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).