Figure 2. Mammalian mitophagy receptors and E3 ligases. In cells with healthy polarized mitochondria, AMPK activity is limited, and the E3 ligase PARK2 remains in the cytoplasm. In the presence of adequate nutrients and growth factors, MTOR is active, inhibiting ULK1 and preventing autophagy induction. By contrast, mitochondrial dysfunction and reduced intracellular ATP levels result in AMPK activation, which not only inhibits MTOR but also directly phosphorylates ULK1 to induce autophagy. Moreover, PINK1 is stabilized on the outer mitochondrial membrane, facilitating PARK2 recruitment. PARK2 subsequently ubiquitinates and promotes degradation of several outer mitochondrial membrane proteins, facilitates mitochondrial aggregation and clustering, and phagophore nucleation. Phagophores are targeted to the mitochondria via receptors such as FUNDC1, BNIP3L, BNIP3, ceramide, and cardiolipin. Sequestered mitochondria are then degraded via fusion to lysosomes, and recycled metabolites are exported back to the cytosol. Other E3 ligases, namely MUL1 and SMURF1, are also implicated in mitophagy. ER, endoplasmic reticulum; PM, plasma membrane; Mito, mitochondria; +, membrane potential; ∆, PINK1; ○, vesicles; ~, phosphatidylethanolamine (PE).