Mitochondria-SR Tethering: Its Role in Cardiac Bioenergetics and Ca2+ Dynamics
线粒体-SR 束缚:其在心脏生物能学和 Ca2 动力学中的作用
基本信息
- 批准号:10534750
- 负责人:
- 金额:$ 54.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAffectAffinity ChromatographyAreaBioenergeticsCardiacCardiac MyocytesCardiotoxicityChargeChronicComplexCouplingDataDisabled PersonsDiseaseDominant-Negative MutationEFRACEnergy MetabolismEnsureEquilibriumFailureFunctional disorderFundingGenerationsGenetic ModelsGoalsHealthHeartHeart DiseasesHeart InjuriesHeart failureInjuryInner mitochondrial membraneIschemiaIsoproterenolKnock-outKnowledgeLiteratureLocationMediatingMembraneMitochondriaMitochondrial MatrixMitochondrial Membrane ProteinModelingMolecularMouse StrainsMusMuscle CellsN-terminalOrganellesOuter Mitochondrial MembraneOxidative StressPathogenicityPathologicPhenotypePlayProductionProteinsProteomicsPublishingRattusRegulationReperfusion InjuryReperfusion TherapyRoleRouteSarcoplasmic ReticulumSignal TransductionStressSurfaceSystemTailTestingTherapeuticToxic effectTransgenic OrganismsTranslatingWorkWorkloadadrenergic stressbiological adaptation to stresscalcium uniportercohortconditional knockoutcrista membranedesigndimerfightingheart functioninsightintermolecular interactionmouse geneticsmutantnovelnovel therapeutic interventionoverexpressionparalogous genepreservationpreventprotein protein interactionpyruvate dehydrogenaserecruitscaffoldsensorstress toleranceuptake
项目摘要
This MPI proposal has the overarching theme that mitochondrial Ca2+ uptake plays dual “ying-yang”
roles when the heart is under stress: it ensures that extra energy demands are met under workload stress,
while it is the route for Ca2+ overload/toxicity under oxidative stress. The project uses a new conditional knock-
out rat model for EMRE/Smdt1, an essential subunit of the main mitochondrial Ca2+ uptake system, the mito-
chondrial Ca2+ uniporter channel complex (MCUC). The excitation-bioenergetics (EB) coupling is a signaling
loop that uses the Ca2+ released by sarcoplasmic reticulum (SR) to activate MCUC and generate mitochon-
drial matrix Ca2+ signals to upregulate ATP production. Our long-term goal is to translate the fundamental
mechanism of EB coupling to health and disease of the heart. Our previous work demonstrated that MCUC is
recruited to hotspots at the mitochondria-SR (Mito-SR) contacts to effectively mediate EB coupling by a yet
unknown mechanism.
This proposal aims to address the following gaps in our knowledge about EB coupling:
i). The role of MCUC in cardiac stress tolerance, diastolic dysfunction and heart failure with preserved ejection
fraction (HFpEF). ii). Molecular mechanisms, protein-protein interactions of MCUC recruitment to hotspots at
Mito-SR contacts. iii). How are organelle dynamics (contact formation, fusion/fission) integrated with the dy-
namics of Ca2+ transport distribution? iv). The role of a dominant negative subunit MCUB in the MCUC hotspot
formation, control of the inactive and activatable MCUC channel pool distribution to attain balance between EB
coupling and Ca2+ toxicity.
The Central Hypothesis is that the dichotomy of mitochondrial Ca2+ in controlling health and disease of
cardiomyocytes hinges on the crucial role of EMRE and MCUB in regulating the location and quantity of func-
tional MCUC; this elaborate regulation is critical in cardiac adaptation to “fight or flight” and oxidative stress re-
sponses. Three specific aims are set up to test this hypothesis:
Aim 1. Assess the regulation of EB coupling by MCUC during “fight or flight” sympathetic stress and determine
if cessation of this function could lead to diastolic dysfunction or HFpEF.
Aim 2. Elucidate the molecular mechanism of the MCUC hotspot recruitment in the rat cardiomyocytes.
Aim 3. Study the dynamic interactions between EMRE, MCU and MCUB in regulating the MCUC localization
to maintain EB coupling efficiency while preventing Ca2+ toxicity under pathological stresses.
Completion of the proposed studies will generate a new paradigm for the regulatory mechanisms of mi-
tochondrial Ca2+ in cardiac energetics. The new findings will provide mechanistic basis for a new therapeutic
strategy to treat heart failure.
该MPI提案的总体主题是线粒体Ca2+摄取扮演双重“ ying-yang”
当心脏承受压力时的角色:它确保在工作量压力下满足额外的能量需求,
虽然它是在氧化应激下的Ca2+过载/毒性的途径。该项目使用了新的条件性敲门
EMRE/SMDT1的OUT大鼠模型,这是主线粒体Ca2+摄取系统的必不可少的亚基。
软骨Ca2+ unitporter通道复合物(MCUC)。兴奋生物能学(EB)耦合是一个信号
使用肌浆网(SR)释放的Ca2+的循环来激活MCUC并产生线条 -
钻矩阵Ca2+信号以上调ATP生产。我们的长期目标是翻译基本
EB耦合与心脏健康和疾病的机制。我们以前的工作表明MCUC是
在线粒体-SR(mito-sr)触点上招募到热点,以有效地介导EB耦合
未知机制。
该建议旨在解决我们有关EB耦合的知识中的以下差距:
我)。 MCUC在心脏胁迫耐受性,舒张功能障碍和心力衰竭中的作用并保留了射血
分数(HFPEF)。 ii)。 MCUC募集到热点的分子机制,蛋白质 - 蛋白质相互作用
MITO-SR触点。 iii)。如何与Dy-集成的细胞器动力学(接触形成,融合/裂变)
CA2+运输分布的名称? iv)。 MCUC热点中主要的负亚基MCUB的作用
形成,控制不活跃和可激活的MCUC通道池分布以达到EB之间的平衡
耦合和Ca2+毒性。
中心假设是线粒体Ca2+在控制健康和疾病中的二分法
心肌细胞取决于EMRE和MCUB在调节中的关键作用
Tional McUc;这种详尽的调节对于对“战斗或飞行”的心脏适应至关重要,氧化应激恢复至关重要
赞助。建立了三个具体目标来检验以下假设:
目标1。评估MCUC在“战斗或飞行”同情压力期间对EB耦合的调节并确定
如果该功能的停止可能导致舒张功能障碍或HFPEF。
目标2。阐明大鼠心肌细胞中MCUC热点募集的分子机制。
AIM 3。研究EMRE,MCU和MCUB之间的动态相互作用
保持EB偶联效率,同时防止病理应力下CA2+毒性。
拟议的研究的完成将为MI-I的调节机制产生新的范式
心脏能量学中的小节Ca2+。新发现将为新疗法提供机械基础
治疗心力衰竭的策略。
项目成果
期刊论文数量(0)
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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GYORGY CSORDAS其他文献
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{{ truncateString('GYORGY CSORDAS', 18)}}的其他基金
ER-mitochondrial communication in calcium signaling, energy metabolism and liver disease
钙信号传导、能量代谢和肝脏疾病中的内质网线粒体通讯
- 批准号:
10785141 - 财政年份:2021
- 资助金额:
$ 54.75万 - 项目类别:
ER-mitochondrial communication in calcium signaling, energy metabolism and liver disease
钙信号传导、能量代谢和肝脏疾病中的内质网线粒体通讯
- 批准号:
10631482 - 财政年份:2021
- 资助金额:
$ 54.75万 - 项目类别:
ER-mitochondrial communication in calcium signaling, energy metabolism and liver disease
钙信号传导、能量代谢和肝脏疾病中的内质网线粒体通讯
- 批准号:
10555276 - 财政年份:2021
- 资助金额:
$ 54.75万 - 项目类别:
ER-mitochondrial communication in calcium signaling, energy metabolism and liver disease
钙信号传导、能量代谢和肝脏疾病中的内质网线粒体通讯
- 批准号:
10211656 - 财政年份:2021
- 资助金额:
$ 54.75万 - 项目类别:
ER-mitochondrial communication in calcium signaling, energy metabolism and liver disease
钙信号传导、能量代谢和肝脏疾病中的内质网线粒体通讯
- 批准号:
10378151 - 财政年份:2021
- 资助金额:
$ 54.75万 - 项目类别:
Structural-functional zoning of the mitochondrion in cardiac Ca2+, ROS, and energetics regulation
线粒体在心脏 Ca2 、ROS 和能量调节中的结构功能分区
- 批准号:
9762152 - 财政年份:2018
- 资助金额:
$ 54.75万 - 项目类别:
Structural-functional zoning of the mitochondrion in cardiac Ca2+, ROS, and energetics regulation
线粒体在心脏 Ca2 、ROS 和能量调节中的结构功能分区
- 批准号:
9913581 - 财政年份:2018
- 资助金额:
$ 54.75万 - 项目类别:
Study of the mitochondrial-cellular response to environmental stress by flourescence imaging
通过荧光成像研究线粒体细胞对环境应激的反应
- 批准号:
9513726 - 财政年份:2017
- 资助金额:
$ 54.75万 - 项目类别:
Mitochondria-SR Tethering: Its Role in Cardiac Bioenergetics and Ca2+ Dynamics
线粒体-SR 束缚:其在心脏生物能学和 Ca2 动力学中的作用
- 批准号:
8657284 - 财政年份:2014
- 资助金额:
$ 54.75万 - 项目类别:
Mitochondria-SR Tethering: Its Role in Cardiac Bioenergetics and Ca2+ Dynamics
线粒体-SR 束缚:其在心脏生物能学和 Ca2 动力学中的作用
- 批准号:
8803808 - 财政年份:2014
- 资助金额:
$ 54.75万 - 项目类别:
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