PDF(Pubmed)
Abstract：
Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (TRNT1), the nuclear gene encoding the CCA-adding enzyme essential for modifying both nuclear and mitochondrial tRNAs, causes a multisystemic and clinically heterogenous disease termed SIFD (sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SIFD). However, it is not clear how mutations in a general and essential protein like TRNT1 cause disease with such clinically broad but unique symptomatology and tissue involvement. Using biochemical, cell, and mass spectrometry approaches, we demonstrate that TRNT1 deficiency is associated with sensitivity to oxidative stress, which is due to exacerbated, angiogenin-dependent cleavage of tRNAs. Furthermore, reduced levels of TRNT1 lead to phosphorylation of Eukaryotic Translation Initiation Factor 2 Subunit Alpha (eIF2α), increased reactive oxygen species (ROS) production, and changes in the abundance of distinct proteins. Our data suggest that the observed variable SIFD phenotypes are likely due to dysregulation of tRNA maturation and abundance, which in turn negatively affects the translation of distinct proteins.
摘要：
线粒体疾病是由线粒体功能失调引起的一组异质性疾病。有趣的是,大部分线粒体疾病是由与tRNA代谢相关的基因缺陷引起的。我们最近发现tRNA核苷酸转移酶1（TRNT1）的部分功能丧失突变，编码对修饰核和线粒体tRNAs至关重要的CCA添加酶的核基因，引起多系统和临床异质性疾病，称为SIFD（具有B细胞免疫缺陷的铁粒母细胞性贫血，周期性发烧,和发育迟缓；SIFD）。然而,目前尚不清楚TRNT1等一般和必需蛋白的突变如何导致具有如此广泛的临床症状和组织受累的疾病.利用生化，cell,和质谱方法，我们证明TRNT1缺乏与对氧化应激的敏感性有关，这是由于加剧，血管生成素依赖性的tRNA裂解。此外，TRNT1水平降低导致真核翻译起始因子2亚基α（eIF2α）磷酸化，增加活性氧（ROS）的产生，以及不同蛋白质丰度的变化。我们的数据表明，观察到的可变SIFD表型可能是由于tRNA成熟和丰度的失调，这反过来对不同蛋白质的翻译产生负面影响。
