Molecular and physiological analysis of mitochondrial calcium uptake
线粒体钙摄取的分子和生理分析
基本信息
- 批准号:9036744
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-10-01 至 2018-09-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelAnimalsAtaxiaAutophagocytosisBehaviorBinding ProteinsBiochemicalBioenergeticsBiologicalBiological AssayBiological ModelsBody CompositionBody WeightCRISPR/Cas technologyCalciumCell DeathCell LineCell physiologyCellsCo-ImmunoprecipitationsComplexConfocal MicroscopyCultured CellsDiseaseEF Hand MotifsEmbryoEnergy MetabolismExhibitsFibroblastsFunctional disorderGatekeepingGenerationsGeneticGenus HippocampusHealthHomeostasisHumanInnovative TherapyKnock-outKnockout MiceLeadLearning DisordersLinkMeasurementMeasuresMembrane ProteinsMetabolismMitochondriaMitochondrial DiseasesMitochondrial MatrixModelingMolecularMolecular WeightMusMyopathyNamesNecrosisPatientsPermeabilityPhenocopyPhenotypePhysiologicalPhysiologyPlayProductionPropertyProteinsRegulationResourcesRespirationRoleSignaling MoleculeSiteStimulusStructureSwellingTestingTissuesTremorVDAC1 geneWild Type Mousecalcium uniporterclinically relevantextracellularhuman diseaseloss of function mutationmitochondrial permeability transition poremotor disordermouse modelmutantparalogous geneprotein complexpublic health relevanceresponseuptake
项目摘要
DESCRIPTION (provided by applicant): Popularly known as "the powerhouse of the cell," mitochondria are not only the site of metabolism and energy generation but also a hub for other cellular processes, including the initiation of cell death. Mitochondrial uptake of the signaling molecule calcium plays a role in the stimulation of ATP production, but too much calcium can lead to opening of the mitochondrial permeability transition pore (mPTP), triggering necrosis. The recent identification of the molecule forming the pore through which calcium can rapidly enter the mitochondria, the mitochondrial calcium uniporter (MCU), has provided a genetic means to directly test the functional importance of calcium uptake. In particular, MCU is part of a
large multi-protein complex including other protein components. EMRE and MICU1 are two of these proteins that in cell lines have been shown to play critical roles in regulation of calcium uptake. EMRE was found to be necessary for MCU activity, and its deletion blocked calcium from entering mitochondria. Though its mechanism is controversial, MICU1 has been characterized as a gatekeeper of MCU, inhibiting MCU activity at low levels of extramitochondrial calcium and stimulating MCU when calcium levels rise.
This project began with the generation of the first animal models of EMRE and MICU1 deletion. The aims of this project are to determine the impact of EMRE and MICU1 deletion on isolated mitochondria, on primary cells, and on the physiology of the whole animal. The new EMRE and MICU1 knockout mice also make it possible to determine the topology of the calcium uniporter complex, measure effects on basal bioenergetics, and elucidate the role of EMRE and MICU1 respectively in the regulation of mitochondrial calcium uptake and homeostasis. Furthermore, mouse models will reveal the consequences of mitochondrial calcium deregulation on cell death responses, physiological phenotypes including body weight and composition, and disease pathophysiology. Interestingly, human patients with loss-of-function mutations in MICU1 present with conditions such as proximal myopathy and extrapyramidal motor disorder. MICU1 knockout mice are preliminarily observed to exhibit ataxia and tremors, suggesting that this model may mirror human disease features and thus potentially motivate innovative therapies to treat mitochondrial disorder. Altogether, EMRE and MICU1 knockout mice are valuable resources for answering biological questions with both basic and clinical relevance.
描述(申请人提供):线粒体通常被称为“细胞的发动机”,它不仅是新陈代谢和能量产生的场所,而且也是其他细胞过程的中心,包括启动细胞死亡。线粒体摄取信号分子钙在刺激ATP产生中起作用,但过多的钙可导致线粒体通透性转换孔(MPTP)开放,引发坏死。线粒体钙单转运蛋白(MCU)是一种形成钙离子快速进入线粒体的孔道的分子,最近的发现为直接测试钙摄取的功能重要性提供了一种遗传学手段。特别是,MCU是一个
包括其他蛋白质组分的大型多蛋白质复合体。EmRE和MICU1是其中的两种蛋白,在细胞系中已被证明在钙吸收调节中发挥关键作用。EMRE被发现是MCU活动所必需的,它的缺失阻止了钙进入线粒体。尽管其机制存在争议,但MICU1被认为是MCU的守门人,在低水平的线粒体外钙时抑制MCU的活性,当钙水平上升时刺激MCU的活性。
该项目始于第一批EmRE和MICU1缺失动物模型的建立。本项目的目的是确定EmRE和MICU1缺失对分离的线粒体、原代细胞以及整个动物生理的影响。新的EmRE和MICU1基因敲除小鼠还可以确定钙单转运体复合体的拓扑结构,测量对基础生物能量学的影响,并分别阐明EmRE和MICU1在线粒体钙摄取和动态平衡调节中的作用。此外,小鼠模型将揭示线粒体钙调控放松对细胞死亡反应、包括体重和成分在内的生理表型以及疾病病理生理学的影响。有趣的是,具有MICU1功能缺失突变的人类患者会出现近端肌病和锥体外系运动障碍等情况。初步观察到MICU1基因敲除小鼠表现出共济失调和震颤,这表明这个模型可能反映了人类疾病的特征,从而潜在地激励创新的治疗方法来治疗线粒体疾病。总之,EmRE和MICU1基因敲除小鼠是回答具有基础和临床相关性的生物学问题的宝贵资源。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Julia Chang Liu其他文献
Julia Chang Liu的其他文献
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{{ truncateString('Julia Chang Liu', 18)}}的其他基金
Modulating mitochondrial calcium in cardiac homeostasis and disease
调节心脏稳态和疾病中的线粒体钙
- 批准号:
10683219 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Molecular mechanism and physiological function of mitochondrial calcium regulation
线粒体钙调节的分子机制及生理功能
- 批准号:
10455701 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Molecular mechanism and physiological function of mitochondrial calcium regulation
线粒体钙调节的分子机制及生理功能
- 批准号:
10192800 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Molecular mechanism and physiological function of mitochondrial calcium regulation
线粒体钙调节的分子机制及生理功能
- 批准号:
9370196 - 财政年份:2020
- 资助金额:
-- - 项目类别:
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