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. 2023 Apr 6;103(4):2349–2422. doi: 10.1152/physrev.00058.2021

FIGURE 2.

FIGURE 2.

Mitophagy. Mitophagy is a selective process for the turnover of mitochondria by the lysosome-dependent autophagy pathway. Distinct modes of mitophagy include receptor-dependent mitophagy (A) and PINK1/Parkin-dependent mitophagy (B), the primary pathway by which dysfunctional or depolarizing mitochondria are cleared. Under resting conditions PINK1 is imported into the mitochondria via TIM and TOM and processed by the IMM rhomboid protease PARL. A truncated form of PINK1 (ΔPINK1) is exported from the mitochondria and processed for proteasomal degradation via E3 ubiquitin ligases. In response to mitochondrial depolarization, PINK1 is stabilized on the OMM, phosphorylates ubiquitin (UB), and recruits Parkin to the mitochondria. Parkin, an E3 ubiquitin ligase, ubiquitinates OMM proteins, including Mfn1/Mfn2 and others. Ubiquitinated OMM proteins interact with mitophagy cargo adaptors, which, through LIR domains, interact with LC3 on nascent autophagosome membranes. This process facilitates recruitment of additional autophagy initiating factors, including Atg16L, and others. Mitophagy cargo adaptors include NDP52, p62 (SQSTM1), NBR1, and OPTN activated by TBK1. Receptor-dependent mitophagy (A) is important for physiological regulation of mitochondrial populations and utilizes OMM receptor proteins that interact directly with autophagosomal membrane protein LC3. These include BNIP3, Nix1, the membrane lipid cardiolipin (CL), and others (i.e., PHB2, FKB8). FUNDC1 is a mitophagy receptor that is specifically activated by hypoxia and that can also inhibit fusion via interaction with Opa1. Targeting of mitochondria to autophagosome membranes ultimately results in their assimilation in mature autophagosomes and degradation in the lysosomal compartment. See glossary for abbreviations.