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，但其在心力衰竭发生和进展中的作用仍不明确。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过渡的信号通路的关键调节剂。为了验证这一假设，我们通过删除Ndufs4亚基（Ndusf4H-/-），建立了心脏特异性复合物I功能缺陷的小鼠模型。我们的初步数据表明，缺乏Ndusf4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依赖呼吸显著降低（约70%）。有趣的是，在非应激条件下，这种损伤在长达一年的时间里不会影响Ndusf4H-/-小鼠的心脏能量和功能。然而，当压力过载时，Ndusf4H-/-小鼠会出现严重的心脏肥厚和加速心力衰竭。因此，该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脏肥厚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厚和心力衰竭发展的分子机制。目的1：探讨复合物I缺乏对心力衰竭加速进程与能量代谢的相互作用。假设1a：有缺陷的复合体I功能在静息条件下得到补偿，但在慢性工作量增加时限制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缺乏导致的能量代谢受损。目的2：验证Ndusf4H-/-线粒体在慢性能量需求增加时产生更多ROS的假设，过量的线粒体ROS会加剧病理性肥厚和心力衰竭。目的3：通过分析基因共表达网络，鉴定连接线粒体功能障碍和心力衰竭的新型分子介质。

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.