Complex I Deficiency Triggered Acceleration of Heart Failure

描述(申请人提供)：复合体I缺乏引发心力衰竭加速线粒体功能障碍在心力衰竭中被多次观察到，但它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肌肥厚和向心力衰竭过渡的信号通路的关键修饰物。为了验证这一假设，我们通过删除Ndufs4亚单位(Ndusf4H-/-)建立了心脏特异性复合体I功能缺陷的小鼠模型。我们的初步数据显示，缺乏Ndusf4会损害复合I的组装和功能，导致复合I活性和复合I依赖呼吸显着下降(~70%)。有趣的是，在非应激条件下，Ndusf4H-/-小鼠在长达一年的时间里，这种损伤不会影响心脏能量和功能。然而，当压力超负荷时，Ndusf4H-/-小鼠会出现严重的心肌肥厚和加速的心力衰竭。因此，这个模型提供了一个独特的工具来剖析线粒体功能障碍在改变心肌肥厚和衰竭过程中的机制作用。我们提出了以下具体目标，以确定线粒体功能障碍与病理性肥厚和心力衰竭的发展之间的分子机制。目的1：探讨复合碘缺乏引起的能量代谢与心力衰竭加速病程的相互作用。假设1a：有缺陷的复合体I功能在静息条件下得到补偿，但在慢性工作负荷增加时限制了ATP的合成。假设1b：在心肌肥厚中，底物利用从脂肪酸向葡萄糖的转变加剧了由于复合体I缺乏而造成的能量受损。目的：验证Ndusf4H-/-线粒体在慢性能量需求增加时产生大量ROS的假说，线粒体ROS过多会加剧病理性肥厚和心力衰竭。目的：通过对基因共表达网络的分析，寻找线粒体功能障碍与心力衰竭相关的新分子介质。

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.