Mfn2调控的线粒体网络在晶状体衰老中的作用与机制研究

线粒体融合蛋白2（Mfn2）位于线粒体外膜，是动态调控线粒体融合的关键蛋白，并参与线粒体、内质网、溶酶体之间的信号通讯，在衰老等生命活动中发挥重要的作用。项目前期工作发现：老年小鼠晶状体内Mfn2的表达水平降低；Mfn2基因在晶状体内敲除可致小鼠晶状体混浊、线粒体内质网的胞内分布发生变化，但机制不清。本项目拟从Mfn2调控晶状体细胞的线粒体网络入手，以研究Mfn2影响线粒体-内质网-溶酶体间信号通讯及物质转运为核心，利用最新的Mfn2基因可诱导敲除小鼠模型，对Mfn2影响线粒体及细胞器间信号及物质传递、导致mtDNA突变、干扰细胞能量代谢等，最终导致晶状体细胞衰老这一病理过程进行从表型、亚细胞结构到分子机理的研究。本研究有助于深入理解线粒体及相关细胞器间通讯在决定晶状体细胞代谢、衰老与细胞命运中的重要作用，有助于从亚细胞结构调控的角度寻找年龄相关性白内障治疗与预防的新靶点。

Mitochondrial fusion protein 2 (Mfn2) located at the outer mitochondrial membrane. It is a key protein that regulates the mitochondria outer membrane fusion and participates in crosstalk between mitochondria, endoplasmic reticulum(ER) and lysosome, and plays an important role in cellular metabolism such as aging. Our previous work indicated that Mfn2 expression decreased in the lens of elderly mice; knocked out Mfn2 gene in lens could lead to lens opacity and changed mitochondria- endoplasmic reticulum(ER) distributio . The mechanism is still unclear. On this basis, we mainly focus on investigating the mechanism of Mfn2 regulating the inter-mitochondrial network of lens cells, and the function of Mfn2 in mitochondrial-ER-lysosome crosstalk and signal transportation. This research intends to build inducible conditional knockout mice animal model to observe the function of Mfn2 on signal transduction between mitochondria and organelles, mtDNA mutations, interferes with cellular energy metabolism, etc, and ultimately leads to lens cell senescence. In this project, the pathological process is studied from phenotype, subcellular structure and molecular mechanism. This study helps to understand the important role of crosstalk between mitochondria and related organelles in determining lens cell metabolism, aging and cell fate, and helps to find new target for the treatment and prevention of age-related cataracts from the perspective of subcellular structure regulation .