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Fig. 2. (A) In healthy mitochondria, PINK1 is targeted to the mitochondria and is cleaved by the proteases PARL and MPP in the matrix and mitochondrial inner membrane, respectively. Cleaved PINK1 is degraded in the cytosol through the proteasome. (B) In damaged mitochondria, PINK1 accumulates on the mitochondrial outer membrane and is activated through autophosphorylation. Activated PINK1 phosphorylates ubiquitin on its substrates. Phosphorylated ubiquitin-substrates interact with OPTN or NDP52 to subsequently recruit initiation factors of autophagy or Parkin, an E3 ubiquitin ligase, which is then activated by PINK1 for polyubiquitination. K63-linked polyubiquitinated substrates are recognized by five LC3 adapters (p62, NDP52, OPTN, TAX1BP1 and NBR1) to interact with LC3 on autophagosomes through the LIR motif. TBK1 phosphorylates OPTN to facilitate the recognition by LC3 and NIX is polyubiquitinated to be recognized by LC3 through NBR1. K27-linked Miro and K48-linked VDAC1 and MFN 1 and 2 are degraded by proteasome. The ubiquitin-independent LC3 adapters CHDH and TBC1D15 recognize p62 and FIS1, respectively. (C) Under hypoxic condition, homodimerized BNIP3 is phosphorylated at Ser17 and 24, and NIX is phosphory-lated at Ser81 to facilitate the interaction with LC3. FUNDC1 is dephosphorylated at Ser13 by PGAM5 and phosphorylated at Ser17 by ULK1. Phosphorylation of Ser272 in BCL2L13 enhances the interaction with LC3. PHB2 in the mitochondrial inner membrane interacts with LC3 when PHB2 LIR is exposed to the cytosol following Parkin-mediated rupture of the mitochondrial outer membrane. Cardiolipin translocates to the mitochondrial outer membrane and promotes mitophagy through direct interaction with LC3.
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