2.1. Mitophagy receptors
Mammalian cells would mandate a sophisticated quality control system, mitophagy, to sustain mitochondrial homeostasis. Once mitochondria are depolarized, mitophagy receptors are recruited to the mitochondrial outer membrane (MOM) and recognize the depolarized/damaged mitochondria (Ajoolabady, Aslkhodapasandhokmabad, Aghanejad, Zhang & Ren, 2020). Mitophagy receptors are integrated into MOM via a C-terminal transmembrane domain, and also bind to mammalian Atg8-family proteins localized on phagophore membrane, including components of the MAP1LC3 (microtubule associated protein 1 light chain 3) and GABARAP (GABA type A receptor-associated protein) subfamilies via a specific LC3-interacting region (LIR) motif. This interaction connects the cargo with the autophagy machinery to promote sequestration of the mitochondria within autophagosomes (Fig. 1) (Yamaguchi, Murakawa, Nishida & Otsu, 2016).
BNIP3 (BCL2 interacting protein 3) is an essential mitophagy receptor that participates in mitochondrial turnover upon hypoxia (Zhang & Ney, 2009). Mutations in the BNIP3 monomer or its LIR motif can contribute to mitophagy defects (Hanna, Quinsay, Orogo, Giang, Rikka & Gustafsson, 2012). Also, BNIP3L/NIX (BCL2 interacting protein 3 like), another mitophagy receptor, exhibits a 53-56% homology to BNIP3 (Matsushima et al., 1998), and is activated upon reticulocyte maturation and ROS accumulation (Melser et al., 2013; Schweers et al., 2007). LIR motif of BNIP3L binds MAP1LC3B, GABARAPL2 (GABA type A receptor associated protein like 2), GABARAP, and GABARAPL1 (GABA type A receptor associated protein like 1) (Marinković, Šprung & Novak, 2020).
Upon hypoxia challenge, FUNDC1 (FUN14 domain containing 1) also functions as a mitophagy receptor. Mechanistically, PGAM5 (PGAM family member 5, mitochondrial serine/threonine protein phosphatase) phosphatase dephosphorylates FUNDC1 at serine 13 residue and mediates its binding to MAP1LC3B to favor mitophagy induction (Ma et al., 2020; Ren et al., 2020). Furthermore, BCL2L13 (BCL2 like 13) and FKBP8 (FKBP prolyl isomerase 8) are two other MOM integral proteins that serve as mitophagy receptors in mammalian cells (Fig. 1) (Bhujabal et al., 2017; Fujiwara et al., 2019).