基于p32-GCS1复合物的线粒体-内质网互作体系鉴定与功能研究
结题报告
批准号:
92054106
项目类别:
重大研究计划
资助金额:
83.0 万元
负责人:
刘泳
依托单位:
学科分类:
细胞器及亚细胞结构、互作与功能
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
刘泳
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中文摘要
线粒体-内质网互作结构(MAM)通过介导钙离子和脂质交换维持细胞代谢稳态平衡。然而,MAM结构与线粒体代谢机制的内在关联未知,MAM响应代谢应激的分子靶点有待揭示。申请人前期研究发现一组全新的线粒体内质网蛋白互作:线粒体蛋白p32通过与内质网蛋白GCS1相互作用调节内质网应激,高表达p32或GCS1显著促进MAM,提示二者可能参与MAM分子桥接。鉴于p32本身对于线粒体呼吸起决定作用,同时参与调控钙摄取,因此推断其可能是关联线粒体代谢与MAM的关键分子。本研究将鉴定基于p32-GCS1复合物的线粒体-ER互作及其功能:发现p32-GCS1复合物与MAM结构尤其是IP3R-GRP75-VDAC1-CypD钙转运复合体的关系;解读p32在感知代谢变化并通过MAM调控钙转运从而维持代谢稳态平衡中的作用。本课题的开展将弥补MAM调节细胞能量代谢平衡的缺失环节,有助于理解MAM的生理和和病理功能。
英文摘要
Inter-organelle communications play an important role in the regulation of cellular homeostasis. Among them, endoplasmic reticulum had been found to contact and communicate with mitochondria, for the exchange of calcium, lipids and other metabolites. So far, mitochondria-associated ER membranes (MAM) has been reported to be responsible for the exchange of calcium and lipid species between mitochondria and ER, and regulating mitochondrial biogenesis and quality control, autophagy and metabolic homeostasis. However, none of the known MAM components are involved in mitochondrial respiration machinery, the core of energy metabolism. Therefore, it is plausible that a mitochondria-residing and metabolic-active protein is able to bind to MAM structure, sense the changes of cellular energy level, and control calcium flux towards mitochondria, thus maintain metabolic homeostasis. .p32 is a predominantly mitochondrial protein, which is required for the assembly of mitochondrial ribosome and thus is essential for mtDNA translation and mitochondrial respiration. Previous studies have also revealed that p32 interacts with GRP75 and CypD, the two MAM components, and regulates mitochondrial calcium uptake. We have recently found that p32 interacts with an ER protein, GCS1. Through the interaction, p32 negative regulates GCS1, which is important for proper folding of proteins in the ER. As a result, down-regulation of p32 alleviates ER stress and suppresses de novo lipid biosynthesis, leading to an obesity-resistant phenotype in p32 heterozygosity mice. These above findings strongly suggest that p32-GCS1 interaction intensively involves in mitochondria-ER crosstalk, in particular to the IP3R-GRP75-VDAC1-CypD complex. In this proposal, we will elucidate whether p32 and GCS1 are MAM proteins and indeed responsible for the mutual regulation between mitochondria and ER. Given that mitochondria centralize catabolic network whereas ER is the organelle accommodating anabolic pathways, we hypothesize that MAM-residing p32-GCS1 complex function as a sensor of cellular energy stress and effector to coordinate mitochondrial catabolism and anabolism in ER for survival. This study will provide evidence in understanding the molecular machinery of mitochondria-ER crosstalk. The fulfillment of this proposal will expand our knowledge of the physiological and pathological functions of MAM.
期刊论文列表
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科研奖励列表
会议论文列表
专利列表
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DOI:10.1038/s41467-022-30431-3
发表时间:2022-05-13
期刊:Nature communications
影响因子:16.6
作者:
通讯作者:
DOI:10.1186/s10020-022-00537-x
发表时间:2022-09-07
期刊:MOLECULAR MEDICINE
影响因子:5.7
作者:Wang, Bingwu;Gao, Jian;Zhao, Zhongjun;Zhong, Xuefei;Cui, Hao;Hou, Hui;Zhang, Yanping;Zheng, Junnian;Di, Jiehui;Liu, Yong
通讯作者:Liu, Yong
DOI:10.1016/j.bcp.2023.115950
发表时间:2023-12-05
期刊:BIOCHEMICAL PHARMACOLOGY
影响因子:5.8
作者:Cui,Hao;Zhu,Bao;Liu,Yong
通讯作者:Liu,Yong
ANXA1丙二酰化通过调节细胞囊泡转运和膜损伤修复双联机制影响肾癌转移的研究
  • 批准号:
    82373073
  • 项目类别:
    面上项目
  • 资助金额:
    49万元
  • 批准年份:
    2023
  • 负责人:
    刘泳
  • 依托单位:
MET-MCD负反馈调节环路在肾癌转移中的作用及分子机制研究
  • 批准号:
    81972723
  • 项目类别:
    面上项目
  • 资助金额:
    55.0万元
  • 批准年份:
    2019
  • 负责人:
    刘泳
  • 依托单位:
CHCHD2 及其介导的线粒体功能在乳腺癌转移过程中的作用机制研究
  • 批准号:
    81672618
  • 项目类别:
    面上项目
  • 资助金额:
    57.0万元
  • 批准年份:
    2016
  • 负责人:
    刘泳
  • 依托单位:
国内基金
海外基金