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Review
. 2014 Jul;24(7):787-95.
doi: 10.1038/cr.2014.75. Epub 2014 Jun 6.

Receptor-mediated mitophagy in yeast and mammalian systems

Lei Liu  1 , Kaori Sakakibara  2 , Quan Chen  1 , Koji Okamoto  2
Affiliations
Review

Receptor-mediated mitophagy in yeast and mammalian systems

Lei Liu et al. Cell Res. 2014 Jul.

Abstract

Mitophagy, or mitochondria autophagy, plays a critical role in selective removal of damaged or unwanted mitochondria. Several protein receptors, including Atg32 in yeast, NIX/BNIP3L, BNIP3 and FUNDC1 in mammalian systems, directly act in mitophagy. Atg32 interacts with Atg8 and Atg11 on the surface of mitochondria, promoting core Atg protein assembly for mitophagy. NIX/BNIP3L, BNIP3 and FUNDC1 also have a classic motif to directly bind LC3 (Atg8 homolog in mammals) for activation of mitophagy. Recent studies have shown that receptor-mediated mitophagy is regulated by reversible protein phosphorylation. Casein kinase 2 (CK2) phosphorylates Atg32 and activates mitophagy in yeast. In contrast, in mammalian cells Src kinase and CK2 phosphorylate FUNDC1 to prevent mitophagy. Notably, in response to hypoxia and FCCP treatment, the mitochondrial phosphatase PGAM5 dephosphorylates FUNDC1 to activate mitophagy. Here, we mainly focus on recent advances in our understanding of the molecular mechanisms underlying the activation of receptor-mediated mitophagy and the implications of this catabolic process in health and disease.

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Figures

Figure 1
Figure 1
(A) Mitophagy-related proteins in yeast. Aup1 is a protein phosphatase in the mitochondrial IMS that may be linked to Rtg3, a transcription factor responsible for signaling from mitochondria to the nucleus,. Uth1 is a mitochondrial inner membrane protein of unknown function,. Atg33 is a mitochondrial outer membrane protein of unknown function,. Whi2 is a stress response protein in the Ras-PKA signaling pathway,. Mss4 is a phosphatidylinositol-4-phosphate 5-kinase. Slt2 and Hog1 are MAP kinases acting in the Wsc1-Pkc1-Bck1-Mkk1/2-Slt2 and Ssk1-Pbs2-Hog1 signaling cascades, respectively,. (B) Atg32 and its interacting partners. See text for details.
Figure 2
Figure 2
Mitophagy receptors in mammalian systems. FUNDC1, NIX/BNIP3L and BNIP3 interact with LC3 through LIRs in their N-terminal region. The interaction between FUNDC1 and LC3 is regulated by reversible phosphorylation. In normal conditions, FUNDC1 is phosphorylated at Try18 and Ser13 by Src kinase and CK2, respectively. Hypoxia and FCCP promote FUNDC1 dephosphorylation by inactivating Src kinase and CK2, and by activating PGAM5. Dephosphorylated FUNDC1 has a significantly higher affinity to LC3. The interaction between BNIP3 and LC3 is positively regulated by phosphorylation of Ser17 and Ser24 in BNIP3. The kinase for BNIP3 phosphorylation remains unknown.
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