心力衰竭的保护新机制：Syntaxin17通过招募CDK1调控Drp1依赖的线粒体质量控制

心力衰竭是各种心脏疾病的严重和终末阶段，心肌线粒体损伤和能量供应障碍在心力衰竭发生发展中起重要作用。STX17是一种分布于内质网和线粒体膜的保守蛋白，调控囊泡运输和自噬。我们前期发现心衰患者及主动脉缩窄术后心衰小鼠的心肌中STX17表达显著下调，而过表达STX17明显增加心肌线粒体能量供应，减缓心肌重构，改善心脏功能，但分子机制尚不明确。本课题组及其他研究证实，Drp1介导的线粒体质量控制失调及后续能量供应障碍在心衰进程中起关键作用，而STX17与Drp1在线粒体相关内质网膜区（MAMs）关系紧密。IP质谱分析提示STX17可能与Cyclin依赖激酶1（CDK1）结合，而CDK1正是Drp1的磷酸化激酶。因此，我们推测STX17可能在MAMs处通过结合CDK1，促进Drp1磷酸化及线粒体转位，调控线粒体质量控制及后续能量供应，保护心力衰竭，为心衰治疗寻找可能的新干预靶点提供理论依据。

Heart failure is the serious and terminal stage of various cardiac diseases, the pathogenesis of which is closely related to mitochondrial dysfunction and insufficient energy supply. Syntaxin17 (STX17), as a conserved protein distributed in the endoplasmic reticulum and mitochondrial membrane, regulates vesicle trafficking and autophagy. Our previous data have displayed that the expression level of STX17 was significantly down-regulated in the heart tissues of patients with heart failure and the mice with transverse aortic constriction (TAC) induced heart failure. Cardiac specific overexpression of STX17 markedly improved myocardial mitochondrial energy supply, cardiac remodeling and systolic function of mice with TAC-induced heart failure. However, the molecular mechanism remains unclear. Recent studies have revealed the disorder of Drp1-mediated mitochondrial quality control (MQC) and subsequent insufficiency of energy supply play crucial role in the pathogenesis of heart failure. It has been suggested that STX17 interacted with Drp1 in mitochondrial-associated membranes (MAMs) to regulate MQC in vitro. Through immunoprecipitation followed by a mass spectrometry analysis, it is speculated that STX17 may regulate Drp1-dependent MQC by binding to cyclin dependent kinase 1 (CDK1). Thus, this project intends to explore the molecular mechanisms of STX17, which may recruit and bind CDK1 at MAMs, thereby promoting the phosphorylation of Drp1 at Ser616 site and mitochondrial translocation, maintaining mitochondrial energy supply, thus protecting the heart function. Through this work, we will take a step to reveal the pathogenesis of heart failure and identify a new therapeutic target for heart failure.