线粒体结构和功能紊乱是缺血性心力衰竭(心衰)细胞死亡和功能异常的重要因素，线粒体自噬和融合分裂在其进程中是双刃剑，但其确切作用和机制未明。线粒体解耦联蛋白UCP3具心肌保护作用，但在缺血性心衰中的重要性和机制不清。我们发现UCP3与心肌细胞mPTP组分结合；在心肌缺血时下调；而过表达逆转心肌缺血/复灌后线粒体膜电位异常、维持线粒体功能稳态，改善心功能和心梗面积；UCP3下调/敲除则反之；并发现过表达UCP3进一步升高缺氧及心梗后心肌细胞线粒体自噬、调节线粒体分裂融合蛋白表达，故推测UCP3可能通过调控线粒体自噬和融合分裂干预缺血性心衰进程。为验证此，本项目拟探讨1)UCP3在缺血性心衰进程中的作用；2)UCP3对缺血性心衰进程中线粒体自噬和融合分裂的作用、分子机制；3)调控UCP3干预心衰进程的方式。研究发现将揭示线粒体自噬和融合分裂在缺血性心衰中的作用、调控新机制和干预心衰的潜在靶点。

Myocardial ischemia caused by coronary artery disease is the main cause that lead to heart failure. The disorder of dynamic balance among mitochondrial ATP critically contributes to the development of myocardial dysfunction and cell death. A growing body of research suggests that autophagy including mitophagy and mitochondrial dynamics play an essential role in mitochondrial quality control, but their exact functions and underlying mechanisms in ischemic heart failure remain largely unknown. Our study synergy with other research demonstrated that mitochondrial uncoupling protein 3 (UCP3) confer cardioprotective effects during ischemic heart failure, however its precise mechanisms remain largely unknown. Recently, we found that UCP3 expression was downregulated during ischemic stress and its overexpression reverses ischemia-induced loss of mitochondrial inner membrane potential and reactive ROS burst, resulting in the improvement of cardiomyocyte survival and postischemic cardiac performance. These protective effects are critically related to the interaction of UCP3 with the component, adenine nucleotide translocator (ANT) of mitochondrial permeability transition pore (mPTP), and partially related to the activation of PI3K/Akt pathway. In contrast, UCP3 knockdown has the opposite effects. Furthermore, UCP3 overexpression activates Parin/PINK1-mediated mitophagy, regulates abundance of key proteins related to mitochondrial fusion and fission, and reduces hypoxia- or myocardial infarction-induced cell death. We thus hypothesize that UCP3 may play an important beneficial role during the ischemic heart failure via regulating mitochondrial dynamics and mitophagy through affecting the mitochondrial membrane potential and ATP level. To test it, in the present study, we are going to i) determine the role of UCP3 during ischemic heart failure; ii) investigate the effect, molecular mechanisms, and impact of UCP3 on mitochondrial dynamics and mitophagy during ischemic heart failure; and iii) explore the strategy and methods targeting at the intervention of progression of ischemic heart failure by regulating UCP3-related mechanisms. The findings will provide the new insight into the importance and regulatory mechanisms of mitochondrial dynamics and mitophagy during ischemic heart failure and will provide laboratory data to help for the development of the new strategy against ischemic heart failure.