Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations
Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations
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DOI：
10.1016/j.expneurol.2008.01.010
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发表时间：
2008-05-01
影响因子：
5.3
通讯作者：
Shaw, Janet M.
中科院分区：
文献类型：
--
作者：
Amiott, Elizabeth A.;Lott, Paul;Shaw, Janet M.
Charcot-Marie-Tooth 2A型是一种显性遗传性周围神经病，其特征是感觉和运动神经的轴突变性。这种疾病是由线粒体融合基因MFN 2突变引起的。Mfn 2是一种完整的线粒体外膜蛋白，由一个大的GT3结构域和两个面向细胞质的七肽重复（HR）结构域组成。线粒体膜融合和分裂是维持管状线粒体形态、呼吸功能和细胞器在整个细胞中均匀分布所必需的平衡过程。我们利用CMT 2A患者的原代成纤维细胞来调查与在生理水平表达的杂合MFN 2等位基因相关的线粒体表型。我们的研究结果表明，在成纤维细胞中，线粒体融合蛋白的表达，线粒体形态，超微结构，mtDNA含量和呼吸能力不受突变Mfh 2蛋白的存在。与缺乏线粒体功能障碍一致，我们还表明线粒体融合有效地发生在CMT 2A患者来源的成纤维细胞中。我们的观察结果与该疾病的神经元特异性一致，并且与最近的一项发现一致，即线粒体融合可以在表达突变型Mfh 2蛋白的细胞中维持，这是由于第二种线粒体融合蛋白Mfn 1的互补作用。我们讨论了我们的结果和其他人在一个全面的模型的机制（S）MFN 2突变可能导致CMT 2A疾病。(C)2008年爱思唯尔公司All rights reserved.
Charcot-Marie-Tooth Type 2A is a dominantly inherited peripheral neuropathy characterized by axonal degeneration of sensory and motor nerves. The disease is caused by mutations in the mitochondrial fusion gene MFN2. Mfn2 is an integral outer mitochondrial membrane protein composed of a large GTPase domain and two heptad repeat (HR) domains that face the cytoplasm. Mitochondrial membrane fusion and division are balanced processes that are necessary to maintain tubular mitochondrial morphology, respiratory function, and uniform distribution of the organelle throughout the cell. We have utilized primary fibroblasts from CMT2A patients to survey mitochondrial phenotypes associated with heterozygous MFN2 alleles expressed at physiological levels. Our results indicate that, in fibroblasts, mitofusin expression, mitochondrial morphology, ultrastructure, mtDNA content, and respiratory capacity are not affected by the presence of mutant Mfh2 protein. Consistent with a lack of mitochondrial dysfunction, we also show that mitochondrial fusion occurs efficiently in CMT2A patient-derived fibroblasts. Our observations are in agreement with the neuronal specificity of the disease and are consistent with a recent finding that mitochondrial fusion can be maintained in cells that express mutant Mfh2 protein due to complementation by a second mitofusin, Mfn1. We discuss our results and those of others in terms of a comprehensive model for the mechanism(s) by which mutations in MFN2 may lead to CMT2A disease. (C) 2008 Elsevier Inc. All rights reserved.