Mitophagy Receptors in Tumor Biology

Abstract

Mitochondria are multifunctional organelles that regulate cancer biology by synthesizing macromolecules, producing energy, and regulating cell death. The understanding of mitochondrial morphology, function, biogenesis, fission and fusion kinetics, and degradation is important for the development of new anticancer strategies. Mitophagy is a type of selective autophagy that can degrade damaged mitochondria under various environmental stresses, especially oxidative damage and hypoxia. The key regulator of mitophagy is the autophagy receptor, which recognizes damaged mitochondria and allows them to enter autophagosomes by binding to MAP1LC3 or GABARAP, and then undergo lysosomal-dependent degradation. Many components of mitochondria, including mitochondrial membrane proteins (e.g., PINK1, BNIP3L, BNIP3, FUNDC1, NIPSNAP1, NIPSNAP2, BCL2L13, PHB2, and FKBP8) and lipids (e.g., cardiolipin and ceramides), act as mitophagy receptors in a context-dependent manner. Dysfunctional mitophagy not only inhibits, but also promotes, tumorigenesis. Similarly, mitophagy plays a dual role in chemotherapy, radiotherapy, and immunotherapy. In this review, we summarize the latest advances in the mechanisms of mitophagy and highlight the pathological role of mitophagy receptors in tumorigenesis and treatment.

Nujiangexanthone A Inhibits Cervical Cancer Cell Proliferation by Promoting Mitophagy

“…Therefore, finding new drugs that are effective under conditions of nutrient deprivation is worthwhile. Autophagic degradation products can be reused for protein synthesis and energy production [ 8 ]. Mitophagy is a selective type of autophagy targeting mitochondria, which serves as the main source of energy for cancer cells under starvation.…”

“…Parkin is transported from the cytoplasm to the mitochondria, and then ubiquitinates the proteins on the outer mitochondrial membrane, such as TOM20, MFN1, and MFN2, thereby recruiting P62 and optineurin (OPTN). These proteins then bind to autophagosome proteins (mostly LC3), directing phagophores on the autophagosome to surround the damaged mitochondria [ 8 ]. Finally, the enclosed mitochondria are degraded and eliminated.…”

Mitophagy in Pancreatic Cancer

“…Ub-independent mitophagy is mediated by receptors, rather than E3 ligases. Recently, depending on the stimulus and cell type, the list of mitophagy receptors is increasing (34). In addition to the early reports of BCL2 interacting protein 3 like (BNIP3L/NIX) acting as a mitophagy receptor in red cells (35), other mitophagy receptors, including FUN14 domain containing 1 (FUNDC1) (36), BCL2 interacting protein 3 (BNIP3) (37), nipsnap homolog 1 (NIPSNAP1) (38), nipsnap homolog 2 (NIPSNAP2) (38), prohibitin 2 (PHB2) (39), BCL2 like 13 (BCL2L13) (40) and FKBP prolyl isomerase 8 (FKBP8) (41), have also been identified in cancer and non-cancer cells ( Figure 1B).…”

Mitophagy in Antiviral Immunity

“…Although there is no clear difference between adapter and receptor, it is known that the receptor usually resides on the mitochondrial membrane, whereas the adapter is usually cytoplasmic and needs to be repositioned to the mitochondria during mitophagy. A variety of mammalian mitophagy receptors and adaptors have been reported, including OPTN, NDP52, FUNDC1, BNIP3, PHB2, NIX, p62, cardiolipin, and Bcl2L13 (Montava-Garriga and Ganley, 2020; Xie et al, 2020). These receptors contain the LC3 interaction region (LIR), a tetrapeptide sequence [W/F/Y]xx[L/I/V] motif that interacts with LC3.…”

“…In damaged mitochondria, PINK1 is stabilized on the OMM and recruits Parkin to promote mitophagy. Parkin is an E3 ubiquitin ligase located in the cytoplasm that catalyzes the covalent attachment of substrates to ubiquitin (Xie et al, 2020). Upon recruitment to damaged mitochondria, Parkin ubiquitinates some OMM proteins such as MFN1 and MFN2 (Figure 1).…”