CMT2A是MFN2突变所导致的最常见的遗传性轴索性周围神经病，MFN2突变如何导致CMT2A发病是近年来的研究热点。本项目组前期研究发现轴索内线粒体变圆、变小以及分布异常是CMT2A的主要病理改变特点，提示存在线粒体动力学异常，在轴索病变的过程中发挥重要作用，但具体机制不明。根据MFN2蛋白的功能，本研究提出基因突变通过抑制线粒体间连接、线粒体-溶酶体连接以及破坏线粒体-内质网连接而致使线粒体从溶酶体、内质网中摄取Ca2+减少，导致线粒体Ca2+失衡以及产生ATP水平下降，引起线粒体轴索分布异常和发病。以MFN2基因突变转染细胞为模型，探索突变对线粒体间连接、线粒体-溶酶体连接、线粒体-内质网连接、线粒体内钙离子浓度以及线粒体轴索运输分布和轴索病变的影响，这对阐明MFN2基因突变导致CMT2A轴索内线粒体分布异常及其发病的机制具有重要意义，也将为CMT2A的治疗提供新的理论依据。

Charcot-Marie-Tooth type 2A(CMT2A) is the most common hereditary axonal peripheral neuropathy caused by Mitofusin 2 gene (MFN2) mutations. The mechanism of how MFN2 mutations cause the pathogenesis of CMT2A is a hot topic in recent years. Previous studies found that rounding, shrinking and abnormal distribution of mitochondria in axons are the main pathological characteristics of CMT2A, suggesting that mitochondrial dynamics abnormality plays an important role in the pathogenesis of axonal lesions, but the specific mechanism is unknown. According to the function of MFN2, this study proposes that gene mutations reduce mitochondrial Ca2+ uptake from lysosomes and endoplasmic reticulum by inhibiting mitochondrial tethering, mitochondrial-lysosomal contact, and disrupting mitochondrial-endoplasmic reticulum tethering, leading to mitochondrial Ca2+ imbalances and decreased ATP levels cause abnormal mitochondrial axonal distribution. Using MFN2 gene mutation-transfected cells as a model to explore the effects of mutations on mitochondrial tethering, mitochondrial-lysosomal contact and mitochondrial-endoplasmic reticulum tethering, mitochondrial calcium concentrations, axonal transport distribution, and axonal lesions. It is of great significance to clarify the mechanism of the abnormal mitochondrial distribution in CMT2A axons caused by mutations in MFN2 gene and its pathogenesis. It will also provide a new theoretical basis for the treatment of CMT2A.