Fig. 1. Mitochondrial quality control. At the protein level, DNA repair proteins (mitochondrial DNA polymerase gamma) repair mitochon-drial DNA; Chaperones import nuclear-encoded mitochondrial proteins into the mitochondria and correctly fold misfolded proteins inthe matrix; Mitochondrial outer membrane proteins are ubiquitinated by MARCH5 and extracted by P97 to be degraded by the pro-teasome; Proteases in the mitochondrial matrix and inter membrane space degrade damaged proteins; Antioxidants reduce reactiveoxygen species to protect mitochondria. At the organelle level, mitochondria biogenesis occurs upon specific signaling; the mitochon-drial network changes mitochondrial shape through fusion and fission to accommodate metabolic requirement; Mitofusin 1/2 andOPA1 mediate fusion in the mitochondrial outer and inner membrane, respectively. MitoPLD converts cardiolipin to phosphatic acidinducing the fusion of mitochondria. When mitochondrial fission occurs, Drp1 binds to its receptors (MFF, MID49, MID51 and FIS1) toform Drp1 oligomers and tightens mitochondria to divide it. Also, increase of short form OPA1 induces mitochondrial fission. Damagedmitochondria are recognized by autophagosome, isolated and then fused with the lysosome to form an autolysosome and finally de-graded.
Fig. 2. Mitochondria recognition by LC3 adaptors and receptors during mitophagy. (A) In healthy mitochondria, PINK1 is targeted to themitochondria and is cleaved by the proteases PARL and MPP in the matrix and mitochondrial inner membrane, respectively. CleavedPINK1 is degraded in the cytosol through the proteasome. (B) In damaged mitochondria, PINK1 accumulates on the mitochondrial outermembrane and is activated through autophosphorylation. Activated PINK1 phosphorylates ubiquitin on its substrates. Phosphorylatedubiquitin-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 OPTNto facilitate the recognition by LC3 and NIX is polyubiquitinated to be recognized by LC3 through NBR1. K27-linked Miro and K48-linkedVDAC1 and MFN 1 and 2 are degraded by proteasome. The ubiquitin-independent LC3 adapters CHDH and TBC1D15 recognize p62and 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 byULK1. Phosphorylation of Ser272 in BCL2L13 enhances the interaction with LC3. PHB2 in the mitochondrial inner membrane interactswith LC3 when PHB2 LIR is exposed to the cytosol following Parkin-mediated rupture of the mitochondrial outer membrane. Cardiolipintranslocates to the mitochondrial outer membrane and promotes mitophagy through direct interaction with LC3.
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