FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism.
FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism.
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果蝇的FARS2缺陷表现为发育迟缓和癫痫发作，表现为线粒体tRNA代谢异常。
DOI：
10.1093/nar/gkab1187
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发表时间：
2021-12-16
影响因子：
14.9
通讯作者：
Ge W
中科院分区：
文献类型：
--
作者：
Fan W;Jin X;Xu M;Xi Y;Lu W;Yang X;Guan MX;Ge W
编码线粒体氨酰-tRNA合成酶的基因突变与多种疾病有关。然而，这些突变影响线粒体功能和疾病发展的确切机制尚未完全了解。在这里，我们开发了一个果蝇模型来研究dFARS 2的功能，dFARS 2是线粒体苯丙氨酰-tRNA合成酶的果蝇同源物，并进一步表征人类疾病相关的FARS 2变体。果蝇中dFARS 2的失活导致发育延迟和癫痫发作。生化研究表明，dFARS 2是必需的线粒体tRNA氨酰化，线粒体蛋白质的稳定性，组装和酶活性的OXPHOS复合物。有趣的是，通过模拟果蝇中与人类疾病相关的FARS 2突变，我们提供了两种人类FARS 2变体p.G309S和p.D142Y的表达分别诱导癫痫发作行为和运动缺陷的证据。总之，我们的研究结果不仅显示了线粒体氨酰化系统功能障碍与病理之间的关系，而且还说明了果蝇模型在人类致病变异体功能分析中的应用。
Mutations in genes encoding mitochondrial aminoacyl-tRNA synthetases are linked to diverse diseases. However, the precise mechanisms by which these mutations affect mitochondrial function and disease development are not fully understood. Here, we develop a Drosophila model to study the function of dFARS2, the Drosophila homologue of the mitochondrial phenylalanyl–tRNA synthetase, and further characterize human disease-associated FARS2 variants. Inactivation of dFARS2 in Drosophila leads to developmental delay and seizure. Biochemical studies reveal that dFARS2 is required for mitochondrial tRNA aminoacylation, mitochondrial protein stability, and assembly and enzyme activities of OXPHOS complexes. Interestingly, by modeling FARS2 mutations associated with human disease in Drosophila, we provide evidence that expression of two human FARS2 variants, p.G309S and p.D142Y, induces seizure behaviors and locomotion defects, respectively. Together, our results not only show the relationship between dysfunction of mitochondrial aminoacylation system and pathologies, but also illustrate the application of Drosophila model for functional analysis of human disease-causing variants.
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