Failing Mitochondrial Quality Control in Aging and Neurodegeneration
Every one of our cells contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now fully integrated into our biochemistry. Mitochondria contain their own small remnant genome, the mitochondrial DNA, replicate like bacteria, and toil to produce adenosine triphosphate (ATP), a chemical energy store molecule used to power cell processes. Mitochondrial function declines with age, unfortunately, and our cells suffer for it. This contributes meaningfully to many age-related conditions. This decline appears to result in large part from changes in gene expression that impair the various quality control processes that (a) ensure mitochondrial proteins are correctly formed, and (b) that damaged mitochondria are recycled. Those changes in gene expression are maladaptive responses to other aspects of aging, perhaps in part the shift to an inflammatory environment, perhaps in part due to changes in nuclear structure resulting from cycles of double strand DNA repair, and so forth.
The search for ways to improve mitochondrial function in old age is an area of considerable focus in the aging research community and longevity industry. Partial reprogramming is perhaps the most well funded approach, but numerous efforts are being undertaken to find ways to improve mitochondrial quality control to greater degrees than can be achieved via supplements and exercise. Beyond this, a number of groups are building the infrastructure needed to manufacture large amounts of mitochondria for transplantation. This latter approach seems the most viable path if the goal is near term success; researchers have demonstrated that mitochondrial can be delivered into tissues and taken up to improve cell function. It is just a matter of being able to cost-effectively manufacture very large numbers of these organelles.
Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function.
In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.