2.2. PINK1-PRKN-mediated mitophagy
PINK1 (PTEN induced kinase 1), a serine/threonine kinase, and PRKN
(parkin RBR E3 ubiquitin protein ligase), an E3 ubiquitin ligase, are
causal factors that drive hereditary recessive Parkinson disease
(Truban, Hou, Caulfield, Fiesel & Springer, 2017). Under physiological
conditions, PINK1 is recruited to the mitochondrial inner membrane and
is cleaved/inactivated by mitochondria-residing proteasomes. Conversely,
upon mitochondrial depolarization/impairment, PINK1 begins to accumulate
in MOM, recruiting PRKN to this location for phosphorylation
(activation). Phosphorylated PRKN ubiquitinates specific MOM proteins
such as VDAC1 (voltage dependent anion channel 1), RHOT1 (ras homolog
family member T1), MFN1 (mitofusin 1), and certain mitophagy receptors
recognized by an Atg8-family protein on phagophores (Fig. 1) (Eiyama &
Okamoto, 2015; Springer & Kahle, 2011).
PINK1 stabilization on MOM is an essential initial step in mitophagy.
Under normal circumstances, the serine protease PARL (presenilin
associated rhomboid like) relocates to the mitochondrial inner membrane
and degrades PINK1 and PGAM5. Once mitophagy is activated, PHB2
(prohibitin 2) deactivates PARL, leading to PINK1 stabilization and
PGAM5 activation. Then, PGAM5 interacts with PINK1 and further increases
its stabilization on the mitochondria (Yan et al., 2020). Also,
HSPA/HSP70 participates in PINK1 stabilization by retarding its
degradation (Zheng et al., 2018). In addition, overexpression of TAMM41
(TAM41 mitochondrial translocator assembly and maintenance homolog; a
mitochondrial protein) accelerates PRKN recruitment and enhances PINK1
stabilization (Yang et al., 2019).
PINK1 also phosphorylates ubiquitin chains, which accelerates PRKN
recruitment to the mitochondria, leading to polyubiquitination of MOM
proteins (Gao, Yu, Lv, Liang, Sun & Zhang, 2021). Ultimately, autophagy
cargo receptors such as OPTN (optineurin), SQSTM1 (sequestosome 1),
TAX1BP1 (Tax1 binding protein 1), CALCOCO2 (calcium binding and
coiled-coil domain 2), and NBR1 (NBR1 autophagy cargo receptor), which
contain a ubiquitin-binding domain (UBD), recognize polyubiquitinated
proteins, and also interact with MAP1LC3 on phagophores via their LIR
motif (Onishi, Yamano, Sato, Matsuda & Okamoto, 2021).
As aforementioned, PRKN polyubiquitinates certain mitophagy receptors
such as BNIP3L, which is recognized by the UBD domain of the autophagy
receptor NBR1 (Gao et al., 2015). NBR1 also binds to MAP1LC3B and
GABARAP on the phagophore membrane to promote engulfment of mitochondria
(Gao et al., 2015).
CALCOCO2, another receptor, is also recruited to MOM, where, it binds
polyubiquitinated proteins, resulting in the activation and recruitment
of the ULK1 (unc-51 like autophagy activating kinase 1) complex to the
MOM, resulting in amplified PINK1-PRKN-mediated mitophagy (Padman,
Nguyen, Uoselis, Skulsuppaisarn, Nguyen & Lazarou, 2019). ULK1
phosphorylates serine 14 residue of BECN1 (beclin 1, an essential
protein in autophagy), and thereby, promotes BECN1-PRKN interactions,
which enhances PRKN recruitment to mitochondria (Fig. 1) (Kumar &
Shaha, 2018).
Furthermore, the interaction between BNIP3 and PINK1 facilitates PINK1
accumulation in MOM, and consequently, fosters PRKN recruitment to MOM
(Zhang et al., 2016). It is thought that autophagy receptors known thus
far can participate in PINK1-PRKN-mediated mitophagy. This process
ultimately leads to the bridge formation between phagophores and
depolarized mitochondria. Eventually, mitochondria-encapsulating
autophagosome/mitophagosomes fuse with lysosomes for ultimate
degradation of sequestered mitochondria into macromolecules that are
released into the cytosol for reuse (Ding & Yin, 2012).
Other molecules have been discovered that mediate mitophagy independent
of PINK1 and PRKN including cardiolipin, DNM1L (dynamin 1 like), HUWE1
(HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1),
MARCHF5 (membrane associated ring-CH-type finger 5), ARIH1 (ariadne RBR
E3 ubiquitin protein ligase 1), SQSTM1-KEAP1 (kelch like ECH associated
protein 1)-RBX1 (ring-box 1), and MUL1 (mitochondrial E3 ubiquitin
protein ligase 1) (Ambivero, Cilenti, Main & Zervos, 2014; Di Rita et
al., 2018; Kageyama et al., 2014; Villa et al., 2017).