Fig. 3

Mechanisms of mitophagy. Mitophagy receptors such as FUNDC1, BNIP3, NIX, BCL2L13, and FKBP8 localize to the OMM and interact with LC3 directly through LIR to induce mitochondrial clearance. The phosphorylation status of these mitophagy receptors and their association with LC3 are influenced by multiple kinases (CK2, SRC, UKL1, JNK1/2, PRKA), phosphatases such as PGAM5, and a variety of stimuli. Together, these influencing factors control the initiation and progression of mitophagy. Dephosphorylation of FUNDC1 promotes its separation from OPA1 and interaction with DRP1, which in turn facilitates mitochondrial fission and the targeted elimination of damaged mitochondria. The E3 ligase MARCH5 and deubiquitinase USP19 also control the protein level of FUNDC1 and mitochondrial fission activity. HIF-1α controls the levels of the proteins BNIP3 and NIX, which are essential for hypoxia-induced mitophagy. Parkin recruitment to damaged mitochondria depends on the stability of PINK1 on the OMM, which occurs as a result of ΔΨm dissipation. Parkin ubiquitinates several OMM proteins, while PINK1 phosphorylates and activates Parkin. Autophagy initiation proteins (ATG9, FIP200) are attracted to damaged mitochondria by several autophagy adaptor proteins, including NDP52 and OPTN, which are brought to the OMM by phosphorylated poly-Ub chains. OPTN is phosphorylated by TBK1, enhancing its interaction with poly-Ub chains and serving as a feed-forward mechanism promoting mitophagy