The Role of Mitochondrial Quality Control in Anthracycline-Induced Cardiotoxicity: From Bench to Bedside

Figure 2

Regulatory mechanisms of mitophagy. PINK1 is degraded by presenilin-associated rhomboid-like (PARL) protease in the mitochondrial matrix under physiological conditions. When the MMP is impaired and decreased, PINK1 accumulates on the OMM, which recruits cytosolic Parkin to the impaired mitochondria and activates its E3 ligase activity through phosphorylation. The recruited Parkin catalyzes OMM protein ubiquitination and form poly-ubiquitin chains on OMM. These ubiquitinated proteins function as the recognition sequence domain of LC3 via interaction with adaptor proteins, such as p62/SQSTM1, leading to the transportation of damaged mitochondria into autophagosomes. Bnip3/Nix possess an LC3-interacting motif (LIR) can directly interact with LC3 on the phagophore independently of the adaptor protein p62/SQSTM1. Fundc1 is activated via phosphorylation under hypoxic conditions. Fundc1 interacts with LC3 directly through its LIR motif. Finally, the elongated isolation membrane encloses the impaired mitochondria and forms mitophagosomes, which then fuse with lysosomes for bulk degradation: PTEN-induced putative kinase 1 (PINK1), BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), BNIP3-like (also known as BNIP3L) (Nix), and FUN14 Domain Containing 1 (FUNDC1).