Mitophagy is a process that specifically degrades damaged or superfluous mitochondria via the autophagy-lysosome machinery.1,2 As a main mitochondrial quality control, dysfunctional mitophagy, mostly defective mitophagy, is associated with various human diseases, including neurodegenerative disorders, cancer, cardiovascular disease, autoimmune disease, and aging. Thus, in the past decade, mechanistic and functional studies of mitophagy have attracted extensive attention. Among many important mitophagy regulators identified so far, PINK1 and Parkin are the key factors to orchestrate the mitophagic process. First, upon mitochondrial damage, PINK1 as a serine/threonine kinase phosphorylates ubiquitin (Ub) and Parkin, forming the first feedforward amplification loop to initiate mitophagy. Second, TBK1 phosphorylates autophagy receptors, such as OPTN and NDP52, forming the second feedforward amplification loop to mediate the specific recognition of damaged mitochondria by autophagy machinery. Third, ULK1 complex recruits LC3 and more autophagy receptors onto damaged mitochondria, forming the third feedforward amplification loop to sequester damaged mitochondria with autophagosomes. Finally, autophagosomes containing damaged mitochondria are delivered to lysosome for degradation. Mutation or deletion of PINK1 and Parkin are found in autosomal-recessive juvenile Parkinsonism (AR-JP),3 which theoretically results in defective/insufficient mitophagy and dopaminergic neuron death. Therefore, it is believed that enhancement of mitophagy by pharmacological agents may provide a therapeutic opportunity for some neurodegenerative disorders such as Parkinson’s disease (PD).
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