Parkin通过对SURF1转录调节调控线粒体功能介导病理性心肌肥大的机制研究

细胞核转录调控障碍和线粒体蛋白转录后修饰异常介导的线粒体功能紊乱是病理性心肌肥大向心衰发展的核心病理过程。帕金森病蛋白2 (Parkin)通过线粒体自噬及转录调控在调节细胞功能中发挥关键作用。我们发现心肌肥大进程中Parkin入核增多加剧了线粒体功能障碍及心肌肥大反应，但其介导的心肌肥大并不依赖于线粒体自噬。进一步筛查发现电子传递链复合物IV的组装蛋白即Surfeit基因座白1 (SURF1)可能是Parkin核内调控的关键下游分子。据此我们提出Parkin的入核调控转录可能是造成线粒体功能障碍并介导心肌肥大的关键。本课题将重点研究 Parkin入核调控转录对线粒体功能和心肌肥大的具体影响，明确Parkin对SURF1的转录调控是其诱导线粒体功能异常及心肌肥大的关键，并深入研究其作用控机制，从转录调控及细胞器互作角度研究Parkin新功能，为防治心肌肥大提供新思路。

Disordered transcriptional regulation and post-translational modification of mitochondrial proteins are the core pathological mechanism of cardiac hypertrophy to heart failure. Parkin (Parkinson's disease protein 2) plays a critical role in regulation cellular function through mitochondrial autophagy and transcriptional regulation. During the development of cardiac hypertrophy, we found that Parkin accumulated in the nucleus and exacerbated mitochondrial dysfunction and cardiac hypertrophy, which was independent of mitophagy. Further screening found that SURF1 (Surfeit locus protein 1) the assembly factor of electron transport chain complex IV (ETC-complex IV) might be the pivotal downstream target of Parkin in the nucleus. Therefore, we speculate that the transcriptional regulation of nuclear-localized Parkin plays a pivotal role in aggravating mitochondrial dysfunction and cardiac hypertrophy. In this study, we will focus on the transcriptional regulatory role of Parkin in the regulation of mitochondrial function and cardiac hypertrophy. Furthermore, we will explore whether SURF1 is the key downstream of Parkin for the regulation of mitochondrial function during cardiac hypertrophy and the detailed mechanism. From the perspective of transcriptional regulation and interaction between organelles, this study will reveal new function of Parkin and provide new ideas for the treatment of cardiac hypertrophy.