Complex I Deficiency Triggered Acceleration of Heart Failure

复合物 I 缺乏会加速心力衰竭

基本信息

批准号：
8195391
负责人：
Rong Tian
金额：
$ 76.71万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8195391
关键词：
ATP Synthesis Pathway Acceleration Affect Cardiac Cardiomyopathies Cell Death Cell physiology Cells Chronic Comorbidity Complex Data Development Disease Echocardiography Electron Transport Energy Metabolism Equilibrium Exercise Fatty Acids Fluorescent Probes Functional disorder Genes Glucose Goals Heart Heart Hypertrophy Heart failure Homeostasis Hydrogen Peroxide Hypertension Hypertrophy Image Impairment In Vitro In Vivo NMR Spectroscopy Ions Left Ventricular Remodeling Link Measurement Mediating Mediator of activation protein Mitochondria Mitochondrial Diseases Modeling Molecular Mus Muscle Fibers Myocardial Myocardial Ischemia NADH Oxidation-Reduction Oxidative Stress Pathway Analysis Phenotype Physiological Play Production Regulation Respiration Respiratory Chain Rest Role Secondary to Signal Pathway Signal Transduction Site Source Stimulus Stress Superoxides Testing Time Workload catalase cell growth in vivo mitochondrial dysfunction mouse model novel overexpression pressure response tool

项目摘要

DESCRIPTION (provided by applicant): Complex I Deficiency Triggered Acceleration of Heart Failure Mitochondrial dysfunction has been repeatedly observed in heart failure but its role in the development and progression of heart failure remains elusive. We hypothesize that mitochondrial function is a critical modifier of the signaling pathways that cause pathological cardiac hypertrophy and the transition to heart failure. To test this hypothesis, we generated a mouse model with cardiac-specific deficiency of Complex I function by deleting the Ndufs4 subunit (Ndusf4H-/-). Our preliminary data show that the lack of Ndusf4 impairs Complex I assembly and function resulting marked decrease (by ~70%) of Complex I activity and Complex I dependent respiration. Interestingly, the impairment does not affect cardiac energetics and function in up to one year in the Ndusf4H-/- mice under unstressed conditions. However, when stressed with pressure overload the Ndusf4H-/- mice develop severe cardiac hypertrophy and accelerated heart failure. Thus, this model provides a unique tool to dissect the mechanistic role of mitochondrial dysfunction in modifying the course of cardiac hypertrophy and failure. We propose the following specific aims to determine the molecular mechanisms linking mitochondrial dysfunction to the development of pathological hypertrophy and heart failure. Aim 1: To determine the interaction of energy metabolism and the accelerated course of heart failure by Complex I deficiency. Hypothesis 1a: Defective Complex I function is compensated under resting conditions but limits ATP synthesis during chronic increases in workload. Hypothesis 1b: The shift of substrate utilization from fatty acids to glucose in cardiac hypertrophy exacerbates the impaired energetics due to Complex I deficiency. Aim 2: To test the hypothesis that Ndusf4H-/- mitochondria produce a greater amount of ROS in response to chronic increases in energy demand and excessive mitochondrial ROS exacerbates the pathological hypertrophy and heart failure. Aim 3: To identify novel molecular mediators linking mitochondrial dysfunction and heart failure by analyzing a gene co-expression network. PUBLIC HEALTH RELEVANCE: This project investigates the mechanistic role of mitochondrial dysfunction in the development of heart failure. Our goal is to identify novel signals and target molecules that link mitochondrial dysfunction to the worsening of heart failure.

描述（由申请人提供）：复合物 I 缺乏引发心力衰竭的加速在心力衰竭中已反复观察到线粒体功能障碍，但其在心力衰竭发生和进展中的作用仍然难以捉摸。我们假设线粒体功能是导致病理性心脏肥大和向心力衰竭转变的信号通路的关键调节剂。为了检验这一假设，我们通过删除 Ndufs4 亚基 (Ndusf4H-/-) 生成了具有心脏特异性复合物 I 功能缺陷的小鼠模型。我们的初步数据表明，Ndusf4 的缺乏会损害复合物 I 的组装和功能，导致复合物 I 活性和复合物 I 依赖性呼吸显着下降（约 70%）。有趣的是，在无应激条件下，这种损伤不会影响 Ndusf4H-/- 小鼠长达一年的心脏能量和功能。然而，当压力超负荷时，Ndusf4H-/- 小鼠会出现严重的心脏肥大并加速心力衰竭。因此，该模型提供了一种独特的工具来剖析线粒体功能障碍在改变心脏肥大和衰竭过程中的机制作用。我们提出以下具体目标，以确定线粒体功能障碍与病理性肥大和心力衰竭发展之间的分子机制。目标 1：确定能量代谢与复合物 I 缺乏导致的心力衰竭加速进程之间的相互作用。假设 1a：有缺陷的复合物 I 功能在休息条件下得到补偿，但在工作负荷长期增加时限制 ATP 合成。假设 1b：在心脏肥大中，底物利用从脂肪酸转向葡萄糖，加剧了复合物 I 缺乏导致的能量学受损。目标 2：检验以下假设：Ndusf4H-/- 线粒体会产生大量 ROS，以应对能量需求的长期增加，过量的线粒体 ROS 会加剧病理性肥大和心力衰竭。目标 3：通过分析基因共表达网络来识别与线粒体功能障碍和心力衰竭相关的新型分子介质。公共卫生相关性：该项目研究线粒体功能障碍在心力衰竭发展中的机制作用。我们的目标是确定将线粒体功能障碍与心力衰竭恶化联系起来的新信号和目标分子。