Dysregulation of the DNA/RNA-binding protein FUS causes certain subtypes of ALS/FTD by largely unknown mechanisms. Recent evidence has shown that FUS toxic gain of function due either to mutations or to increased expression can disrupt critical cellular processes, including mitochondrial functions. Here, we demonstrate that in human cells overexpressing wild-type FUS or expressing mutant derivatives, the protein associates with multiple mRNAs, and these are enriched in mRNAs encoding mitochondrial respiratory chain components. Notably, this sequestration leads to reduced levels of the encoded proteins, which is sufficient to bring about disorganized mitochondrial networks, reduced aerobic respiration and increased reactive oxygen species. We further show that mutant FUS associates with mitochondria and with mRNAs encoded by the mitochondrial genome. Importantly, similar results were also observed in fibroblasts derived from ALS patients with FUS mutations. Finally, we demonstrate that FUS loss of function does not underlie the observed mitochondrial dysfunction, and also provides a mechanism for the preferential sequestration of the respiratory chain complex mRNAs by FUS that does not involve sequence-specific binding. Together, our data reveal that respiratory chain complex mRNA sequestration underlies the mitochondrial defects characteristic of ALS/FTD and contributes to the FUS toxic gain of function linked to this disease spectrum.

中文翻译：

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ALS / FTD相关蛋白FUS通过优先隔离呼吸链复合物mRNA诱导线粒体功能障碍。

DNA / RNA结合蛋白FUS的失调通过很大程度上未知的机制导致ALS / FTD的某些亚型。最近的证据表明，由于突变或表达增加而引起的FUS毒性功能增强会破坏关键的细胞过程，包括线粒体功能。在这里，我们证明了在人类细胞中，过表达野生型FUS或表达突变衍生物的蛋白质中，蛋白质与多个mRNA缔合，并且富含编码线粒体呼吸链成分的mRNA。明显地，这种螯合导致编码蛋白的水平降低，这足以引起线粒体网络混乱，降低了有氧呼吸并增加了活性氧。我们进一步表明，突变FUS与线粒体和线粒体基因组编码的mRNA相关。重要的是，在具有FUS突变的ALS患者的成纤维细胞中也观察到了相似的结果。最后，我们证明FUS功能丧失不构成观察到的线粒体功能障碍的基础，并且还为FUS优先隔离呼吸链复合物mRNA提供了一种机制，该机制不涉及序列特异性结合。在一起，我们的数据表明呼吸链复合物mRNA螯合是ALS / FTD的线粒体缺陷特征的基础，并有助于FUS与该疾病谱有关的功能的毒性增加。我们证明FUS功能丧失不构成观察到的线粒体功能障碍的基础，并且还为FUS优先隔离呼吸链复合物mRNA提供了一种机制，该机制不涉及序列特异性结合。在一起，我们的数据表明呼吸链复合物mRNA螯合是ALS / FTD的线粒体缺陷特征的基础，并有助于FUS与该疾病谱有关的功能的毒性增加。我们证明FUS功能丧失不构成观察到的线粒体功能障碍的基础，并且还为FUS优先隔离呼吸链复合物mRNA提供了一种机制，该机制不涉及序列特异性结合。在一起，我们的数据表明呼吸链复合物mRNA螯合是ALS / FTD的线粒体缺陷特征的基础，并有助于FUS与该疾病谱有关的功能的毒性增加。