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弗里德赖希共济失调（FRDA）是常见的遗传性共济失调，是一种终生常染色体隐性遗传性神经退行性疾病，由共济蛋白遗传缺陷引起的。共济蛋白是一种对Fe / S团簇形成和生物能量学至关重要的线粒体蛋白。FRDA的发生可能与线粒体功能障碍有关。线粒体动力学通过在细胞中单个线粒体细胞器或互连网络的融合和裂变的协调循环作用，在生物能量、代谢，细胞分裂和细胞凋亡中起关键作用。然而，FRDA中线粒体动力学与共济蛋白的病理生理作用尚不清楚。本研究旨在探讨共济蛋白功能及其功能障碍是否与FRDA中的线粒体动力学相关。

研究人员使用针对内源性线粒体标记物GRP75和转染的mito-GFP免疫荧光法检测FRDA患者和健康者的原代成纤维细胞中线粒体网络的形态。随后使用mito-DsRed2和mito-PAGFP共转染成纤维细胞，在共聚焦显微镜下对线粒体融合/裂变情况进行实时延时成像，采用免疫共沉淀，双免疫细胞化学染色和蛋白质重叠实验评估共济蛋白与线粒体裂变蛋白和磷脂的关系。

主要研究结果：在FRDA患者成纤维细胞中，线粒体网络过于分散，不能融合在一起。共济蛋白基因敲除可显著增加对照组成纤维细胞线粒体网络的断裂，而过高表达则可减少患者成纤维细胞的断裂。此外，免疫共沉淀和蛋白质-脂质重叠分析表明，共济蛋白与线粒体分裂蛋白Drp 1和磷脂酸相互作用，它们是协调线粒体融合/分裂平衡的核心成分。另外，共济蛋白基因敲除显著增加了人成纤维细胞线粒体网络分裂位点上磷酸-Drp 1（Ser 616）活性形式的水平和簇数。

结论：该研究结果提示，在FRDA发病机制中，共济蛋白缺乏会导致线粒体Drp1和磷脂酸过度断裂，而磷脂酸是控制线粒体融合/裂变平衡的核心成分，从而将FRDA的功能和功能障碍与线粒体动力学联系起来。

Title: Frataxin deficiency causes excessive mitochondrial fragmentation associated with mitochondrial fission core components

Authors: Joseph Johnson, Elisia Clark, Elizabeth Mercado-Ayon, David Lynch, Hong Lin

Objective: To investigate if frataxin function and dysfunction is associated with mitochondrial dynamics in FRDA.

Background: Friedreich ataxia (FRDA), the most common inherited ataxia, is a life shortening autosomal recessive neurodegenerative disease caused by a genetic deficiency of frataxin, a mitochondrial protein crucial for Fe/S cluster formation and bioenergetics. Mitochondrial dysfunction has thus been suggested in FRDA. Mitochondrial dynamics play crucial roles in bioenergetics, metabolism, cell division and apoptosis through coordinated cycles of fusion and fission of individual mitochondrial organelles or interconnected networks in cells. However, the pathophysiological role of frataxin in association with mitochondrial dynamics in FRDA remains largely unknown.

Design/Methods: The morphology of the mitochondrial network in primary fibroblasts derived from FRDA patients and healthy individuals were examined using immunofluorescence to endogenous mitochondrial marker GRP75 and transfected mito-GFP. Live time-lapse imaging was performed using cotransfection of mito-DsRed2 and mitophotoactivable GFP into fibroblasts to monitor mitochondrial fusion/fission under confocal microscopy. Coimmunoprecipitation,double immunocytochemical staining and protein-overlay assays were performed to examine the association of frataxin with mitochondrial fission protein and phospholipids.

Results: The mitochondrial network is excessively fragmented and fails to fuse together in FRDA patient fibroblasts. Knockdown of frataxin significantly increases fragmentation of mitochondrial network in control fibroblasts, whereas overexpression of frataxin decreases fragmentation in patient fibroblasts. Furthermore, coimmunoprecipitation and protein-lipid overlay assays show that frataxin interacts with mitochondrial fission protein Drp1 and phosphatidic acid, the core components that coordinate mitochondrial fusion/fission balance. Moreover, frataxin knockdown significantly increases the levels and the clusters of active form of phospho-Drp1 (Ser616) at the fission sites of mitochondrial network in human fibroblasts.

Conclusions: Our findings thus demonstrate that frataxin deficiency causes excessive mitochondrial fragmentation associated with Drp1 and phosphatidic acid, the core components controlling mitochondrial fusion/fission balance, thereby linking frataxin function and dysfunction with mitochondrial dynamics in FRDA pathogenesis.

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