Mitophagy

Mitophagy is the degradation of mitochondria via a selective form of autophagy, a fundamental mechanism conserved from yeast to humans that controls mitochondrial quality and quantity. ^[1] It serves as a cytoprotective mechanism that removes superfluous or dysfunctional mitochondria to maintain mitochondrial homeostasis and intracellular balance. ^{[2] [3]}

Mitophagy is promoted through specific mitochondrial outer-membrane receptors or through ubiquitin molecules conjugated to proteins on the mitochondrial surface, leading to the formation of autophagosomes surrounding mitochondria. ^[1] In the PINK1-Parkin pathway, PINK1 acts as the damage sensor that probes mitochondrial import integrity and activates the E3 ubiquitin ligase Parkin, which marks damaged mitochondria with ubiquitin for mitophagy. ^[4] Mitochondrial cargo receptors such as BNIP3, BNIP3L/NIX and FUNDC1 target mitochondria to autophagosomes through interaction with members of the LC3/GABARAP family. ^[5] Mitophagy is tightly coordinated with mitochondrial biogenesis, the two opposing mechanisms together regulating mitochondrial mass and quality in response to cellular energy needs. ^{[6] [7]}

Maintaining optimal mitochondrial function is a feature of health, and impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. ^[7] Defects in mitophagy are associated with pathological conditions including neurodegeneration, heart failure, cancer and aging. ^[1] In Alzheimer's disease, impaired removal of damaged mitochondria leads to their accumulation and contributes to synaptic dysfunction and cognitive deficits through increased oxidative damage and energy deficits. ^[8]

Strategies to boost mitophagy have been successfully tested in model organisms and, more recently, some have been translated into clinical studies through exercise and nutritional and pharmacological interventions. ^[7] The natural compound urolithin A enhances cellular health by increasing mitophagy and mitochondrial function, with benefits in muscle supported by clinical trials in elderly people. ^[9] Numerous small-molecule modulators of mitophagy have been reported as an emerging direction for the treatment of some diseases. ^{[3] [2]}