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

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
Mechanisms of cardiovascular disease
心血管疾病的机制
  • 批准号:
    10546496
  • 财政年份:
    2019
  • 资助金额:
    $ 3.57万
  • 项目类别:
Mechanisms of cardiovascular disease
心血管疾病的机制
  • 批准号:
    9908028
  • 财政年份:
    2019
  • 资助金额:
    $ 3.57万
  • 项目类别:

相似海外基金

The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
  • 批准号:
    10633608
  • 财政年份:
    2023
  • 资助金额:
    $ 3.57万
  • 项目类别:
Characterization of Adenine Nucleotide Translocase (ANT) and Actin-Interacting Protein 1 (AIP1) as Protectors Against Cigarette Smoke
腺嘌呤核苷酸转位酶 (ANT) 和肌动蛋白相互作用蛋白 1 (AIP1) 作为香烟烟雾保护剂的表征
  • 批准号:
    9917578
  • 财政年份:
    2019
  • 资助金额:
    $ 3.57万
  • 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
  • 批准号:
    10459434
  • 财政年份:
    2018
  • 资助金额:
    $ 3.57万
  • 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
  • 批准号:
    10226893
  • 财政年份:
    2018
  • 资助金额:
    $ 3.57万
  • 项目类别:
The Role of Adenine Nucleotide Translocase in the Protection of Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在保护慢性阻塞性肺疾病 (COPD) 气道上皮细胞中的作用
  • 批准号:
    9764469
  • 财政年份:
    2018
  • 资助金额:
    $ 3.57万
  • 项目类别:
HNE damage of adenine nucleotide translocase in ethanol-mediated neuron apoptosis
乙醇介导的神经元凋亡中腺嘌呤核苷酸转位酶的 HNE 损伤
  • 批准号:
    7934507
  • 财政年份:
    2009
  • 资助金额:
    $ 3.57万
  • 项目类别:
Origin of mitochondrial proton leak: comparative investigation of Adenine Nucleotide, Translocase, Phosphate and Aspartat/Glutamate Carriers
线粒体质子泄漏的起源:腺嘌呤核苷酸、易位酶、磷酸盐和天冬氨酸/谷氨酸载体的比较研究
  • 批准号:
    40116377
  • 财政年份:
    2007
  • 资助金额:
    $ 3.57万
  • 项目类别:
    Research Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了