Abstract
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. 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, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria.
Highlights
Mitochondrial dysfunction is considered a hallmark of aging [1]
Several lines of evidence strongly suggest that mitophagy plays a role in aging, and recent studies have demonstrated that mitophagy is crucial in delaying physiological aging and age-related disorders, such as neurodegenerative and cardiovascular diseases
Along with the observation that mitophagy is enhanced in Alzheimer’s disease (AD) brains, accompanied by depletion of cytosolic Parkin over disease progression, these data suggest that impaired mitophagy significantly contributes to the accumulation of dysfunctional mitochondria in AD-affected neurons [127]
Summary
Mitochondrial (mt) dysfunction is considered a hallmark of aging [1]. Dysfunctional mitochondria are recognized and degraded either by non-selective autophagy or by a selective type of macroautophagy, named mitophagy [2]. Mitophagy process starts when dysfunctional mitochondria are targeted with specific receptors or adaptors and are engulfed in a double-membrane vacuole named autophagosome. Based on the ability of receptor to recruit ubiquitin, the mitophagy regulatory pathways could be classified as ubiquitindependent or ubiquitin-independent (receptor-dependent) [3,9] This process is triggered by multiple stimuli and can be activated on the basis of cell requirement. Antioxidants 2021, 10, 794 stress-induced mitophagy is activated by stimuli, such as oxidative stress, starvation, hypoxia, and loss of the mitochondrial membrane potential (MMP), with the aim of reducing mitochondrial amount and, in turn, decreasing the production of reactive oxygen species (ROS) and oxygen consumption by damaged mitochondria [17]. We discuss the main findings linking mitophagy, oxidative stress, and aging, both in physiological aging, and in age-related diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)
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