Drp1/AGC1调控线粒体动态改变介导慢性心力衰竭心肌结构和代谢异常的机制研究

心脏病发展至慢性心力衰竭有多种复杂机制。线粒体通过不断融合与分裂动态过程维系着细胞生理功能，但过度融合或过度分裂均破坏线粒体质量控制平衡机制，影响细胞能量代谢和功能。我们前期研究发现扩张型心肌病患者细胞有线粒体过度分裂现象、主司线粒体分裂的动力相关蛋白1（Drp1）明显上调；在心力衰竭动物模型中药物干预下调Drp1能明显改善心功能。预试验中应用蛋白质组学和免疫共沉淀法证实Drp1和天冬氨酸/谷氨酸载体1（AGC1）有相互作用。AGC1是位于线粒体内膜上钙离子依赖性蛋白，担负产能物质运输。本研究构建心脏特异性敲除Drp1模式小鼠，通过线粒体ATP/ADP比值、膜电位、细胞氧耗速率、NADH和丙酮酸浓度，蛋白定位，蛋白表达等指标明确Drp1/AGC1调控线粒体动态改变介导心力衰竭心肌结构和代谢异常机制，针对线粒体过度分裂这一靶点，提出改善细胞能量代谢和逆转心肌功能新思路。

Cardiovascular diseases develop into chronic heart failure have variety of complex pathological mechanisms. The myocardial mitochondrial maintain the normal function through continuous fission and fusion. However, increased mitochondrial fission and decreased fusion can break the balance of mitochondrial dynamics and can influence metabolism and function. Our preliminary study found excessive mitochondrial fission and increased dynamin-related protein 1 （Drp1）expression in dilated cardiomyopathy （DCM） patients. We inferred inhibit mitochondrial fission can improve heart function in DCM mice models. In preliminary experiment, we use proteomic and Co-immunoprecipitation technique to detect the relationship between Drp1 and aspartate-glutamate carrier 1 (AGC1). AGC1 is calcium dependent mitochondrial carrier and play an important role in transport metabolites. In our study, we induced Drp1 conditional knockout mice. Then, we try to evaluate the mitochondrial ATP/ADP synthesis, mitochondria membrane potential, the rate of oxygen consumption rate, NADH and pyruvate concentration，protein location and expression in order to clarify the mechanism of Drp1/AGC1 mediated mitochondrial dynamics in myocardial structural and metabolism. Therefore, these findings will target the excessive mitochondrial fission and provide novel information in improving myocardial metabolism and reversing heart function.