Mitochondria as Crucial Players in Demyelinated Axons: Lessons from Neuropathology and Experimental Demyelination

Abstract

Mitochondria are the most efficient producers of energy in the form of ATP. Energy demands of axons, placed at relatively great distances from the neuronal cell body, are met by mitochondria, which when functionally compromised, produce reactive oxygen species (ROS) in excess. Axons are made metabolically efficient by myelination, which enables saltatory conduction. The importance of mitochondria for maintaining the structural integrity of myelinated axons is illustrated by neuroaxonal degeneration in primary mitochondrial disorders. When demyelinated, the compartmentalisation of ion channels along axons is disrupted. The redistribution of electrogenic machinery is thought to increase the energy demand of demyelinated axons. We review related studies that focus on mitochondria within unmyelinated, demyelinated and dysmyelinated axons in the central nervous system. Based on neuropathological observations we propose the increase in mitochondrial presence within demyelinated axons as an adaptive process to the increased energy need. An increased presence of mitochondria would also increase the capacity to produce deleterious agents such as ROS when functionally compromised. Given the lack of direct evidence of a beneficial or harmful effect of mitochondrial changes, the precise role of increased mitochondrial presence within axons due to demyelination needs to be further explored in experimental demyelination in-vivo and in-vitro.

Newly lesioned tissue in multiple sclerosis--a role for oxidative damage?

“…Zambonin et al (2011) report that established remyelinated axons in multiple sclerosis lesions contain more mitochondria than normal, but fewer mitochondria than established demyelinated axons. If axonal mitochondria are a potential source of excessive production of reactive oxygen species, the increased number of mitochondria in remyelinated [and demyelinated axons (Campbell and Mahad, 2011)] may place the axons at increased danger for degeneration; and this is consistent with findings in multiple sclerosis. Thus, some remyelinating and remyelinated axons in multiple sclerosis can have greater evidence of axonal injury than occurs in established demyelinating lesions (Kuhlmann et al, 2002).…”

“…If mitochondria are an important source of reactive oxygen species, as well as ATP, they can be viewed not only as helpful 'saviours' in a battle against impending energy deficits, but also as risky components that increase the chance of triggering an oxidative firestorm with microglia (Campbell and Mahad, 2011;van Horssen et al, 2011) even from a quiescent beginning. Especially with this in mind, the new findings in a second paper published in this issue of Brain, from Don Mahad and his colleagues, are very interesting.…”

“…The mechanisms by which oxidative damage can occur, impair mitochondrial function, and contribute to tissue damage in neuroinflammatory disease, have been summarized in a number of excellent reviews and papers (Andrews et al, 2005;Dutta et al, 2006;Dutta and Trapp, 2007;Kalman et al, 2007;Gonsette, 2008;Mahad et al, 2009;Witte et al, 2009;Mao and Reddy, 2010;Campbell and Mahad, 2011;Nakamura and Lipton, 2011;van Horssen et al, 2011). These studies describe the numerous 'downstream' consequences of oxidative and mitochondrial damage, including energy failure; but it is interesting to look at the new findings by Haider and colleagues (2011) and consider whether they might indicate earlier 'upstream' mechanism(s) contributing to the formation of newly lesioned tissue.…”

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

“…In acute inflammatory lesions mitochondrial nicotinamide adenine dinucleotide-hydrogen (NADH) oxidase [63] and complex IV defects (COX I) have been described, in axons, oligodendrocytes, and astrocytes [58]. In chronic inactive plaques, ionic imbalance and high energy demands result to swollen and dysfunctional mitochondria [64,65], a phenomenon in which is partially reversed in remyelinating axons [66]. There are also additional mtDNA deletions in GM structures of patients with SPMS [67].…”

On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis

“…34 Also, MtD has been found to play a key role in a progressive axonal loss in MS. 17,35,36 Following axonal demyelination in MS, it has been hypothesized that mitochondria play a greater role in maintaining axonal function as an adaptive process to the increased energy need of demyelinated axons but MtD results over time leading to severe and chronic axonal damage. 35,37,38 F I G U R E 1 The role of mitochondria dysfunction and oxidative stress in MS | 307 TOBORE Aside from MtD, OS plays a role in demyelination and axonal damage in MS. [39][40][41][42] Findings from several studies have suggested that OS plays the most important role in the demyelination and neurodegeneration observed in MS. [42][43][44][45][46] OS causes selective oligodendrocyte death and can disrupt the process of oligodendrocyte differentiation, leading to demyelination. 47,48 Damage from OS on oligodendrocytes and neurons has been found to be associated with active demyelination and axonal or neuronal damage in MS. 42 Studies have revealed that OS modulates OPC signal processes which are vital for OPC proliferation and differentiation resulting in hypomyelination.…”