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：
10758687
负责人：
Richard N Kitsis
金额：
$ 2.05万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10758687
关键词：
ATP Synthesis Pathway Acceleration Acute Address Adrenergic Agents Adult Biology Cardiac Cardiac Myocytes Cells Complement Deterioration Disease EFRAC Echocardiography Exercise Funding Gene Deletion Generations Goals Health Heart failure Human Resources Hyperthyroidism Isoproterenol Knock-out Knockout Mice Mammalian Cell Mediating Mitochondria Mitochondrial Proton-Translocating ATPases Modeling Mus Pathologic Pathway interactions Performance Phenotype Physiological Pregnancy Protocols documentation Rest Running Stimulus Stress Wild Type Mouse Work cardiac pacing chronotropic conditioning heart function mouse model parent grant pharmacologic physiologic stressor pressure response treadmill

ATP Synthesis Pathway Acceleration Acute Address Adrenergic Agents Adult Biology Cardiac Cardiac Myocytes Cells Complement Deterioration Disease EFRAC Echocardiography Exercise Funding Gene Deletion Generations Goals Health Heart failure Human Resources Hyperthyroidism Isoproterenol Knock-out Knockout Mice Mammalian Cell Mediating Mitochondria Mitochondrial Proton-Translocating ATPases Modeling Mus Pathologic Pathway interactions Performance Phenotype Physiological Pregnancy Protocols documentation Rest Running Stimulus Stress Wild Type Mouse Work cardiac pacing chronotropic conditioning heart function mouse model parent grant pharmacologic physiologic stressor pressure response treadmill

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项目摘要

We have created two independent mouse models of adult cardiomyocyte-specific mitochondrial ATP synthase deficiency: cardiomyocyte-specific ATP5L knockout (KO) mice and cardiomyocyte-specific ATP5J KO mice. Analysis of both models have shown that mice with ~90% depletion of the mitochondrial ATP synthase unexpectedly remain healthy with normal cardiac function for several weeks before transitioning to lethal heart failure with reduced ejection fraction (HFrEF). Studies in the parent grant are investigating the compensatory mechanisms that maintain cardiac function in the face of severe mitochondrial ATP synthase depletion in cardiomyocytes and the mechanisms that eventually mediate the transition to heart failure which, interestingly, do not appear to involve further deterioration of cardiac energetics. Given the traditional view that the mitochondrial ATP synthesis is essential to sustain energetics in mammalian cells – especially energy- demanding cells such as cardiomyocytes – it is surprising that ~10% of its usual levels in cardiomyocytes are adequate to sustain basal mouse health and cardiac function. Our results suggest that the full complement of mitochondrial ATP synthase in cardiomyocytes is not needed at rest. This observation raises the question as to how much of the mitochondrial ATP synthase is needed in cardiomyocytes to sustain cardiac function under more energetically demanding conditions, a question that could not be previously addressed without these mouse models. To answer this question, it is necessary to impose a physiological stress on the mice that increases the energetic demands of cardiomyocytes – but without simultaneously activating pathological stress pathways. We have chosen to use acute β-adrenergic stimulation with isoproterenol and, independently, acute exercise. A second objective of the Supplement is to deepen our baseline characterization of the ATP5J KO mice, which were generated by the candidate. The baseline characterization of the ATP5L KO mice is already complete. However, studies performed after the parent grant was funded, show that the ATP5J KO mice appear to have an accelerated phenotype. Hence, these mice need a thorough baseline characterization. Thus, the specific aims are: 1. To extend the baseline characterization of the cardiomyocyte-specific ATP5J knockout mice. 2. To assess the response of cardiomyocyte-specific ATP5L KO and ATP5J KO mouse lines to physiological stimuli that increase cardiomyocyte energetic demands. The scientific questions addressed in this Supplement are directly related to those of the parent grant and the resulting information will enhance our understanding of the findings of the parent grant. However, both the proposed work in the Supplement and the personnel required to perform it are distinct from that in the parent grant.

我们创建了两个独立的成年心肌细胞特异性线粒体ATP合酶的鼠标模型缺陷：心肌细胞特异性ATP5L敲除（KO）小鼠和心肌细胞特异性ATP5J KO小鼠。两种模型的分析都表明，线粒体ATP合酶的耗尽约90％的小鼠出乎意料的是，在过渡到致命心脏之前，在正常的心脏功能中保持健康数周射血分数减少（HFREF）的失败。父母赠款的研究正在调查补偿性面对严重的线粒体ATP合成酶部署的机制心肌细胞和有时介导心力衰竭过渡的机制，有趣的是，似乎不涉及进一步恶化心脏能量学。鉴于传统观点线粒体ATP合成对于维持哺乳动物细胞的能量至关重要 - 尤其是能量 - 苛刻的细胞，例如心肌细胞 - 令人惊讶的是，其常规水平的心肌细胞中的约10％是足以维持基本的小鼠健康和心脏功能。我们的结果表明，完整完成在静止时，不需要心肌细胞中的线粒体ATP合酶。这种观察提出了一个问题在心肌细胞中需要多少线粒体ATP合酶来维持心脏功能更苛刻的条件，一个问题，没有这些问题就无法解决鼠标模型。要回答这个问题，有必要对小鼠施加身体上的压力增加心肌细胞的能量需求 - 但没有简单地激活病理压力途径。我们选择使用异丙肾上腺素使用急性β-肾上腺素能刺激，并且独立于急性锻炼。补充的第二个目标是加深我们对ATP5J KO的基线表征小鼠，由候选人产生。 ATP5L KO小鼠的基线表征已经完全的。但是，在父母赠款资助后进行的研究表明，ATP5J KO小鼠出现了具有加速表型。因此，这些小鼠需要彻底的基线表征。那，具体目的是：1。扩展心肌细胞特异性ATP5J敲除小鼠的基线表征。 2。评估心肌细胞特异性ATP5L KO和ATP5J KO小鼠线对生理的响应增加心肌细胞能量需求的刺激。此补充中解决的科学问题与父母赠款直接相关，由此产生的信息将增强我们对父母赠款的发现。但是，补充剂中的拟议工作和所需的人员执行它与父母赠款中的不同。