Multiple sclerosis (MS) is an autoimmune disorder that leads to demyelination (damage to the myelin sheaths surrounding nerve fibers) and clinical debilitation. This is the conventional medical wisdom. New research is shedding light on other data that may change how we understand MS. In addition to the neurodegenerative processes of MS, mitochondrial dysfunction is a key contributing mechanism. This may happen due to increased permeability of the transition pore opening and calcium dysregulation, which are central to mitochondrial dysfunction and neurodegeneration in MS.
Let’s take a deeper dive into this new way of understanding MS.
Mitochondrial dysfunction and neurodegeneration in MS
Scientists are investigating mitochondrial dysfunction to explain the diffuse neurodegeneration found in MS patients. Mitochondria are involved in ATP synthesis and calcium regulation. They are also a major source of reactive oxygen species (ROS). This, mitochondrial dysfunction could lead to insufficient energy production and intracellular dysregulation. This type of dysfunction is particularly damaging to neurons given their dependence on ATP to generate electrical signals, facilitate transportation along axons, and maintain ionic gradients.
Evidence of mitochondrial dysfunction in MS is growing. For instance, NAA, the commonly used MRS marker of neuronal integrity, is produced by neuronal mitochondria. Therefore, changes in NAA levels can also reflect mitochondrial dysfunction within neurons.
Alterations in NAA levels are linked with relapses. These changes fall significantly in acute inflammatory lesions, and they partially reverse as inflammation lessens. The initial decline in NAA points to reversible mitochondrial dysfunction in neurons within these acute lesions. Similar decreases of NAA in NAWM and focal white matter lesions may also point to mitochondrial dysfunction within the neurons. Scientists have also found evidence of mitochondrial dysfunction linked to neurodegeneration. And they have found evidence of oxidative damage of mitochondrial DNA along with the impaired activity of mitochondrial enzymes. Several studies have shown structural damage in the earliest phases giving researchers convincing evidence that mitochondrial function may play a significant role in MS neurodegenerative mechanisms.
Mitochondrial dysfunction and the permeability transition pore (PTP)
One study recently looked into mitochondrial dysfunction in relation to the pathological opening of the mitochondrial permeability transition pore (PTP). The PTP is a pore located in the inner mitochondrial membrane that allows solutes with molecular masses up to 1500 Daltons to enter. The pore opens to certain stimuli, including reactive oxygen, calcium, and nitrogen species. When the pore remains open when it should close, it results in an influx of solutes that causes a decrease in mitochondrial membrane function and destabilizes ionic gradients. This can prevent ATP synthesis and result in matrix expansion, mitochondrial swelling, and membrane ruptures. All of this can lead to cell death.
Reactive oxygen species and the PTP
Another study of mitochondrial dysfunction led scientists to investigate the critical upstream promoters of PTP opening, including ROS. The ROS are potent oxidants that include hydrogen peroxide, superoxide, and hydroxyl radicals. They are commonly produced by dedicated enzymes, the NADPH oxidases. Because of their potentially damaging effects on cellular macromolecules such as nucleic acids, proteins, and lipids, intracellular superoxides regulated the ROS levels closely. Still, stressors may lead to a significant increase in ROS levels causing intracellular damage. This is true for mitochondria, which are major sites of ROS production due to aerobic respiration and oxidative phosphorylation.
In addition, mitochondrial ROS production involves a protein called p66, which is part of a positive feed-forward signaling pathway for mitochondria-mediated cell death, serving as both a ROS sensor and amplifier. Phosphorylated p66 translocates into the mitochondrial intermembrane space when it interacts with Pin1 isomerase. Then it amplifies the ROS by generating mitochondrial ROS to induce PTP opening, which further elevates oxidative stress levels and activates mitochondria-mediated cell death.
Eliminating p66 has been shown to offer protection against several disease models and organ systems. Studies using mice have shown decreased aortic lesions and lower levels of substances linked to diabetes including proteinuria, albuminuria, and glomerular sclerosis index. These studies also indicate that elimination of p66 results in lower levels of apoptotic cell death. The protective effects of p66 elimination extended to other diseases including ethanol-induced liver damage, in which p66-KO mice fed with an alcohol-rich diet showed reduced liver swelling, serum ALT levels, and attenuated fatty changes.
Neuroprotective treatments that target mitochondria
These studies support the development of treatments that target the elimination of p66. Therapeutics that promote mitochondrial preservation may become essential to current treatment protocols for neurodegenerative diseases including MS.
Mitochondria-directed therapies are still being developed and are still confined to animal studies to test the effectiveness. They investigate a wide array of mitochondria-specific targets including the electron transport chain, ATP synthase, mitochondrial ROS, and the PTP. Recent findings show that the enzyme complex may be involved in signal activation of cell death pathways. However, more studies are needed to determine how this mechanism works.
New drugs may be developed that target mitochondrial ROS including mitochondria-directed antioxidants such as MitoQ and MitoVit E. Both compounds use lipophilic agent TPP+ to increase uptake into mitochondria, which is more effective than untargeted antioxidants.
Another unique class of mitochondria-targeting compounds includes the Szeto-Schiller (SS) peptides, which have an aromatic-cationic motif that allows them to be cell permeable and to selectively target the intramitochondrial membrane. Unlike MitoQ and MitoVit E, the SS peptides do not require mitochondrial membrane potential for uptake. Another treatment in development may provide significant protection in cultured neurons induced with hypoglycemic, oxidative, and ischemic damage, as well as in several kidney, liver, and heart disease models. As for novel therapeutic targets for mitochondrial preservation, the recent work on p66 suggests that it may provide neuroprotective benefits to patients with MS and perhaps other neurodegenerative diseases.
Final thoughts
Autopsies performed in the late 19th century found plaques or scleroses in patients that had exhibited the classic symptoms of what we now call MS. Scientists have amassed a great deal of knowledge about the disease since then. We know that there is an immunologic component that leads to the destruction of myelin by activated immune cells leading to MS symptoms. This understanding has led to an extensive effort to develop immunomodulatory and immunosuppressant drugs to treat MS, which work to combat the pernicious autoimmune attack on the CNS, prevent the breakdown of the protective blood brain barrier, and suppress the infiltration of activated immune cells targeting myelin.
However, these pharmacological treatments do not combat the progressive, debilitating decline in function that plagues a significant number of patients. The neuronal loss in demyelinated lesions of MS patients, and this pathology has been convincingly in modern studies.
While the study of neurodegenerative pathways in MS is still a relatively new area of research, the past decade of research has led to a better understanding of the mechanisms involved. It has helped to define potential pharmacologic targets. In addition, scientists have a much better understanding of mitochondrial dysfunction on neurodegenerative processes in MS, with particular emphasis on the PTP, its modulator CyPD, and mitochondrial ROS sensor and amplifier p66. Thus, MS is not a mitochondrial disease, but it may be that mitochondrial dysfunction is critical to axonal injury within the inflammatory lesions and in the progressive neurodegenerative phase of the illness. Continuing to study these elements of MS may lead to multifaceted mitochondria-targeted neuroprotective therapies that may become part of a standard treatment regimen for not only MS but other neurodegenerative diseases as well.