Complex I Deficiency Triggered Acceleration of Heart Failure

描述（由申请人提供）：复合物I缺乏引发心力衰竭加速线粒体功能障碍已在心力衰竭中反复观察到，但其在心力衰竭的发展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修饰剂。为了验证这一假设，我们通过删除Ndufs 4亚基（Ndusf 4 H-/-）产生了具有心脏特异性复合物I功能缺陷的小鼠模型。我们的初步数据显示，Ndusf 4的缺乏损害复合物I组装和功能，导致复合物I活性和复合物I依赖性呼吸的显著降低（约70%）。有趣的是，在非应激条件下，Ndusf 4 H-/-小鼠在长达一年的时间内，这种损伤不会影响心脏能量和功能。然而，当压力超负荷应激时，Ndusf 4 H-/-小鼠发生严重的心脏肥大和加速的心力衰竭。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的病理性肥大和心力衰竭的发展的分子机制。目的1：确定能量代谢与复合物I缺乏加速心力衰竭进程的相互作用。假设1a：有缺陷的复合体I功能在静息状态下得到补偿，但在慢性工作负荷增加期间限制ATP合成。假设1b：心肌肥厚时底物利用从脂肪酸向葡萄糖的转变加剧了复合物I缺乏引起的能量代谢受损。目标二：为了检验Ndusf 4 H-/-线粒体响应于能量需求的慢性增加而产生更大量的ROS并且过量的线粒体ROS加剧病理性肥大和心力衰竭的假设。目的3：通过分析基因共表达网络，鉴定新的线粒体功能障碍和心力衰竭相关的分子介质。

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.