5.4. New perspective on targeting PINK1-PRKN-mediated mitophagy
PINK1 and PRKN activators were proposed to drive PINK1-PRKN-mediated
mitophagy. However, PINK1 and PRKN are also parts of other signaling
pathways in biological processes; thus, targeting these molecules may
yield off-target effects (Miller & Muqit, 2019). Thus, we propose new
trends to reinvigorate PINK1-PRKN-mediated mitophagy. To do this, we
divide this process into three major stages including (i) the initiation
stage, which is commenced by mitochondrial depolarization or damage,
(ii) the maintenance stage, which requires PINK1 stabilization, and
(iii) the amplification stage, which mainly involves ULK1 activation.
We propose that inducing mild mitochondrial depolarization along with
manipulating other stages might boost PINK1-PRKN-mediated mitophagy
(Georgakopoulos, Wells & Campanella, 2017). Mild induction of
mitochondrial depolarization mainly influences already depolarized
mitochondria. Such an approach might avert unwanted depolarization of
plasma membrane and intact/healthy mitochondria. For this purpose, two
polymethoxylated flavones including nobiletin and tangeretin have shown
promising effects (Wu et al., 2013). Nonetheless, new compounds should
be developed to be applicable in clinical settings.
As discussed above, for PINK1 stabilization at the MOM, the
PHB2-PARL-PGAM5 pathway, TAMM41, and HSPA2 (heat shock protein family A
[Hsp70] member 2) are essential components. Therefore, future
attempts should be directed towards pharmaceutical/natural agents to
modulate these components and strengthen PINK1-PRKN-mediated mitophagy
in macrophages. Of note, before drug development, to limit off-target
effects and avert excessive mitophagy, altered expression, dysfunction,
and activation of these components in macrophages of atherosclerotic
lesions should be explored. Table 1 lists the mitophagy modulators under
clinical investigation.