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).