Protective Effect of Natural Medicinal Plants on Cardiomyocyte Injury in Heart Failure: Targeting the Dysregulation of Mitochondrial Homeostasis and Mitophagy

Figure 3

Regulatory mechanisms of receptor-dependent mitophagy mediated by BNIP3 and FUNDC1 in cellular physiology and pathology. BNIP3 and NIX are multifunctional mitochondrial outer membrane proteins. In myocardial tissue, BNIP3 and NIX expression are regulated by hypoxia, and promote cardiomyocyte apoptosis, resulting in decreased cardiac function. However, BNIP3 and NIX localized to the mitochondrial outer membrane can also act as mitophagy receptors, by binding LC3 through their LC3 interacting regions (LIRs), and directly recruit phagocytic vesicles to the mitochondria to mediate mitophagy. Oxidative stress induces BNIP3 homodimerization to activate mitophagy. Furthermore, BNIP3 and NIX may directly activate mitophagy by disrupting the interaction of BcL-2 with Beclin1. FUNDC1 is a highly conserved mitochondrial outer membrane protein that is widely expressed in various cells, tissues, and the heart. As a mitophagy receptor, it mediates mitophagy by interacting with LC3. Under stress conditions such as hypoxia and mitochondrial membrane uncoupler treatment, FUNDC1 is activated by phosphorylation of its serine 17 site by ULK1 and dephosphorylation of its serine 13 site by PGAM5, enhancing the binding of its LIR to LC3 to promote mitophagy. The mitophagy receptor is PHB2. Although PHB2 has LIR in the inner mitochondrial membrane, LC3 usually cannot reach it. Therefore, its mediated mitophagy relies on the outer mitochondrial membrane (OMM) protein degradation mechanism that can lead to the rupture of the OMM. In mammalian cells, Parkin-mediated mitophagy also requires the regulation of PHB2, especially in response to oligomycin-induced mitochondrial stress, but its association with other stressors remains to be further verified.