Mitochondria changes found early on in progressive MS: Mouse study

Changes in mitochondria — cells’ energy production centers — are evident in early disease stages in a mouse model of progressive multiple sclerosis (MS), but were not found in a model of relapsing-remitting MS (RRMS), according to researchers.

These changes, seen before symptoms of the disease started, were observed selectively in axons, or nerve cell projections, which are known to degenerate in later stages of MS.

“We provide here the first evidence that axonal-restricted derangement of mitochondrial homeostasis already occurs during the asymptomatic state exclusively in a mouse model of [progressive] MS,” the research team wrote.

In addition to advancing understanding of the cellular mechanisms underlying these mouse models, the researchers say these findings “point to very early axonal mitochondrial dysfunction as central to the [mechanisms] of MS evolution.”

Their study, “Early derangement of axonal mitochondria occurs in a mouse model of progressive but not relapsing-remitting multiple sclerosis,” was published in Neurobiology of Disease.

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While RRMS is marked by bouts of disease exacerbations, or relapses, followed by remission — periods of partial or complete symptom resolution — progressive MS is characterized by steadily worsening symptoms and the accumulation of disability. Disease progression occurs even in this MS type even if a person doesn’t experience relapses.

Dysfunction of mitochondria, the organelles responsible for cellular energy production, is thought to be a key feature of MS.

In general, it’s thought that changes in energy in mitochondria within nerve cells may spur oxidative stress, a type of cell damage in which production of toxic reactive oxygen species is increased, overriding the cellular antioxidant defense systems that combat them.

Still, it isn’t clear whether early dysfunction of mitochondria is involved in driving the evolution of MS, or whether it appears later as a consequence of nerve cell damage. Moreover, whether early changes in mitochondria are similar between RRMS and progressive MS has not been established.

Now, a team of researchers in Italy sought to learn more using separate mouse models of progressive MS and RRMS. The scientists examined mitochondria structure and function in the early, asymptomatic stages of progressive MS, and compared those findings with the evidence found in the RRMS mouse model.

Both models were produced using the experimental autoimmune encephalomyelitis (EAE) approach, in which a myelin protein fragment is introduced to the animal, driving an MS-like autoimmune response against it. Myelin is the protective coating surrounding nerve fibers that’s attacked by self-reactive antibodies in MS.

When a strain of mice called NOD are used, the animals develop a progressive worsening of symptoms and are resistant to immunosuppressive treatments, much like what happens in humans with progressive MS. Conversely, the SJL-EAE model has a disease course that is a widely used model of RRMS.

In the asymptomatic stages of disease, both NOD-EAE and SJL-EAE mice exhibited significant increases of inflammatory cells in the spinal cord, namely a form of T-cells called Th1 and neutrophils.

However, while mitochondria in spinal cord nerve fibers were disrupted in the progressive MS model, these organelles were normal in the asymptomatic stages of RRMS.

According to the researchers, the NOD-EAE mice showed lower than normal levels of mitochondrial DNA and exhibited an increased area of cristae — folds in the inner membrane of mitochondria that house the molecular machinery used to produce cellular energy. Activity of genes involved in regulating mitochondria structure were similarly increased.

The team also found — in the asymptomatic NOD-EAE model but not the SJL-EAE mice — a significant increase in the levels of proteins from the mitochondria respiratory complexes, involved in chemical reactions needed to produce cellular energy.

This is in contrast to previous work that demonstrated decreases in these genes in the chronic, symptomatic stages of NOD-EAE, according to researchers.

Altogether, the findings suggest that axonal mitochondria are disrupted during asymptomatic stages of disease, but this seems to be “an exclusive feature of the progressive and not of the relapsing-remitting pattern,” the researchers wrote.

Understanding the underlying molecular mechanisms might help identifying innovative therapies to tackle MS progression.

These early changes “can be interpreted as a sort of homeostatic response aimed at increasing mitochondrial functioning,” in early progressive disease stages, the team noted.

All of these findings were observed in axons within the spinal cord, which are known to later degenerate in EAE models. Interestingly, similar observations were not made in mitochondria lying outside of axons in the spinal cord, or in the liver.

When the asymptomatic NOD-EAE mice were treated with a mitochondria-targeted antioxidant, mitochondrial DNA levels and cristae were normalized, but inflammation and activity of genes involved in mitochondrial homeostasis remained abnormal.

These findings overall point to a link between axonal mitochondrial dysfunction and the later occurrence of neurodegeneration and disease progression in progressive MS, the team noted.

“Understanding the underlying molecular mechanisms might help identifying innovative therapies to tackle MS progression,” the team concluded.