BNIP3/NIX-mediated mitophagy versus Parkin-mediated mitophagy: mechanistic differences and functional implications

Mitophagy is a form of selective autophagy in which an isolation membrane (IM or phagophore) sequesters damaged or superfluous mitochondria for lysosomal degradation. Recent advances in receptor-mediated mitophagy, particularly the BNIP3/NIX-mediated mitophagy, have highlighted the importance of this pathway in mitochondrial regulation across various biological settings, along with the well-established Parkin-mediated pathway. Parkin-mediated mitophagy senses mitochondrial damage through loss of membrane potential, whereas BNIP3/NIX-mediated mitophagy plays an important role in basal or physiologically induced mitochondrial turnover, thereby contributing to mitochondrial quality control and remodeling. These two pathways employ distinct sets of molecules to recruit the autophagy machinery to the mitochondria and exhibit different IM dynamics that are closely linked to mitochondrial fission and segregation. In this review, we first provide an updated overview of the autophagy process and then compare these two major forms of mitophagy, with particular emphasis on the molecular mechanisms of mitophagy initiation and IM dynamics. We also discuss the functional implications of these mechanistic differences in physiological and pathological context.