Mitochondrial ATP Synthase in Cardiac Biology and Disease
线粒体 ATP 合酶在心脏生物学和疾病中的作用
基本信息
- 批准号:10812556
- 负责人:
- 金额:$ 3.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2023-10-15
- 项目状态:已结题
- 来源:
- 关键词:ATP Synthesis PathwayAdenine Nucleotide TranslocaseAgeApoptosisAttenuatedBiologyCardiacCardiac MyocytesCell DeathCessation of lifeCollaborationsComplexCytoplasmDataDepressed moodDiseaseElectron TransportEngineeringEventExhibitsFunctional disorderGene DeletionGeneticHeartHeart failureHumanIndividualInfarctionInvestigationKnockout MiceLeftMammalian CellMediatingMetabolicMitochondriaMitochondrial Proton-Translocating ATPasesModelingMusMyocardial IschemiaMyocardial dysfunctionNecrosisPathway interactionsPatientsPharmaceutical PreparationsProtein Complex SubunitRadioisotopesRegulationReperfusion TherapyRoleSpecimenSurgeonTestingUncertaintyVentricularWild Type Mousedefined contributionexperimental studygain of functionheart functionin vivoinhibitorloss of functionmitochondrial permeability transition poremortalitymouse modelnovelpressureresponse
项目摘要
The mitochondrial ATP synthase is a multi-subunit complex that catalyzes the synthesis of >90% of ATP in
mammalian cells. The ATP synthase is also hypothesized to function as the mitochondrial permeability transition
pore (mPTP), a major trigger for necrotic cell death. Except for short-term drug inhibitor experiments, the
functions of the ATP synthase have never been assessed in the heart in vivo. We have created the first mouse
models deficient in the entire ATP synthase complex in cardiomyocytes. To accomplish this, we individually
deleted at 5 weeks of age ATP5L and ATP5J, ATP synthase subunits required for complex assembly. Thus far,
we have analyzed the ATP5L KO mice. Because the half-lives of most mitochondrial ATP synthase subunits
exceed 35 days in cardiomyocytes, the abundance of the complex decreased gradually with 15% remaining at
12 weeks post-deletion. KO mice uniformly developed heart failure (HF) with reduced systolic function and died
between 12-16 weeks post-deletion. Analysis of cardiac mitochondria confirmed reduced ATP synthesis rates
as expected. Unexpectedly, however, ATP concentrations in whole heart lysates, as well as in cytoplasmic and
mitochondrial fractions, were elevated in KO, compared with control, mice. Parallel investigations into the role of
the ATP synthase as the mPTP revealed that, rather than inhibiting Ca2+-induced mPTP opening, deficiency of
the ATP synthase sensitized this event. Moreover, mice with cardiomyocyte-specific deficiency of the ATP
synthase exhibited larger – not smaller – infarcts following myocardial ischemia/reperfusion in vivo. Finally, we
observed that ATP synthase levels and activity in mitochondria decrease during pressure overload-induced HF
in wild type mice. These results suggest: (a) Loss of the mitochondrial ATP synthase activates marked
metabolic/energetic responses and unleashes previously unrecognized mechanisms that promote lethal HF.
Regarding the latter, our preliminary studies implicate Complex II to I reverse electron transport (RET) promoting
ROS-induced cardiomyocyte apoptosis. (b) Our studies cast doubt that the ATP synthase also functions as the
mPTP and rather suggest that it is a negative regulator. (c) Deficient ATP synthase function may contribute to
acquired forms of HF. We propose studies to understand the mechanistic basis of our observations and to assess
the role deficient mitochondrial ATP synthase function in human HF. Aim 1. To define metabolic/energetic
pathways that are activated and mechanisms that contribute to HF in mice with cardiomyocyte-specific deficiency
of the mitochondrial ATP synthase. Aim 2. To test definitively whether the mitochondrial ATP synthase is the
mPTP. Aim 3. To assess the role of deficient mitochondrial ATP synthase abundance/function in pressure
overload-induced HF in mice and in human HF. These studies break new ground in investigating functions of
the mitochondrial ATP synthase in cardiomyocytes in vivo. Deliverables include the assessment of RET as a
novel HF mechanism, a definitive determination of the role of the ATP synthase as the mPTP, and a delineation
of the role deficient ATP synthase function in human HF.
线粒体ATP合成酶是一种多亚基复合体,催化细胞内90% ATP的合成
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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Richard N Kitsis其他文献
Eat your heart out
羡慕死你。
- DOI:
10.1038/nm0507-539 - 发表时间:
2007-05-01 - 期刊:
- 影响因子:50.000
- 作者:
Richard N Kitsis;Chang-Fu Peng;Ana Maria Cuervo - 通讯作者:
Ana Maria Cuervo
Richard N Kitsis的其他文献
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{{ truncateString('Richard N Kitsis', 18)}}的其他基金
Mitochondrial ATP Synthase in Cardiac Biology and Disease
线粒体 ATP 合酶在心脏生物学和疾病中的作用
- 批准号:
10632143 - 财政年份:2022
- 资助金额:
$ 3.57万 - 项目类别:
Caspase-9 as a nodal point connecting necrotic and apoptotic cell death in myocardial infarction
Caspase-9作为连接心肌梗死细胞坏死和凋亡的节点
- 批准号:
10666668 - 财政年份:2022
- 资助金额:
$ 3.57万 - 项目类别:
Caspase-9 as a nodal point connecting necrotic and apoptotic cell death in myocardial infarction
Caspase-9 作为连接心肌梗死细胞坏死和凋亡的节点
- 批准号:
10504387 - 财政年份:2022
- 资助金额:
$ 3.57万 - 项目类别:
Mitochondrial ATP Synthase in Cardiac Biology and Disease
线粒体 ATP 合酶在心脏生物学和疾病中的作用
- 批准号:
10758687 - 财政年份:2022
- 资助金额:
$ 3.57万 - 项目类别:
Mitochondrial ATP Synthase in Cardiac Biology and Disease
线粒体 ATP 合酶在心脏生物学和疾病中的作用
- 批准号:
10446745 - 财政年份:2022
- 资助金额:
$ 3.57万 - 项目类别:
Modulation of Mitofusin Activity to Treat Heart Disease
调节丝裂霉素活性治疗心脏病
- 批准号:
10280485 - 财政年份:2021
- 资助金额:
$ 3.57万 - 项目类别:
Modulation of Mitofusin Activity to Treat Heart Disease
调节丝裂霉素活性治疗心脏病
- 批准号:
10458699 - 财政年份:2021
- 资助金额:
$ 3.57万 - 项目类别:
Modulation of Mitofusin Activity to Treat Heart Disease
调节丝裂霉素活性治疗心脏病
- 批准号:
10655447 - 财政年份:2021
- 资助金额:
$ 3.57万 - 项目类别:
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