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.