A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase.
A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase.
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DOI：
10.1242/dmm.019323
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Rand DM
中科院分区：
文献类型：
--
作者：
Holmbeck MA;Donner JR;Villa-Cuesta E;Rand DM
线粒体和核基因组之间的通讯对细胞功能至关重要。线粒体酶复合物的组装产生大部分细胞能量，需要细胞和核编码蛋白的协调表达和翻译。该系统的联合遗传结构使线粒体疾病的基础复杂化，并且线粒体DNA（mtDNA）和核编码基因中的突变都与线粒体功能障碍有关。在此之前，在一组细胞核渐渗株，我们的特点是一个双基因组上位性，其中自然发生的突变在果蝇simulans simw 501 mtDNA编码的酪氨酸转移RNA（tRNA）（tRNATyr）与突变的核编码的神经本地化的酪氨酸-tRNA合成酶从果蝇相互作用。在这里，我们表明，不兼容的神经细胞核的组合导致运动缺陷，线粒体呼吸能力降低，氧化磷酸化（OXPHOS）酶活性降低和线粒体形态的严重改变。含有酪氨酰-tRNA合成酶的核变体的转基因拯救菌株足以拯救与simw 501 mtDNA配对时鉴定的许多有害表型。然而，这种有缺陷的线粒体-核相互作用的严重程度在性状和遗传背景中各不相同，这表明线粒体功能障碍的影响可能是组织特异性的。由于线粒体tRNATyr的突变与人类的运动不耐受相关，果蝇中的这种细胞核基因渗入模型提供了一种方法来剖析这些和其他线粒体疾病的分子基础，这些疾病是线粒体功能的联合遗传结构的结果。总结：细胞编码的tRNA和核编码的tRNA合成酶中的相互作用突变导致一系列病理，包括改变的运动能力、线粒体功能和形态以及线粒体翻译。
Communication between the mitochondrial and nuclear genomes is vital for cellular function. The assembly of mitochondrial enzyme complexes, which produce the majority of cellular energy, requires the coordinated expression and translation of both mitochondrially and nuclear-encoded proteins. The joint genetic architecture of this system complicates the basis of mitochondrial diseases, and mutations both in mitochondrial DNA (mtDNA)- and nuclear-encoded genes have been implicated in mitochondrial dysfunction. Previously, in a set of mitochondrial-nuclear introgression strains, we characterized a dual genome epistasis in which a naturally occurring mutation in the Drosophila simulans simw501 mtDNA-encoded transfer RNA (tRNA) for tyrosine (tRNATyr) interacts with a mutation in the nuclear-encoded mitochondrially localized tyrosyl-tRNA synthetase from Drosophila melanogaster. Here, we show that the incompatible mitochondrial-nuclear combination results in locomotor defects, reduced mitochondrial respiratory capacity, decreased oxidative phosphorylation (OXPHOS) enzyme activity and severe alterations in mitochondrial morphology. Transgenic rescue strains containing nuclear variants of the tyrosyl-tRNA synthetase are sufficient to rescue many of the deleterious phenotypes identified when paired with the simw501 mtDNA. However, the severity of this defective mito-nuclear interaction varies across traits and genetic backgrounds, suggesting that the impact of mitochondrial dysfunction might be tissue specific. Because mutations in mitochondrial tRNATyr are associated with exercise intolerance in humans, this mitochondrial-nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other, mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function. Summary: Interacting mutations in a mitochondrially encoded tRNA and nuclear-encoded tRNA synthetase result in a suite of pathologies, including altered locomotor capacity, mitochondrial function and morphology, and mitochondrial translation.