Mutations in Mitofusin2 (MFN2) associated with the pathology of the debilitating neuropathy Charcot–Marie–Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. Previously, such mutations have been shown to elicit two diametrically opposite phenotypes – while some mutations have been causally linked to enhanced mitochondrial fragmentation, others have been shown to induce hyperfusion. Our study identifies one such MFN2 mutant, T206I that causes mitochondrial hyperfusion. Cells expressing this MFN2 mutant have elongated and interconnected mitochondria. T206I-MFN2 mutation in the GTPase domain increases MFN2 stability and renders cells susceptible to stress. We show that cells expressing T206I-MFN2 have a higher predisposition towards mitophagy under conditions of serum starvation. We also detect increased DRP1 recruitment onto the outer mitochondrial membrane, though the total DRP1 protein level remains unchanged. Here we have characterized a lesser studied CMT2A-linked MFN2 mutant to show that its presence affects mitochondrial morphology and homeostasis.

已知与衰弱性夏科-玛丽-图斯 2A 型神经病 (CMT2A) 病理学相关的线粒体融合蛋白 2 (MFN2) 突变会改变线粒体形态。此前，此类突变已被证明会引发两种截然相反的表型——虽然一些突变与线粒体碎片增强有因果关系，但其他突变已被证明会诱导过度融合。我们的研究发现了一种这样的 MFN2 突变体 T206I，它会导致线粒体过度融合。表达这种 MFN2 突变体的细胞具有拉长且相互连接的线粒体。 GTPase 结构域中的 T206I-MFN2 突变会增加 MFN2 的稳定性，并使细胞对压力敏感。我们发现表达 T206I-MFN2 的细胞在血清饥饿条件下具有更高的线粒体自噬倾向。我们还检测到线粒体外膜上的 DRP1 招募增加，但总 DRP1 蛋白水平保持不变。在这里，我们对一个研究较少的 CMT2A 连接 MFN2 突变体进行了表征，以表明它的存在会影响线粒体形态和稳态。