Molecular Mechanisms of Mitochondrial Ca2+ Transport
Molecular Mechanisms of Mitochondrial Ca2+ Transport
批准号:
9000157
负责人:
Gyorgy Hajnoczky
金额:
$35.35万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-02-01 至 2017-02-28
关键词:
AffectAffinityAmino AcidsAnimal ModelBindingBioenergeticsC-terminalCalciumCalcium OscillationsCalcium SignalingCell DeathCell RespirationCell SurvivalCellsCellular Metabolic ProcessCellular Stress ResponseChargeComplementComplexDevelopmentDiseaseDominant-Negative MutationDrug TargetingEF Hand MotifsEF-Hand DomainEmployee StrikesEnergy MetabolismEvolutionFastingHepaticHepatocyteHereditary DiseaseHomeostasisHumanInjection of therapeutic agentInjuryInner mitochondrial membraneIschemiaKnockout MiceLinkLiverMeasurementMediatingMethodsMitochondriaModelingMolecularMouse Cell LineMusMutationMyopathyNerve DegenerationNeuronsPaperPathway interactionsPhenotypePhysiologicalPhysiologyProtein IsoformsProteinsPublicationsPublishingRegulationReperfusion TherapyReportingRoleSignal TransductionSiteStressSystemTestingTimeTissuesVDAC1 geneVirusWorkbasecalcium uniportercell injurydriving forcefeedingfluorescence imaginghuman diseasein vivonew therapeutic targetnovelparalogous geneuptake
中文摘要
线粒体Ca~(2+)处理对细胞内钙稳态、能量代谢和细胞存活至关重要
死亡机制。线粒体钙转运受损也被认为是导致
各种疾病的发展。在几十年来令人沮丧的关于分子调节的模棱两可之后
2010-2011年线粒体钙摄取,EF-Hand结构域蛋白MICU1和MCU被鉴定为
分别是钙离子转运蛋白不可或缺的调节剂和成孔成分。现在,它正在成为
有可能解决关于复杂的
钙转运系统及MICU1、MCU等单转运蛋白的生理意义。我们
已经开始调查MICU1的作用方式,与第一份报告相反,我们发现MICU1
不是允许钙离子通过单一转运体吸收所必需的,而是对保持单一转运体关闭在
低细胞质[Ca~(2+)]([Ca~(2+)]c)浓度,并支持单转运体作为
[Ca~(2+)]c升高。这些研究最近在《细胞》杂志上发表了一篇广为人知的论文
新陈代谢。为了进一步研究MICU1的生理意义,我们产生了一个条件
MICU1基因敲除小鼠具有显著的表型,将为拟议的研究提供几个模型。
我们的假设是:(1)MICU1利用其C-末端的正电荷氨基酸残基簇来
与MCU膜间空间环的Dime结构域相互作用,突出一个可能是
新的药物靶点,(2)MICU1和MICU2与其EF-手不同地结合钙和/或镁,提供
它们对MCU协同激活的不同影响的可能机制,以及(3)MICU1是
在肝细胞氧化代谢方面,体内有效解码钙信号所必需的
进食和禁食条件。为了探索MICU1在钙离子转运中的作用,我们将应用高级
荧光成像方法,包括结合细胞评估的一些新方法
生物能量学和细胞存活调节通路的活性在同一模型中。该提案依赖于
在细胞系和小鼠组织中使用强大的MICU1靶向系统。拟议的工作将
揭示单转运蛋白复杂的钙依赖和时间依赖性控制的机制,并将揭示
MICU1的S在保持线粒体健康和对钙的反应中的作用。
英文摘要
Mitochondrial Ca2+ handling is central to cellular calcium homeostasis, energy metabolism and cell survival/cell
death mechanisms. Impaired mitochondrial Ca2+ transport is also thought to be an important contributor in the
development of a variety of diseases. After decades of frustrating ambiguity about the molecules mediating
mitochondrial Ca2+ uptake, in 2010-2011, MICU1, an EF-hand domain protein, and MCU were identified as an
indispensible regulator and pore forming component of the Ca2+ uniporter, respectively. Now, it is becoming
possible to tackle the fundamental questions about the molecular mechanisms that underlie a sophisticated
Ca2+ transport system and the physiological significance of MICU1, MCU and other uniporter components. We
have started to investigate the mode of action of MICU1, and contrary to the first report, we found that MICU1
is not required to allow Ca2+ uptake through the uniporter but, instead, is critical to keep the uniporter closed at
low cytoplasmic [Ca2+] ([Ca2+]c) concentrations and to support cooperative activation of the uniporter as the
[Ca2+]c increases. These studies have been recently published in a widely recognized paper in Cell
Metabolism. To further the study of the physiological significance of MICU1 we have generated a conditional
MICU1 knockout mouse that has a striking phenotype and will provide several models for the proposed study.
Our hypotheses are that (1) MICU1 employs its C-terminal cluster of positively charged amino acid residues to
interact with the DIME domain of the intermembrane space loop of MCU, highlighting a site that might be a
novel drug target, (2) MICU1 and MICU2 differently bind Ca2+ and/or Mg2+ with their EF-hands, providing a
possible mechanisms for their distinct effects on the cooperative activation of the MCU, and (3) MICU1 is
required in vivo for effective decoding of calcium signals in terms of oxidative metabolism in hepatocytes under
fed and fasting conditions. To explore the role of MICU1 in Ca2+ handling we will apply advanced
fluorescence imaging approaches, including some novel methods combined with assessment of cell
bioenergetics and the activity of cell survival regulating pathways in the same models. The proposal relies on
the use of a powerful targeting system of MICU1 in both cell lines and mouse tissues. The proposed work will
uncover the mechanism of the sophisticated Ca2+- and time-dependent control of the uniporter and will expose
MICU1's role in keeping mitochondria healthy and responsive to Ca2+.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mitochondrial Calcium and Neuronal Health
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批准号:10638869
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项目类别:
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资助金额:$61.65万
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财政年份:2023
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负责人:Gyorgy Hajnoczky
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Developing tools for calcium imaging in ITPR2-linked liver pathogenesis
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批准号:10727998
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负责人:Gyorgy Hajnoczky
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依托单位:
Mitochondrial Calcium Uniporter in Signaling and Dynamics
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批准号:10720242
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(PQ5) Relevance of VDAC2 heterogeneity for hepatic tumor growth and targeting
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批准号:10395472
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资助金额:$38.03万
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负责人:Gyorgy Hajnoczky
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依托单位:
(PQ5) Relevance of VDAC2 heterogeneity for hepatic tumor growth and targeting
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批准号:9924258
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资助金额:$38.8万
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财政年份:2018
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负责人:Gyorgy Hajnoczky
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依托单位:
Molecular Mechanisms of Mitochondrial Ca2+ Transport
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批准号:9264336
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项目类别:
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资助金额:$35.57万
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财政年份:2015
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负责人:Gyorgy Hajnoczky
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依托单位:
Redox Regulation of Intracellular Calcium Signaling
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批准号:9022475
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项目类别:
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资助金额:$35.1万
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财政年份:2015
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负责人:Gyorgy Hajnoczky
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依托单位:
Redox Regulation of Intracellular Calcium Signaling
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批准号:8905057
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项目类别:
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资助金额:$35.04万
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财政年份:2015
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负责人:Gyorgy Hajnoczky
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依托单位:
Cell Death in Alcoholic Heart and Muscle
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批准号:8460010
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项目类别:
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资助金额:$32.33万
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财政年份:2012
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负责人:Gyorgy Hajnoczky
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依托单位:
Cell Death in Alcoholic Heart and Muscle
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批准号:9059542
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项目类别:
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资助金额:$34.13万
-
财政年份:2012
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负责人:Gyorgy Hajnoczky
-
依托单位:
Cell Death in Alcoholic Heart and Muscle
-
批准号:8666620
-
项目类别:
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资助金额:$33.11万
-
财政年份:2012
-
负责人:Gyorgy Hajnoczky
-
依托单位:
Cell Death in Alcoholic Heart and Muscle
-
批准号:8275048
-
项目类别:
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资助金额:$34.88万
-
财政年份:2012
-
负责人:Gyorgy Hajnoczky
-
依托单位:
PHYSICAL ASSOCIATION OF THE MITOCHONDRIAL OUTER MEMBRANE WITH THE
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批准号:8172268
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项目类别:
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资助金额:$0.54万
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负责人:Gyorgy Hajnoczky
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依托单位:
PHYSICAL ASSOCIATION OF THE MITOCHONDRIAL OUTER MEMBRANE WITH THE
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批准号:7954566
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项目类别:
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资助金额:$1.12万
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财政年份:2009
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负责人:Gyorgy Hajnoczky
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依托单位:
ER mitochondrial signaling and alcoholic tissue injury
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批准号:7942067
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项目类别:
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资助金额:$98.29万
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财政年份:2009
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负责人:Gyorgy Hajnoczky
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依托单位:
ER mitochondrial signaling and alcoholic tissue injury
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批准号:7860497
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项目类别:
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资助金额:$99.74万
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财政年份:2009
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负责人:Gyorgy Hajnoczky
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依托单位:
Mitochondrial Dynamics in Alcohol-induced Tissue Injury
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批准号:7885694
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项目类别:
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资助金额:$5.0万
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财政年份:2009
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负责人:Gyorgy Hajnoczky
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依托单位:
Mitochondrial Dynamics in Alcohol-induced Tissue Injury
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批准号:8203849
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项目类别:
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资助金额:$4.5万
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财政年份:2008
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负责人:Gyorgy Hajnoczky
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依托单位:
Mitochondrial Dynamics in Alcohol-induced Tissue Injury
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批准号:7919249
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项目类别:
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资助金额:$41.61万
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财政年份:2008
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负责人:Gyorgy Hajnoczky
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依托单位:
Mitochondrial Dynamics in Alcohol-induced Tissue Injury
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批准号:8213116
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项目类别:
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资助金额:$41.2万
-
财政年份:2008
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负责人:Gyorgy Hajnoczky
-
依托单位:
海外基金