Fig. 1.

Mechanism of mitophagy. When mitochondria depolarize or accumulate misfolded membrane proteins, PINK1 is located on the outer mitochondrial membrane and phosphorylates itself. At the same time, phosphorylated Ub can directly bind to Parkin and is recruited to the surface of mitochondria and phosphorylated by PINK1. PINK1 can phosphorylate Ub in the whole cell and form polyubiquitin chains. While recruiting Parkin, the mitochondrial matrix is also ubiquitinated. Mitochondria labeled with ubiquitin recruit mitophagy receptors, such as p62, NDP52, NBR1, and OPTN. These receptors interact with the autophagy protein LC3 on the outer membrane through their LIR motifs, bind to the polyubiquitin chain through the ubiquitin binding domain, and finally initiate mitophagy. In addition, cardiolipids in the brain are present in the mitochondrial intimum, requiring three translocases to be exposed to the OMM, and can directly bind to LC3 to mediate mitophagy.