线粒体钙离子摄取在细胞的生命活动中发挥着极其重要的作用。通过长达半个多世纪的研究，负责线粒体钙离子摄取的蛋白质分子才被鉴定出来:线粒体钙离子单向运输体（MCU）主要负责钙离子运输和线粒体钙离子感受器(MICU1)主要负责感受钙离子。然而，MICU1如何感受线粒体内钙离子浓度变化，进而调控MCU的功能的分子机制还不是很清楚。申请人拟运用生物化学、细胞生物学和分子影像技术来研究线粒体MICU1结合钙前后的构象变化，MICU1和MCU之间的相互作用以及MICU1调控MCU通道的电生理信号，最终阐明MICU1调节钙离子运输进入线粒体基质的分子机制。本项目的研究结果对理解线粒体钙离子摄取的进程将会产生重要的影响，也为进一步设计并筛选小分子抑制剂调节线粒体钙离子摄取提供分子基础，以及为心脏疾病和神经退行性疾病的治疗提供理论指导意义。

Mitochondrial calcium uptake plays very important role in cellular activities. After more than half a century searching, proteins being responsible for mitochondrial calcium uptake have been identified. One is mitochondrial calcium uniport (MCU) which transports calcium and the other is mitochondrial calcium uptake 1 (MICU1) which sensors calcium. However, the molecular mechanism of the regulation of MCU by MICU1 after calcium bound is currently unknown. We will use the combination of various techniques from biochemistry, cell biology and molecular imaging to study the conformation changes of MICU1 bound to calcium, the interaction between MICU1 and MCU as well as the electrophysiology of MCU regulation by MICU1, and eventually to elucidate the molecular mechanism of calcium influx into the mitochondrial matrix regulated by MICU1. Our results will be vital for the further understanding of mitochondrial calcium uptake, and also provide the basis for designing and screening small molecules to regulate the process of mitochondrial calcium influx as well as shed the light on the treatment of cardiovascular disease and neurodegenerative disease.