Role of the MFN2650G>T/C217F mutation in CMT2A fibroblasts

This study investigated mitochondrial dynamics, respiratory capacity, and autophagy/mitophagy, to tackle the multifaceted MFN2 contribution to CMT2A pathogenesis. Transcriptomic analysis of mutated fibroblasts highlighted marked differentially expressed pathways related to cell population proliferation and extracellular matrix organization. The activation of mTORC2/AKT signaling andaccelerated proliferation was consistently found in the CMT2AMFN2 fibroblasts. The study provides the first evidence that CMT2AMFN2 fibroblasts harbor functionally impaired mitochondria that do not accumulate despite a defect of the initial steps of autophagy while performing an acceleration of cell division. So far, MFN2 is considered a tumor suppressor gene in various types of cancer, to our knowledge, this is the first report of increased proliferation of CMT2A patients' fibroblasts driven by MFN2 mutation.

本研究围绕线粒体动力学、呼吸容量及自噬/线粒体自噬展开探究，旨在阐明线粒体融合蛋白2（Mitofusin 2, MFN2）在2A型腓骨肌萎缩症（Charcot-Marie-Tooth disease type 2A, CMT2A）发病机制中的多维度作用。对携带MFN2突变的成纤维细胞进行转录组分析后发现，与细胞群体增殖及细胞外基质组织相关的差异表达通路显著富集。在携带MFN2突变的CMT2A成纤维细胞中，mTORC2/AKT信号通路的激活与细胞增殖加速现象均持续存在。本研究首次证实，携带MFN2突变的CMT2A成纤维细胞存在功能受损的线粒体；尽管其自噬起始步骤存在缺陷，但线粒体并未发生异常蓄积，且细胞分裂进程显著加速。迄今为止，MFN2在多种癌症中被认为是抑癌基因；据我们所知，本研究首次报道了由MFN2突变驱动的CMT2A患者成纤维细胞增殖增强现象。