线粒体内外膜接触调控线粒体与内质网互作研究

The interaction between mitochondria and endoplasmic reticulum (ER) plays a variety of biological functions, including calcium and lipid transport, autophagy, mitochondrial division and mitochondrial DNA distribution. However, the mechanism of dynamic regulation, physiological and pathological functions of this interaction are still unclear, thus, the further exploration and research are needed. We found that Sam50 and Mic19, the key regulators of mitochondrial inner and outer membrane contact, were rich in mitochondrial-associated ER membrane (MAM), and regulated the interaction between mitochondria and ER. Therefore, the current project will focus on the contact between mitochondrial inner and outer membrane, and study the molecular mechanism and related biological functions of mitochondria and ER interaction. In addition, we will create Mic19 liver-specific knockout mice to study the role of Mic19 deletion-induced disorder of mitochondria and ER interaction in the development of liver diseases. In summary, this project will contribute to the illumination of the signaling pathway of mitochondria and ER interaction and the pathogenesis of liver diseases.

线粒体与内质网互作是发挥多种生物学功能，包括钙及脂质运输、细胞自噬、线粒体分裂及线粒体DNA分布等。然而，这种互作的动态调控机制、生理及病理功能尚不清楚，需要进一步深入探索和研究。我们前期研究发现Sam50和Mic19是线粒体内外膜接触调控关键蛋白，它们在线粒体与内质网偶联膜组分MAM中含量丰富，并且可调控线粒体与内质网互作。因此，本项目将以线粒体内外膜接触为出发点，利用建立的线粒体研究平台系统研究线粒体内外膜接触调控线粒体与内质网互作的分子机制及相关生物学功能；此外，利用课题组已有的Mic19条件性基因敲除小鼠去建立Mic19肝特异性基因敲除小鼠，深入研究Mic19缺失引起的线粒体与内质网互作紊乱在肝脏疾病发生发展中的作用。此项目的实施对于阐明线粒体与内质网互作的信号调控通路及其相关肝病发病机制具有重要意义。

线粒体与内质网互作是发挥多种生物学功能，包括钙及脂质运输、细胞自噬、线粒体分裂及线粒体DNA分布等。然而，这种互作的动态调控机制、生理及病理功能尚不清楚，需要进一步深入探索和研究。本项目以线粒体内外膜接触为出发点，利用建立的线粒体研究平台系统研究线粒体内外膜接触调控线粒体-内质网互作的分子机制及相关生理病理功能。此项目研究发现Sam50-Mic19-Mic60轴线介导线粒体内外膜接触，发现Sam50和Mic19在线粒体与内质网偶联膜组分MAM中含量丰富，并且调控线粒体-内质网互作；进一步研究发现Mic19-SLC25A46-EMC2轴调控内质网-线粒体之间的磷脂酸的转运。另外，我们构建了Mic19肝特异性基因敲除小鼠，发现Mic19肝特异性敲除诱发小鼠脂肪肝。此项目的研究成果对于阐明线粒体-内质网互作的信号调控通路及其相关肝病发病机制具有重要意义，在脂肪肝相关药物的筛选及临床应用方面具有重要价值。