Human mitochondrial disease-like symptoms caused by a reduced tRNA aminoacylation activity in flies
Human mitochondrial disease-like symptoms caused by a reduced tRNA aminoacylation activity in flies
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DOI：
10.1093/nar/gkt402
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发表时间：
2013-07-01
影响因子：
14.9
通讯作者：
Ribas de Pouplana, Lluis
中科院分区：
文献类型：
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作者：
Guitart, Tanit;Picchioni, Daria;Ribas de Pouplana, Lluis
编码在线粒体基因组中的基因的翻译需要在细胞器中起作用的特定机制。在与影响线粒体翻译的人类疾病相关的许多突变中，有几个定位于编码线粒体氨酰转移RNA合成酶的核基因。这些突变的分子意义知之甚少，但预计与影响线粒体转移RNA的突变相似。为了更好地了解这些突变引起的疾病的分子特征，并改善其诊断和治疗，我们构建了一个果蝇模型，通过RNA干扰破坏线粒体丝氨酸-tRNA合成酶。在分子水平上，敲低产生转移RNA丝氨酸化的减少，这与观察到的表型的严重性相关。沉默损害生存力、寿命、运动性和组织发育。在细胞水平，敲低改变线粒体形态，生物发生和功能，并诱导乳酸酸中毒和活性氧积累。我们报告说，抗氧化剂化合物的管理有姑息性的影响，这些表型。总之，在这项工作中产生的苍蝇模型再现了线粒体氨酰化系统突变引起的病理学的典型特征，并可用于评估治疗方法。
The translation of genes encoded in the mitochondrial genome requires specific machinery that functions in the organelle. Among the many mutations linked to human disease that affect mitochondrial translation, several are localized to nuclear genes coding for mitochondrial aminoacyl-transfer RNA synthetases. The molecular significance of these mutations is poorly understood, but it is expected to be similar to that of the mutations affecting mitochondrial transfer RNAs. To better understand the molecular features of diseases caused by these mutations, and to improve their diagnosis and therapeutics, we have constructed a Drosophila melanogaster model disrupting the mitochondrial seryl-tRNA synthetase by RNA interference. At the molecular level, the knockdown generates a reduction in transfer RNA serylation, which correlates with the severity of the phenotype observed. The silencing compromises viability, longevity, motility and tissue development. At the cellular level, the knockdown alters mitochondrial morphology, biogenesis and function, and induces lactic acidosis and reactive oxygen species accumulation. We report that administration of antioxidant compounds has a palliative effect of some of these phenotypes. In conclusion, the fly model generated in this work reproduces typical characteristics of pathologies caused by mutations in the mitochondrial aminoacylation system, and can be useful to assess therapeutic approaches.