Figure 2: The diverse pathways to induce mitophagy.

Within the neuron, multiple mechanisms exist to signal cargo engulfment, including PINK1/Parkin, OMM receptors, ubiquitin cascades, and lipids. 1. PINK1/Parkin-mediated mitophagy initiates with PINK1 stabilization on the OMM, which recruits Parkin. Phospho-ubiquitination of OMM substrates (VDAC, Mfn2, etc.) by PINK1/Parkin recruits autophagy receptors, OPTN and NDP52. Phosphorylation of OPTN by TBK1 helps to stabilize it on the mitochondrial surface. These autophagy receptors link the damaged organelle to the autophagosome through interactions with ubiquitin and LC3 on the mitochondrial membrane and growing phagophore, respectively. 2. Several autophagy receptors are anchored within the OMM, including BNIP3 and NIX/BNIP3L. Highlighted is the role of NIX/BNIP3L, which is phosphorylated by an unknown kinase, leading to activation and binding of NIX/BNIP3L to LC3 or GABARAP on the phagophore. 3. Additional E3 ligases have been reported to regulate mitophagy independent of Parkin. MUL1 has similar substrates to Parkin and can directly bind to GABARAP, suggesting that it can function independently to mediate engulfment. 4. Externalization of cardiolipin, normally found on the IMM, to the OMM is a unique mechanism for lipid-mediated mitophagy. Cardiolipin can bind directly to LC3 to induce mitophagy.