Mitochondria play a kay role in various cell processes including ATP production, Ca^2＋ homeostasis, reactive oxygen species （ROS） generation, and apoptosis. The selective removal of impaired mitochondria by autopha...Mitochondria play a kay role in various cell processes including ATP production, Ca^2＋ homeostasis, reactive oxygen species （ROS） generation, and apoptosis. The selective removal of impaired mitochondria by autophagosome is known as mitophagy. Cerebral ischemia is a common form of stroke caused by insuf- ficient blood supply to the brain. Emerging evidence suggests that mitophagy plays important roles in the pathophysiological process of cerebral ischemia. This review focuses on the relationship between ischemic brain injury and mitophagy. Based on the latest research, it describes how the signaling pathways of mitophagy appear to be involved in cerebral ischemia.展开更多
Mitophagy is activated by a number of stimuli, including hypoxia, energy stress, and increased oxidative phosphorylation activity. Mitophagy is associated with oxidative stress conditions and central neurodegenerative...Mitophagy is activated by a number of stimuli, including hypoxia, energy stress, and increased oxidative phosphorylation activity. Mitophagy is associated with oxidative stress conditions and central neurodegenerative diseases. Proper regulation of mitophagy is crucial for maintaining homeostasis; conversely, inadequate removal of mitochondria through mitophagy leads to the generation of oxidative species, including reactive oxygen species and reactive nitrogen species, resulting in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These diseases are most prevalent in older adults whose bodies fail to maintain proper mitophagic functions to combat oxidative species. As mitophagy is essential for normal body function, by targeting mitophagic pathways we can improve these disease conditions. The search for effective remedies to treat these disease conditions is an ongoing process, which is why more studies are needed. Additionally, more relevant studies could help establish therapeutic conditions, which are currently in high demand. In this review, we discuss how mitophagy plays a significant role in homeostasis and how its dysregulation causes neurodegeneration. We also discuss how combating oxidative species and targeting mitophagy can help treat these neurodegenerative diseases.展开更多
Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion(I/R)injury.Mitochondrial quality control(MQC)mechanisms,a series of adaptive responses that preserve mitochondrial structure and function,...Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion(I/R)injury.Mitochondrial quality control(MQC)mechanisms,a series of adaptive responses that preserve mitochondrial structure and function,ensure cardiomyocyte survival and cardiac function after I/R injury.MQC includes mitochondrial fission,mitochondrial fusion,mitophagy and mitochondria-dependent cell death.The interplay among these responses is linked to pathological changes such as redox imbalance,calcium overload,energy metabolism disorder,signal transduction arrest,the mitochondrial unfolded protein response and endoplasmic reticulum stress.Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death.Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression.Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria,thus maintaining mitochondrial network fitness.Nevertheless,abnormal mitophagy is maladaptive and has been linked to cell death.Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate,they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium.Therefore,defects in MQC may determine the fate of cardiomyocytes.In this review,we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury,highlighting potential targets for the clinical management of reperfusion.展开更多
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
5′单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)是细胞的能量感受器,调节细胞能量代谢,在正常细胞和癌细胞中均发挥重要的生物功能,它的激活有助于纠正代谢紊乱,使细胞代谢趋向生理平衡。在细胞应急反应中,细胞感受到...5′单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)是细胞的能量感受器,调节细胞能量代谢,在正常细胞和癌细胞中均发挥重要的生物功能,它的激活有助于纠正代谢紊乱,使细胞代谢趋向生理平衡。在细胞应急反应中,细胞感受到能量危机,ATP浓度下降,AMP浓度上升,细胞内AMP/ATP比例上升,AMPK被激活;而在病理状态下,如代谢综合征、肿瘤等,常伴随能量代谢紊乱和AMPK激活抑制,因此,AMPK被视为治疗代谢性疾病与肿瘤的潜在作用靶点。然而,AMPK对能量代谢的调节与线粒体的功能密不可分,线粒体作为细胞的能量工厂,在健康与疾病中也发挥着重要的作用。越来越多的研究表明,线粒体能影响AMPK的活性,同时AMPK也通过多方面对线粒体进行调节,线粒体相关疾病与AMPK的调节有着密切的关系。该文主要针对AMPK是如何对线粒体的合成、线粒体自噬、内源性凋亡及线粒体相关疾病等方面进行综述。展开更多
基金This work was funded by the Faculty Research Grant of Hong Kong Baptist University （FRG2/15-16/022） and the Guandong Natural Science Foundation （2014A030313766 and 2016A030313008）.
文摘Mitochondria play a kay role in various cell processes including ATP production, Ca^2＋ homeostasis, reactive oxygen species （ROS） generation, and apoptosis. The selective removal of impaired mitochondria by autophagosome is known as mitophagy. Cerebral ischemia is a common form of stroke caused by insuf- ficient blood supply to the brain. Emerging evidence suggests that mitophagy plays important roles in the pathophysiological process of cerebral ischemia. This review focuses on the relationship between ischemic brain injury and mitophagy. Based on the latest research, it describes how the signaling pathways of mitophagy appear to be involved in cerebral ischemia.
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science,ICT and Future Planning,No.2018R1C1B5029745(to HJC),2011-0030072(to YH),2018R1D1A1B07040282(to JJ),2018R1A2B6001123(to NYJ)
文摘Mitophagy is activated by a number of stimuli, including hypoxia, energy stress, and increased oxidative phosphorylation activity. Mitophagy is associated with oxidative stress conditions and central neurodegenerative diseases. Proper regulation of mitophagy is crucial for maintaining homeostasis; conversely, inadequate removal of mitochondria through mitophagy leads to the generation of oxidative species, including reactive oxygen species and reactive nitrogen species, resulting in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These diseases are most prevalent in older adults whose bodies fail to maintain proper mitophagic functions to combat oxidative species. As mitophagy is essential for normal body function, by targeting mitophagic pathways we can improve these disease conditions. The search for effective remedies to treat these disease conditions is an ongoing process, which is why more studies are needed. Additionally, more relevant studies could help establish therapeutic conditions, which are currently in high demand. In this review, we discuss how mitophagy plays a significant role in homeostasis and how its dysregulation causes neurodegeneration. We also discuss how combating oxidative species and targeting mitophagy can help treat these neurodegenerative diseases.
基金supported by grants from the National Natural Science Foundation of China (No. 31770971,81802014)Scientific and Technological Research Project of Division of Science and TechnologyDepartment of Education of Hebei Province,China (No. QN2018146)。
基金partially supported by the China Postdoctoral Science Foundation(2019TQ0128)the National Natural Science Foundation of China(NSFC81900252,81900254 and 81870249)
文摘Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion(I/R)injury.Mitochondrial quality control(MQC)mechanisms,a series of adaptive responses that preserve mitochondrial structure and function,ensure cardiomyocyte survival and cardiac function after I/R injury.MQC includes mitochondrial fission,mitochondrial fusion,mitophagy and mitochondria-dependent cell death.The interplay among these responses is linked to pathological changes such as redox imbalance,calcium overload,energy metabolism disorder,signal transduction arrest,the mitochondrial unfolded protein response and endoplasmic reticulum stress.Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death.Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression.Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria,thus maintaining mitochondrial network fitness.Nevertheless,abnormal mitophagy is maladaptive and has been linked to cell death.Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate,they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium.Therefore,defects in MQC may determine the fate of cardiomyocytes.In this review,we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury,highlighting potential targets for the clinical management of reperfusion.
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.
文摘目的:研究益气解毒方对糖尿病肾病(diabetic nephropathy,DN)大鼠肾小管上皮细胞线粒体自噬作用机制。方法:采用DN大鼠模型,观察益气解毒方对DN的治疗作用。采用苏木素伊红(HE)染色法观察给药后DN大鼠肾脏病理变化,透射电镜观察DN大鼠肾小管上皮细胞线粒体自噬体情况。采用蛋白免疫印迹法检测肾组织中微管相关蛋白1轻链3Ⅱ(microtubule-associatedprotein1lightchain 3Ⅱ,MAP1LC3-Ⅱ,LC3-Ⅱ),自噬标志物p62蛋白(sequestosome-1,p62),促凋亡蛋白Nix(Bcl-2/E1B 19 k Da-interacting protein 3-like,Nix)的表达,并应用实时荧光定量PCR测定Nix mRNA的表达。结果:与模型组比较,益气解毒方能够增加DN大鼠体重,改善DN大鼠血尿素氮(BUN),血肌酐(SCr),血糖(GLU),甘油三酯(TG)及总胆固醇(CHOL),白蛋白(Alb)等血、尿生化指标(P<0.01),并且能抑制由DN导致的肾小管上皮细胞线粒体过度自噬,显著降低LC3-Ⅱ,p62,Nix蛋白的表达(P<0.01),同时降低Nix mRNA的表达(P<0.01)。结论:益气解毒方对DN有较好的治疗效果,这可能与其调节DN肾小管上皮细胞线粒体自噬紊乱有关。
文摘5′单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)是细胞的能量感受器,调节细胞能量代谢,在正常细胞和癌细胞中均发挥重要的生物功能,它的激活有助于纠正代谢紊乱,使细胞代谢趋向生理平衡。在细胞应急反应中,细胞感受到能量危机,ATP浓度下降,AMP浓度上升,细胞内AMP/ATP比例上升,AMPK被激活;而在病理状态下,如代谢综合征、肿瘤等,常伴随能量代谢紊乱和AMPK激活抑制,因此,AMPK被视为治疗代谢性疾病与肿瘤的潜在作用靶点。然而,AMPK对能量代谢的调节与线粒体的功能密不可分,线粒体作为细胞的能量工厂,在健康与疾病中也发挥着重要的作用。越来越多的研究表明,线粒体能影响AMPK的活性,同时AMPK也通过多方面对线粒体进行调节,线粒体相关疾病与AMPK的调节有着密切的关系。该文主要针对AMPK是如何对线粒体的合成、线粒体自噬、内源性凋亡及线粒体相关疾病等方面进行综述。
