The Role of Mitophagy in Regulating Cell Death

Figure 1

Mechanism of mitophagy in different physiological and pathological contexts and mitophagy regulating cell death pathway. Mitophagy plays an important role in maintaining mitochondria homeostasis and various aspects of cellular function. Under physiological conditions, NIX-mediated mitophagy is required for mitochondrial removal during erythroblast differentiation. When in response to mitochondrial stressors, such as membrane depolarization, mitochondrial complex dysfunction, mutagenic stress, and proteotoxicity, distinct mitophagy pathways cooperate to regulate mitochondrial homeostasis. Nix can interplay with Rheb, an important protein for mitophagy, to initiate mitophagy. Nix also functions downstream of Parkin as a substrate. In addition, BNIP3 is able to inhibit PINK1 proteolytic degradation to facilitate Parkin mitochondrial recruitment and mitophagy. Upon mitochondrial depolarization, Mcl-1, as a mitophagy receptor, underwent rapid PINK1/Parkin-dependent polyubiquitination and degradation. AMBRA1-mediated mitophagy is also dependent on Parkin. These findings suggest that these pathways cooperate with each other to ensure efficient mitophagy. With overwhelming mitochondrial damage, the cell death pathway (necrosis, apoptosis, pyroptosis, ferroptosis and necroptosis) becomes dominant, and mitophagy could prevent the accumulation of dysfunctional mitochondria by regulating the cell death pathway.