The destructive inflammation that strips nerve fibres in the central nervous system (CNS) of their myelin coating is the main culprit responsible for the signs and symptoms of relapsing-remitting MS, and all of the approved drug therapies for MS target some aspect of autoimmunity and/or inflammation. On the other hand, the neurological decline and long-term disability that affects so many people living with MS is mainly triggered by a process called neurodegeneration in which the neurons and their fibres become injured, break down and even die. The cause for this neurodegenerative process is still uncertain, but a growing body of evidence is pointing to mitochondria as both victims and perpetrators of neurodegeneration.
What are mitochondria and what is their link to MS?
The mitochondria are essential structures (called organelles) found inside the cells that make up our bodies. Mitochondria are best known as the cell’s power plants: they use complex biochemical reactions involving oxygen to extract energy from glucose and fats. This energy is then used to fuel the cell’s vital activities and meet its various demands. Neurons, for example, are largely dependent on the energy generated by their mitochondria for carrying electrochemical signals across their nerve fibres in order to communicate with other neurons and cells. Needless to say, impairments in the structure and function of mitochondria can have catastrophic consequences for the cell.
Mitochondria are unique organelles in that they possess their own special DNA (separate from the rest of the DNA in the cell) which acts as a blueprint for constructing mitochondrial proteins. The integrity of these blueprints is crucial as they dictate the structure, and thus the proper functioning of the proteins. Think of it as engineers using blueprints to construct a building; if the blueprints are torn, the building will likely be in poor shape and maybe even collapse.
Research has revealed specific alterations or defects in the mitochondrial DNA that may contribute to the risk of developing MS. Neurons in the MS brain that have been examined for their expression of certain mitochondrial genes exhibit a decrease in this expression; this means that the neurons lack the proper instructions to construct mitochondrial proteins. What’s more, taking a closer look at MS lesions has revealed the presence of functionally defective mitochondrial proteins within a variety of cell types, including neurons, oligodendrocytes and astrocytes. These observations all circle back to the idea that mitochondrial dysfunction leads to diminished energy production in the cell. Indeed, studies that have sampled the cerebral spinal fluid (CSF) of people living with MS to look for the by-products of energy metabolism have found that energy depletion correlates with measures of disability, pointing to failure of mitochondrial energy production as a candidate for the neuronal loss that underlies disability progression.
Mitochondria and the MS disease process: Double Trouble
How do mitochondrial dysfunction and defects in energy production contribute to neurodegeneration? Researchers have suggested several mechanisms that may hold the key to this riddle.
During energy production, by-products known as reactive oxygen species (ROS) are generated by the mitochondria. Usually, levels of ROS in the cells are maintained at low concentrations and can in fact be useful in many cellular processes. However, when ROS levels get out of control, these by-products can be destructive and cause something referred to as oxidative stress, which can lead to cellular damage and even cell death due to breakdown of crucial cellular structures.
Normally, immune cells like macrophages or microglia take advantage of this destructive property of ROS during inflammation to help them break down invading pathogens or dead cells. In MS, the ROS generated by immune cells instead contribute to the demyelination of neurons. While cells contain antioxidants that normally counteract the effects of ROS, the vast amounts of ROS that enter the cell can overcome this defense. In MS lesions, ROS has been observed to cause abnormal swelling of the mitochondria as well as oxidative damage to mitochondrial DNA and proteins, which only serves to worsen the problem further. Important innovations in imaging, including those pioneered by Dr. Martin Kerschensteiner at Ludwig-Maximilians-University in Munich (Germany), are allowing researchers to probe the oxidation states in individual mitochondria in real time, giving them a window into the inner mechanisms that leads to neuronal damage in response to ROS and pave the way for treatments that can prevent neurodegeneration and disability.
What’s more, demyelination of the nerve fibres unfavourably reorganizes the cell structure, leading to increases in energy demands for the transmission of information from one neuron to the next. This increase in energy demand combined with impaired mitochondrial function (and a diminished capacity to generate energy) creates a “double-trouble” scenario. Interestingly, increased numbers of mitochondria in response to this high energy demand have been observed in approximately half of the chronically demyelinated neurons in the CNS. This likely represents a compensatory strategy to counteract the chronic energy dysfunction in demyelinated nerve fibres. Nonetheless, this adaptation can only be effective for so long, and injured mitochondria persist and contribute to the overall energy imbalance of the cell. Eventually, this persistent energy dysregulation can cascade into a further release of ROS and, eventually, complete degeneration of the neurons.
Are mitochondria potential targets for new protective and repair strategies?
While immune-modifying therapies are the primary approach to treating MS, new research is turning to other avenues that are examining the neurodegenerative aspects of the disease that are largely resilient to immune modification. This is especially a priority due to the close association between neurodegeneration and disability progression. This means that mitochondria have entered the research spotlight, and mitochondrial targeted therapies carry with them the possibility of slowing or halting the destruction of nerve fibres.
A great deal of attention has also been placed on antioxidant therapies that can improve the capacity of neurons to counteract ROS. Studies (such as this one, and this one) in animals with diseases that mimic MS and optic neuritis have demonstrated the neuroprotective potential of certain antioxidant compounds to remove destructive ROS from the mitochondria and block the degeneration of nerve fibres, leading to reductions in disability progression. One challenge hampering this approach is getting antioxidant compounds to build up to a large enough concentration inside the mitochondria, and researchers are looking at selective delivery methods to overcome this obstacle.
Among the antioxidant compounds that have been identified for their neuroprotective potential, flavonoids stand out as promising candidates. Flavonoids are phenolic compounds found in many fruits and vegetables that have been shown to strengthen mitochondria and protect the brain from injury. MS Society-funded researcher Dr. George Robertson from Dalhousie University has developed a flavonoid-enriched extract from apple peel and is currently testing its ability to reduce neurodegeneration and improve myelin repair in mice with an MS-like disease. His exciting research raises the possibility of using dietary strategies alongside conventional pharmacological approaches to treating MS.
Although the energy failure brought on by mitochondrial damage can have dire consequences, it can also be used as an early warning signal to predict future neurodegeneration and conversion to progressive MS. This critical window after mitochondrial damage has set in but before the onset of neurodegeneration is being explored by Dr. Don Mahad (University of Edinburgh), one of the foremost researchers in the world on mitochondria and progressive MS and lead investigator on one of the recently awarded Planning Award grants announced by the Progressive MS Alliance. Dr. Mahad and colleagues have found that muscle fatigue caused by exercise (known as motor fatigability) is a common symptom reported by people with relapsing-remitting MS who go on to rapidly develop progressive MS, pointing to mitochondrial dysfunction and energy imbalance as likely culprits. The research funded by the planning award is focused on detecting mitochondrial dysfunction earlier by identifying motor fatigability, providing a critical window of opportunity during the disease course for emerging neuroprotective therapies to provide the maximum amount of benefit
A recently published study has revealed a new pathway between mitochondria and the immune system; specifically, an enzyme called RIPK3 that helps to trigger programmed cell death has been shown to interact with specialized immune cells called natural killer T-cells that are involved in autoimmunity and inflammation. The researchers found that deleting the gene for RIPK3 in mice protected them from autoimmune-related damage. Whether this discovery of crosstalk between mitochondria and immune cells has therapeutic applications for people living with MS remains to be seen.
Do you have any questions about mitochondria or thoughts about neuroprotective treatments for MS? Leave them below.
References:
- Ban, M., Elson, J., Walton, A., Turnbull, D., Compston, A., Chinnery, P., Sawcer, S. Investigation of the Role of Mitochondrial DNA in Multiple Sclerosis Susceptibility. PLoS ONE. 3(8): e2891. doi:10.1371/journal.pone.0002891
- Witte, M. E., Mahad, D. J., Lassmann, H. & van Horssen, J. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol. Med. 20, 179–187 (2014).
- Su, K., Bourdette, D. & Forte, M. Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front. Physiol. 4, 1–10 (2013).
- Mao, P. & Reddy, P. H. Is multiple sclerosis a mitochondrial disease? Biochim. Biophys. Acta 1802, 66–79 (2010).