Mitophagy and Oxidative Stress: The Role of Aging

The data and observations discussed in this review indicate that the imbalance of the delicate equilibrium among mitophagy, reactive oxygen species production, and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological or pathological conditions

Anna De Gaetano; Lara Gibellini; Giada Zanini; Milena Nasi; Andrea Cossarizza; Marcello Pinti

2021

Scholarcy highlights

  • Mitochondrial dysfunction is considered a hallmark of aging
  • Along with the observation that mitophagy is enhanced in Alzheimer’s disease 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
  • The observations made on early onset, recessive familial Parkinson’s disease are of particular interest to understand how impairment of mitophagy affects the delicate balance between damage caused by oxidative stress and mitochondrial turnover maintaining the organelle homeostasis
  • The central role of reactive oxygen species 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 mtDNA of transmembrane potential loss and the decrease in ATP
  • The data and observations discussed in this review indicate 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
  • LRKK2 is a kinase enzyme codified by the LRRK2 gene and mutations in LRRK2 are responsible for 1–2% of total PD cases and about 5% of total familial cases, even if LRKK2 represent a risk locus for sporadic PD
  • 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, 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
  • It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by reactive oxygen species that initiates the dysregulation of mitophagy, 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

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