Structural basis for the phosphorylation of FUNDC1 LIR as a molecular switch of mitophagy

Kuang, Yao; Ma, Kaili; Zhou, Changqian; Ding, Pengfei; Zhu, Yushan; Chen, Quan; Xia, Bin

doi:10.1080/15548627.2016.1238552

Cited by 114 publications

(119 citation statements)

References 30 publications

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“…Structurally, FUNDC1 has two essential phosphorylation sites including Tyr18 and Ser13. Phosphorylated FUNDC1 generates steric hindrance for LC3II binding, thus effectively inhibiting mitophagy . Ischaemic or hypoxic stimulus alleviates FUNDC1 phosphorylation at Tyr18, leading to induction of mitophagy in ischaemia .…”

Section: Resultsmentioning

confidence: 99%

“…Phosphorylated FUNDC1 generates steric hindrance for LC3II binding, thus effectively inhibiting mitophagy . Ischaemic or hypoxic stimulus alleviates FUNDC1 phosphorylation at Tyr18, leading to induction of mitophagy in ischaemia . And LC3‐I is lipidated to LC3‐II and associates to the cargo isolation membrane allowing for autophagosome formation .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection

Miao

Qiu

Huang

et al. 2018

J Cellular Molecular Medi

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Both decreased autophagy positive regulator AMP activated protein kinase (AMPK) level and promoted mitophagy are observed in oxygen‐glucose deprivation (OGD) cardiomyocytes treated with pigment epithelium‐derived factor (PEDF). This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Our previous study reveals that PEDF increases the protein kinase Cα (PKCα) and phospho‐PKCα (p‐PKCα) contents to promote mitophagy. Thus, we investigated the association between PKCα and mitophagy. Here we identify an interaction between PKCα and Unc‐51‐like kinase 1 (ULK1), essential component of mitophagy. Further analyses show this is a direct interaction within a domain of ULK1 that termed the serine/threonine‐rich domain (S/T domain). Notably, a deletion mutant ULK1 that lacks the binding domain is defective in mediating PEDF‐induced mitophagy. Furthermore, we demonstrate that ULK1 is phosphorylated at Ser317/555/777 and Raptor is also phosphorylated by phospho‐PKCα. Phospho‐ULK1 (p‐ULK1) at these sites are all essential for PEDF‐induced mitophagy and reduce the release of mitochondrial ROS and DNA. This study therefore identifies a previously uncharacterized interaction between the ULK1 and PKCα that can replace the AMPK‐dependent mitophagy processes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection

Miao

Qiu

Huang

et al. 2018

J Cellular Molecular Medi

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show abstract

“…FUNDC1 can effectively activate the autophagy mechanism and promote mitophagy. The FUNDC1‐dependent mitophagy may also contain a Beclin1‐independent component . Mutations in the Y(18) and L(21) conserved sites of the FUNDC1 LIRs, together with the phosphorylation of Tyr18 and Ser13 can effectively inhibit the interplay with LC3 …”

Section: Mitophagy In Mammalsmentioning

confidence: 99%

“…The FUNDC1-dependent mitophagy may also contain a Beclin1-independent component. 44 Mutations in the Y(18) and L(21) conserved sites of the FUNDC1 LIRs, together with the phosphorylation of Tyr18 and Ser13 can effectively inhibit the interplay with LC3. 45 FUNDC1 is phosphorylated at Ser17 by ULK1 and dephosphorylated at Ser13 by PGAM5 under hypoxia condition.…”

Section: Fundc1-mediated Mitophagymentioning

confidence: 99%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

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“…The cytosol-exposed N-terminal 50 residues of FUNDC1 in human is the determinant region for the interactions with LC3 (Kuang et al, 2016) and DRP1, the mitochondrial fission factor (Chen et al, 2016). In the N-terminal region, there is an LIR motif (Y18-E-V-L21) and three key phosphorylation sites (S13, S17, and Y18).…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic and Molecular Evolutionary Analysis of Mitophagy Receptors under Hypoxic Conditions

et al. 2017

Front. Physiol.

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As animals evolved to use oxygen as the main strategy to produce ATP through the process of mitochondrial oxidative phosphorylation, the ability to adapt to fluctuating oxygen concentrations is a crucial component of evolutionary pressure. Three mitophagy receptors, FUNDC1, BNIP3 and NIX, induce the removal of dysfunctional mitochondria (mitophagy) under prolonged hypoxic conditions in mammalian cells, to maintain oxygen homeostasis and prevent cell death. However, the evolutionary origins and structure-function relationships of these receptors remain poorly understood. Here, we found that FUN14 domain-containing proteins are present in archaeal, bacterial and eukaryotic genomes, while the family of BNIP3 domain-containing proteins evolved from early animals. We investigated conservation patterns of the critical amino acid residues of the human mitophagy receptors. These residues are involved in receptor regulation, mainly through phosphorylation, and in interaction with LC3 on the phagophore. Whereas FUNDC1 may be able to bind to LC3 under the control of post-translational regulations during the early evolution of vertebrates, BINP3 and NIX had already gained the ability for LC3 binding in early invertebrates. Moreover, FUNDC1 and BNIP3 each lack a layer of phosphorylation regulation in fishes that is conserved in land vertebrates. Molecular evolutionary analysis revealed that BNIP3 and NIX, as the targets of oxygen sensing HIF-1α, showed higher rates of substitution in fishes than in mammals. Conversely, FUNDC1 and its regulator MARCH5 showed higher rates of substitution in mammals. Thus, we postulate that the structural traces of mitophagy receptors in land vertebrates and fishes may reflect the process of vertebrate transition from water onto land, during which the changes in atmospheric oxygen concentrations acted as a selection force in vertebrate evolution. In conclusion, our study, combined with previous experimental results, shows that hypoxia-induced mitophagy regulated by FUDNC1/MARCH5 might use a different mechanism from the HIF-1α-dependent mitophagy regulated by BNIP3/NIX.

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Structural basis for the phosphorylation of FUNDC1 LIR as a molecular switch of mitophagy

Cited by 114 publications

References 30 publications

PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection

PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection

Mechanisms and roles of mitophagy in neurodegenerative diseases

Phylogenetic and Molecular Evolutionary Analysis of Mitophagy Receptors under Hypoxic Conditions

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