Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun1...Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 （FUNDC1） was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with micro-tubule-associated protein light chain 3 beta （LC3B） through its LC3 interaction region （LIR）. Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy. However, the structural basis of this regulation mechanism remains unclear. Here, we present the crystal structure of LC3B in complex with a FUNDCI LIR peptide phosphorylated at Ser17 （pS17）, demonstrating the key residues of LC3B for the specific recognition of the phosphorylated or dephosphorylated FUNDC1. Intriguingly, the side chain of LC3B Lys49 shifts remarkably and forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pS17. Alternatively, phosphorylated Tyr18 （PY18） and Ser13 （PS13） in FUNDC1 significantly obstruct their interaction with the hydrophobic pocket and Arg10 of LC3B, respectively. Structural observations are further validated by mutation and isothermal titration calorimetry （ITC） assays. Therefore, our structural and biochemical results reveal a working model for thespecific recognition of FUNDCI by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy.展开更多
Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-d...Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.展开更多
基金This work was supported by National Natural Science Founda- tion （Grant No. 31400629） the Strategic Priority Research Program of the Chinese Academy of Science （No. XDB08010101）+1 种基金 Ministry Of Science And Technology of China （No. 2016YFA0500700） China Postdoctoral Science Foundation （No. 2015M582009 and 2016T90579） and National Natural Science Foundation （Grant No. 31330018）.
文摘Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 （FUNDC1） was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with micro-tubule-associated protein light chain 3 beta （LC3B） through its LC3 interaction region （LIR）. Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy. However, the structural basis of this regulation mechanism remains unclear. Here, we present the crystal structure of LC3B in complex with a FUNDCI LIR peptide phosphorylated at Ser17 （pS17）, demonstrating the key residues of LC3B for the specific recognition of the phosphorylated or dephosphorylated FUNDC1. Intriguingly, the side chain of LC3B Lys49 shifts remarkably and forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pS17. Alternatively, phosphorylated Tyr18 （PY18） and Ser13 （PS13） in FUNDC1 significantly obstruct their interaction with the hydrophobic pocket and Arg10 of LC3B, respectively. Structural observations are further validated by mutation and isothermal titration calorimetry （ITC） assays. Therefore, our structural and biochemical results reveal a working model for thespecific recognition of FUNDCI by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy.
基金funded by National Natural Science Foundation of China(81973402)Natural Science Foundation of Zhejiang Province(LYY22H310009)+1 种基金Hospital Pharmacy Scientific Research Funding Project of Zhejiang Pharmaceutical Association(2020ZYY10)Clinical research fund project of Zhejiang Medical Association(2020ZYC-A07).
文摘Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.
