatory lesions, altered mitochondria are present (Nikic et al, 2011; Witte et al, 2014). In vivo imaging in disease models has revealed reduced mitochondrial transport, which results in accumulations of dysfunctional mitochondria locally and a lack of mitochondria in the distal axonal arbor (Sadeghian et al, 2016; Sorbara et al, 2014). These processes seem largely driven by the inflammatory milieu, which appears to impair transport, as well as to prevent normal function of mitochondria, possibly via reactive oxygen or nitrogen species.…”

“…Disorders that more broadly affect axonal transport, such as tauopathies and SOD1 mutations, may include phenotypes with a significant mitochondrial etiology (De Vos et al, 2008; Millecamps and Julien, 2013). More recently changes in mitostatic processes also have been described during neuroinflammation (Sadeghian et al, 2016; Sorbara et al, 2014; Witte et al, 2014) and after neurotrauma (Cartoni et al, 2016; Han et al, 2016; Sheng, 2017; Zhou et al, 2016). Such links to pathology rightly spur interest in understanding mitostasis.…”

Novel Approaches of Oxidative Stress Mechanisms in the Multiple Sclerosis Pathophysiology and Therapy

“…In addition, recent findings in EAE suggest that mitochondrial dysfunction occurs in the early stage of MS (30). Interestingly, mitochondrial damage seems to develop before the inflammatory process in the disease (31). Mitochondria have a variety of antioxidant enzymes, including antioxidants peroxiredoxin-3 and thioredoxin-2 as well as their regulator PGC-1α.…”