Receptor Mediated Mitophagy

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Homo sapiens
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Mitochondrial autophagy in mammalian cells was first observed in glucagon-stimulated hepatocytes. The mechanisms of mitophagy in mammalian cells remain unclear. Oxidative stress and mPTP are involved in the initiation of mitophagy. Receptor mediated mitophagy links both cellular differentiation signals and markers of mitochondrial function to LC3 and Atg32, scaffold proteins important for cargo selection and autophagosome formation. These scaffold proteins recruit other autophagy proteins to form the autophagosomes; destroying and recycling mitochondria.
Mitophagy receptors have to meet at least three criteria: 1) it must be mitochondrially localized, 2) it must interact with LC3/ ATG8 in response to a certain stimulus, and 3) it must have a consensus sequence of W/F/YxxL/I known as the LIR motif. This tetrapeptide sequence is present in several Atg8 or LC3-binding partners that are important for selective autophagy.

FUNDC1-mediated mitophagy is inhibited by its phosphorylation at the Tyr 18 position in the LIR motif by Src kinase under normoxia conditions. Upon hypoxia stimulation, Src is inactivated and FUNDC1 at the Tyr 18 position is dephosphorylated by an unknown phosphatase, resulting in an increase of the interaction between FUNDC1 and LC3-II, leading to the selective incorporation and autophagic removal of the mitochondrion.

The outer mitochondrial membrane protein NIX/BNIP3L is involved in autophagic turnover of mitochondria in reticulocytes, a process essential for red blood cell maturation [43]. The mechanism through which NIX senses signals from red blood cell differentiation is unclear. Phosphorylation of serine residues 17 and 24 flanking the BNIP3 LIR promotes binding to specific LC3 family members LC3B and GATE-16 and increases lysosomal destruction of mitochondria.

Literature References
PubMed ID Title Journal Year
20010802 Nix is a selective autophagy receptor for mitochondrial clearance

Novak, I, Kirkin, V, McEwan, DG, Zhang, J, Wild, P, Rozenknop, A, Rogov, V, Löhr, F, Popovic, D, Occhipinti, A, Reichert, AS, Terzic, J, Dötsch, V, Ney, PA, Dikic, I

EMBO Rep. 2010
18623629 NIX induces mitochondrial autophagy in reticulocytes

Zhang, J, Ney, PA

Autophagy 2008
24671035 ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy

Wu, W, Tian, W, Hu, Z, Chen, G, Huang, L, Li, W, Zhang, X, Xue, P, Zhou, C, Liu, L, Zhu, Y, Zhang, X, Li, L, Zhang, L, Sui, S, Zhao, B, Feng, D

EMBO Rep. 2014
22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

Liu, L, Feng, D, Chen, G, Chen, M, Zheng, Q, Song, P, Ma, Q, Zhu, C, Wang, R, Qi, W, Huang, L, Xue, P, Li, B, Wang, X, Jin, H, Wang, J, Yang, F, Liu, P, Zhu, Y, Sui, S, Chen, Q

Nat. Cell Biol. 2012
18454133 Essential role for Nix in autophagic maturation of erythroid cells

Sandoval, H, Thiagarajan, P, Dasgupta, SK, Schumacher, A, Prchal, JT, Chen, M, Wang, J

Nature 2008
25840011 Selective removal of mitochondria via mitophagy: distinct pathways for different mitochondrial stresses

Wei, H, Liu, L, Chen, Q

Biochim. Biophys. Acta 2015
23603281 Molecular signaling toward mitophagy and its physiological significance

Feng, D, Liu, L, Zhu, Y, Chen, Q

Exp. Cell Res. 2013
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