Figures:
Fig. 1. PINK1-PRKN-mediated mitophagy and initial signaling cascade of mitophagy.
Once mitochondria are damaged or depolarized, they evoke accumulation of ROS that trigger initial mitophagy induction. Mitochondrial injury also induces AMP and Ca2+ accumulation in the cytosol. ROS along with Ca2+ and AMP accumulation in the cytosol can activate AMPK, which, in turn, phosphorylates and activates a spectrum of mitophagy and autophagy regulators. Mainly, the AMPK-MTORC1-ULK1 axis represents the first complex that mediates phagophore, and subsequently autophagosome, formation. Mitochondrial changes also involve biochemical modulation inside mitochondria. Mitochondrial depolarization triggers PINK1 stabilization on the MOM, which recruits PRKN, and PRKN also mediates ubiquitination of MOM proteins. Further PRKN accumulation on the MOM results in polyubiquitination of MOM proteins. Ultimately, polyubiquitinated MOM proteins are recognized by autophagy cargo receptors such as OPTN, NBR1 and SQSTM1, which connect them with MAP1LC3B/LC3B and the phagophore. ULK1 not only is involved in the formation of phagophores and autophagosomes but also activates BECN1, which interacts with PRKN and amplifies its recruitment to the MOM. Following the sequestration of damaged mitochondria within autophagosomes and the subsequent fusion of the latter with a lysosome, ROS is dramatically scavenged from the cytosol. It is also noteworthy that Golgi-derived membrane can participate in the formation of phagophores.
Fig. 2. Targeted drug delivery to macrophages.
Using mannose-coated nanocarriers such as liposomes and SLNS, melatonin and other therapeutic drugs can be delivered specifically to macrophages. Once nanoparticles arrive, mannose receptors recognize them and endocytosis occurs, culminating in the release of the drugs within the macrophage cytosol.