线粒体炫异常在肥胖性心肌病心肌ATP稳态失调中的作用及机制

项目名称： 线粒体炫异常在肥胖性心肌病心肌ATP稳态失调中的作用及机制

项目编号： No.31500932

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 张星

作者单位： 中国人民解放军第四军医大学

项目金额： 20万元

中文摘要： 我们前期发现正常心肌细胞中Bcl-xL相关质子漏触发的线粒体炫（一种单个线粒体能量消耗事件）能够通过频调方式调控ATP合成和维持ATP稳态，且观察到肥胖性心肌病心肌中ATP合成减少、ATP稳态失调和线粒体炫频率增加，提示肥胖性心肌病心肌ATP异常可能与线粒体炫改变有关，但具体机制不清。无法维持ATP稳态是心肌在应激条件下易损性增加的关键原因，本研究拟利用活细胞实时ATP检测等技术研究线粒体炫改变在肥胖性心肌病心肌ATP合成减少和稳态失调中的作用及机制。首先明确肥胖性心肌病心肌ATP异常与线粒体炫及其调控分子（活性氧和Bcl-xL）变化之间的关系。进一步研究活性氧和Bcl-xL自身的改变及其对线粒体炫调控的改变，明确这些改变在肥胖性心肌病心肌ATP异常中的作用。本研究旨在从线粒体炫角度阐明肥胖性心肌病心肌ATP稳态失调的机制，为提高肥胖患者心肌能量供应稳态和降低心肌易损性提供新策略。

中文关键词： 线粒体炫；活性氧；ATP稳态；质子漏；肥胖性心肌病

英文摘要： Recently, we found that mitochondrial flash (mitoflash), an energy consuming event at the single-mitochondrion level, is essential for the autoregulation of ATP production and homeostasis in normal cardiomyocytes. Mitoflash is triggered by Bcl-xL-associated proton leakage. However, we found that the ATP level is decreased and the ATP homeostasis is disrupted in cardiomyocytes from obesity cardiomyopathy, where mitoflash frequency are increased. These results suggested that the abnormal ATP is associated with the change of mitoflash activity. The disruption of ATP homeostasis increases the vulnerability of heart in stress conditions. The proposal is designed to study the role of mitoflash in the abnormal ATP in cardiomyocytes from obesity cardiomyopathy and its underlying mechanism using real-time imaging methods in live cells. First, the relationship between the abnormal ATP and the abnormal mitoflash activity will be evaluated in cardiomyocytes from obesity cardiomyopathy. Then, the changes of Bcl-xL and reactive oxygen species (ROS) and their regulation of mitoflash will be examined, and the role of these changes in the abnormal ATP will be explored. This study is aimed to decode the underlying mechanism of the disruption of cardiac ATP homeostasis in obesity. It will identify new strategy to improve cardiac energy supply and decrease cardiac vulnerability in obesity.

英文关键词： mitochondrial flash;reactive oxygen species;ATP homeostasis;proton leakage;obesity cardiomyopathy