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.