线粒体功能障碍是导致心肌能量代谢失衡的重要机制，后者在促进病理性心肌重构中起关键作用。我们前期首次报道了线粒体质量控制体系（MQC）中碱基切割修复系统关键基因MUTYH一个新的失功能变异可导致线粒体功能障碍，促进代谢性疾病表型的发生，但其在心血管疾病中的作用尚不明确。预实验发现携带该变异的个体具有更高的心力衰竭风险；病理性心肌重构小鼠心肌MUTYH表达明显降低，敲除该基因可促进病理性心肌重构。据此提出科学假说：MUTYH功能缺陷导致MQC失衡，引发线粒体功能障碍、心肌能量代谢失衡，促进病理性心肌重构的进程。本项目将以氧化损伤应激-MQC-心肌能量代谢-病理性心肌重构为分析轴，利用基因敲除/过表达及特异性抑制剂/激活剂等手段，从动物、细胞、临床队列等多个层面系统观察MUTYH 功能缺陷调控 MQC 失衡在促进病理性心肌重构发生发展中的作用及机制，为心力衰竭的防治提供新的理论依据和干预靶点。

Mitochondrial dysfunction is the major cause of cardiac energy metabolism disorder that plays a crucial role in the development of pathogenic cardiac remodeling. We previously first identified a novel dysfunctional variant of MUTYH, which is one of the key genes for base excision repair system in mitochondrial quality control system. This variant causes the defect of oxidative injury recovery, inducing mitochondrial dysfunction and the development of metabolic diseases. However, the role of MUTYH in cardiovascular diseases remains unclear. Preliminary data indicated that subjects carrying this variant had a high risk for heart failure. Moreover, cardiac MUTYH expression was decreased in mice with cardiac hypertrophy; while knockout MUTYH could promote pathogenic cardiac remodeling. We thus hypothesized that dysfunction of MUTYH may promote the development of pathogenic cardiac hypertrophy via inducing the disorder of mitochondrial quality control system, which in turn results in mitochondrial dysfunction and cardiac energy imbalance. To this end, we will mainly focus on the axis of oxidative stress-mitochondrial quality control system imbalance-mitochondrial energy metabolism dysfunction-pathogenic cardiac remodeling and use genetic animal model, cell model and clinical cohort study to investigate the underlying molecular mechanisms and key regulators. Our study might provide a new insight into the diagnosis and treatment for heart failure.