Enhancing Mitochondrial Function as a Way to Treat Neurodegenerative Conditions
Every cell in the body contains hundreds of mitochondria, their primary task the generation of chemical energy store molecules to power cell processes. Mitochondrial function declines with age, a consequence of damage to mitochondrial DNA and maladaptive changes in gene expression in the cell. This loss of function is thought to be important in degenerative aging, leading to cell and tissue dysfunction and age-related conditions. Tissues with a high energy requirement, such as the brain and skeletal muscle, are the most affected. Thus all neurodegenerative conditions are likely driven in part by loss of mitochondrial function in the brain.
Progressive neurodegenerative diseases affect a significant proportion of the population; in a single year, there are as many as 276 million disabilities and 9 million deaths as a result of neurological diseases. Mitochondrial function, aging, and neurodegenerative processes appear to be intricately linked; central nervous system degeneration is a major feature of loss-of-function mitochondrial diseases, involving mutation of nuclear DNA or mitochondrial DNA. Meanwhile, mitochondrial dysfunction occurs during healthy aging and is further associated with several neurological diseases, including Alzheimer's disease (AD), Huntington's disease, Friedreich's ataxia, multiple sclerosis, motor neuron disease, Parkinson's disease (PD), and vanishing white matter disease (VWMD).
Aging increases neurodegenerative risk factors and processes, including progressively impaired cognitive and/or motor function due to cellular dysfunction, senescence, and/or neuronal death. Furthermore, impaired mitochondrial respiration, biogenesis, mitophagy, and axonal transport can be causative factors in dysfunctional protein synthesis, folding, aggregation, and trafficking, as well as inflammation, oxidative stress, and genomic instability. Thus, targeting mitochondrial function offers the premise of mitigating cellular degeneration. Furthermore, the cumulative impact of oxidative damage is exacerbated by the inherent susceptibility of mitochondrial DNA to reactive oxygen species (ROS)-induced mutations. Consequently, neurons appear to have an inherent susceptibility to mitochondrial dysfunction.
The interrelated nature of mitochondrial dysfunction and the inherent impact of energy dysregulation in cellular stress, proteotoxicity, and cell death implies that mitochondrial therapeutics may be beneficial for multiple neurodegenerative diseases and aging, i.e., to treat degeneration as a secondary mitochondrial disease. In an age of emerging gene and cell-based therapies, further research is warranted to explore the most effective mitochondrial-based strategies to slow neurodegenerative disease progression and aging.