Abstract:
Mitochondrial therapeutics is an emerging field in medicine with a growing interest from the pharmaceutical sector. Many well know conditions, including Alzheimer’s/Parkinson’s disease, multiple sclerosis and diabetes show mitochondrial dysfunction, which has yet to be fully explored as a potential therapeutic target. Other less well-defined chronic conditions, including Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long Covid and Gulf War Syndrome (GWS), also show elements of mitochondrial dysfunction. ME/CFS is the best studied with evidence of energy dysregulation observed in peripheral blood mononuclear cells and a systemic effect with reduced levels of amino acids in plasma possibly linked to alter fuel use. Although it is unclear if mitochondrial dysfunction is directly involved in ME/CFS, there appears to be an abnormal energy balance. Patient’s symptoms will worsening if they expend too much energy during physical exertion or undertaking cognitive tasks. Post exertional malaise (PEM) in ME/CFS and Long Covid is a characteristic feature, which differentiates the conditions from clinical depression, which can also associate with severe fatigue.
Mitochondria are the primary generators of aerobic energy production in eukaryotic tissues, but also have roles in infection, being a key component of the innate immune response to bacterial and viral pathogens, and also dealing with intracellular pathogens. How cells balance the energy and metabolic needs of the cell with other mitochondrial pathogen-associated roles is likely important in the chronic diseases outlined earlier. Most of the conditions outlined above are associated with pathogens at some stage of the disease process. Mammalian tissues differ in their mitochondrial content. Heart has the highest number of mitochondria relative to its volume at 37%, while the brain has very few at 5%. With the brain being the largest consumer of oxygen and glucose in the body: how does the brain generate enough energy to meet its high ATP requirement with so few mitochondria? In this presentation, we speculate that in cells with a high aerobic ATP production need other membrane systems containing mitochondrial components are the primary generators of aerobic ATP. These membrane systems include myelin in neurons, the membranes of the outer segment of Rod cells in the retina and the endoplasmic reticulum in antibody producing plasmablast cell. All of these cells have a very large aerobic energy need but appear to have insufficient mitochondria. This lack of mitochondria may also impact on the ability of these cell to deal with intracellular pathogens. Both mitochondrial DNA shedding to trigger an innate immune response and engulfment of intracellular pathogens both play a role in how we deal with pathogens. With the microbiome, now extending beyond the gut and into our cells and tissues how we work with these invaders is an important factor in our health and well-being. With mitochondria having a significant pathogen defence role, cells lacking mitochondria in the long-term maybe more vulnerable to the establishment of chronic conditions, with genetic and physiological differences in individuals making some more susceptible than others.