Flavin adenine dinucleotide rescues the phenotype of frataxin deficiency.
Flavin adenine dinucleotide rescues the phenotype of frataxin deficiency.
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DOI：
10.1371/journal.pone.0008872
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发表时间：
2010-01-25
期刊：
影响因子：
3.7
通讯作者：
Palau F
中科院分区：
文献类型：
--
作者：
Gonzalez-Cabo P;Ros S;Palau F
Friedreich共济失调是一种由于缺乏线粒体蛋白Frataxin而引起的神经退行性疾病。我们先前证明Frataxin与电子转运链(ETC)的复合II亚基和可能的电子转移黄素蛋白相互作用，提示Frataxin可能参与氧化磷酸化。在此，我们研究了核黄素及其辅因子黄素腺嘌呤二核苷酸(FAD)和黄素单核苷酸(FMN)在酿酒酵母和秀丽线虫Frataxin缺乏模型中的作用。我们使用了一株通过同源重组获得的yfh1基因缺失的酿酒酵母菌株，并评估了在添加核黄素或其衍生物的可发酵和非发酵培养物中的生长情况。通过将dsRNA FRH-1显微注射到幼虫的性腺中产生的瞬时击倒虫(FRH-1[RNAi])，对线虫进行了实验。我们观察到，FAD挽救了这两种缺陷生物的表型。结果表明，FAD能促进YFH1Δ细胞的生长、ETC复合体的酶活性和三磷酸腺苷的产生。此外，FAD还改善了线虫Frataxin基因敲除模型中的寿命和其他生理参数。我们认为补充FAD可以通过改善线粒体呼吸来挽救Frataxin缺乏症。我们认为核黄素在治疗Friedreich共济失调方面可能是有用的。
Friedreich ataxia is a neurodegenerative disease caused by the lack of frataxin, a mitochondrial protein. We previously demonstrated that frataxin interacts with complex II subunits of the electronic transport chain (ETC) and putative electronic transfer flavoproteins, suggesting that frataxin could participate in the oxidative phosphorylation. Here we have investigated the effect of riboflavin and its cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in Saccharomyces cerevisiae and Caenorhabditis elegans models of frataxin deficiency. We used a S. cerevisiae strain deleted for the yfh1 gene obtained by homologous recombination and we assessed growth in fermentable and non-fermentable cultures supplemented with either riboflavin or its derivates. Experiments with C. elegans were performed in transient knock-down worms (frh-1[RNAi]) generated by microinjection of dsRNA frh-1 into the gonads of young worms. We observed that FAD rescues the phenotype of both defective organisms. We show that cell growth and enzymatic activities of the ETC complexes and ATP production of yfh1Δ cells were improved by FAD supplementation. Moreover, FAD also improved lifespan and other physiological parameters in the C. elegans knock-down model for frataxin. We propose that rescue of frataxin deficiency by FAD supplementation could be explained by an improvement in mitochondrial respiration. We suggest that riboflavin may be useful in the treatment of Friedreich ataxia.
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