Is Impaired Mitophagy or Increased Oxidative Stress the First Cause in Mitochondrial Aging?
Mitochondria are vital cellular components, a herd of hundreds of these organelles in every cell working to produce the adenosine triphosphate (ATP) needed to power cellular processes. A side effect of this activity is the production of free radicals, which can increase to the point of causing oxidative stress to a cell when mitochondria are damaged. The herd is culled by the mechanisms of mitophagy, which clear out damaged mitochondria in order to maintain function. With age, mitophagy declines in efficiency, mitochondria become more damaged and dysfunctional, and oxidative stress rises. But in which direction is the arrow of causation? Evidence from the use of mitochondrially targeted antioxidants suggests that reducing oxidative stress improves mitophagy. Equally, improving mitophagy via other means, such as NAD+ upregulation, also seems to reduce oxidative stress.
Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production, and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer's and Parkinson's diseases.
The interplay between mitophagy, ROS production, and aging is complex and far from being completely elucidated. The central role of ROS production and consequent damage to mitochondria in the aging process has been clearly established in the last 50 years, despite some objections to this theory over the past 15 years, and mitophagy is a key mechanism for mitochondrial quality and quantity control, as it limits the production of ROS, the damage to mitochondrial DNA of transmembrane potential loss, and the decrease in ATP production.
Evidence indicates that the imbalance of the delicate equilibrium among mitophagy, ROS production, and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological or pathological conditions. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, and further damage from ROS, or if, on the other hand, an alteration in the regulation of mitophagy constitutes one of the initial events leading to the main of the excessive production of ROS.