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, 41 (1), 18-26

A Molecular Approach to Mitophagy and Mitochondrial Dynamics


A Molecular Approach to Mitophagy and Mitochondrial Dynamics

Seung-Min Yoo et al. Mol Cells.


Mitochondrial quality control systems are essential for the maintenance of functional mitochondria. At the organelle level, they include mitochondrial biogenesis, fusion and fission, to compensate for mitochondrial function, and mitophagy, for degrading damaged mitochondria. Specifically, in mitophagy, the target mitochondria are recognized by the autophagosomes and delivered to the lysosome for degradation. In this review, we describe the mechanisms of mitophagy and the factors that play an important role in this process. In particular, we focus on the roles of mitophagy adapters and receptors in the recognition of damaged mitochondria by autophagosomes. In addition, we also address a functional association of mitophagy with mitochondrial dynamics through the interaction of mitophagy adaptor and receptor proteins with mitochondrial fusion and fission proteins.

Keywords: autophagy; mitochondria; mitochondrial quality control; mitophagy; selective autophagy.


Fig. 1
Fig. 1. Mitochondrial quality control
At the protein level, DNA repair proteins (mitochondrial DNA polymerase gamma) repair mitochondrial DNA; Chaperones import nuclear-encoded mitochondrial proteins into the mitochondria and correctly fold misfolded proteins in the matrix; Mitochondrial outer membrane proteins are ubiquitinated by MARCH5 and extracted by P97 to be degraded by the proteasome; Proteases in the mitochondrial matrix and inter membrane space degrade damaged proteins; Antioxidants reduce reactive oxygen species to protect mitochondria. At the organelle level, mitochondria biogenesis occurs upon specific signaling; the mitochondrial network changes mitochondrial shape through fusion and fission to accommodate metabolic requirement; Mitofusin 1/2 and OPA1 mediate fusion in the mitochondrial outer and inner membrane, respectively. MitoPLD converts cardiolipin to phosphatic acid inducing the fusion of mitochondria. When mitochondrial fission occurs, Drp1 binds to its receptors (MFF, MID49, MID51 and FIS1) to form Drp1 oligomers and tightens mitochondria to divide it. Also, increase of short form OPA1 induces mitochondrial fission. Damaged mitochondria are recognized by autophagosome, isolated and then fused with the lysosome to form an autolysosome and finally degraded.
Fig. 2
Fig. 2. Mitochondria recognition by LC3 adaptors and receptors during mitophagy
(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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