Hypertension-associated mitochondrial DNA 4401A > G mutation caused the aberrant processing of tRNA(Met), all 8 tRNAs and ND6 mRNA in the light-strand transcript
Hypertension-associated mitochondrial DNA 4401A > G mutation caused the aberrant processing of tRNA(Met), all 8 tRNAs and ND6 mRNA in the light-strand transcript
复制标题
高血压相关线粒体 DNA 4401A > G 突变导致轻链转录物中 tRNA(Met)、所有 8 种 tRNA 和 ND6 mRNA 的异常加工
DOI：
10.1093/nar/gkz742
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发表时间：
2019
影响因子：
14.9
通讯作者：
Guan MX
中科院分区：
文献类型：
--
作者：
Zhao X;Cui L;Xiao Y;Mao Q;Aishanjiang M;Kong W;Liu Y;Chen H;Hong F;Jia Z;Wang M;Jiang P;Guan MX
线粒体tRNA加工缺陷与人类疾病有关，但其病理生理机制尚不清楚。高血压相关的m.4401A >g突变位于线粒体trnamet和trnaggene之间的间隔区。Anin体外加工实验显示，m.4401A >g突变导致trnagland和trnamet前体在RNase P催化下的5 '端加工效率分别降低59%和69%。利用人脐静脉内皮细胞衍生的细胞系，我们证明了m.4401A >g突变导致所有8个trna和ND6的减少，和光链转录物中较长和未切割的前体的增加。相反，m.4401A >g突变导致tRNAMetlevel水平降低，但没有改变重链转录物中其他13种tRNAs、12种mrna的水平，包括ND1、12S rRNA和16S rRNA。这暗示了h链和l链多反链转录本的不对称加工机制。tRNA加工缺陷在线粒体翻译受损、呼吸缺陷、膜电位降低、活性氧产生增加和自噬改变中起着确定的作用。此外，m.4401A >g突变改变了血管生成，在突变细胞系中表现为伤口再生异常和管形成减弱。我们的研究结果为线粒体tRNA加工缺陷引起的高血压的病理生理学提供了新的见解。
Mitochondrial tRNA processing defects were associated with human diseases but their pathophysiology remains elusively. The hypertension-associated m.4401A>G mutation resided at a spacer between mitochondrial tRNAMetand tRNAGlngenes. Anin vitroprocessing experiment revealed that the m.4401A>G mutation caused 59% and 69% decreases in the 5′ end processing efficiency of tRNAGlnand tRNAMetprecursors, catalyzed by RNase P, respectively. Using human umbilical vein endothelial cells-derived cybrids, we demonstrated that the m.4401A>G mutation caused the decreases of all 8 tRNAs and ND6 and increases of longer and uncleaved precursors from the Light-strand transcript. Conversely, the m.4401A>G mutation yielded the reduced levels of tRNAMetlevel but did not change the levels of other 13 tRNAs, 12 mRNAs including ND1, 12S rRNA and 16S rRNA from the Heavy-strand transcript. These implicated the asymmetrical processing mechanisms of H-strand and L-strand polycistronic transcripts. The tRNA processing defects play the determined roles in the impairing mitochondrial translation, respiratory deficiency, diminishing membrane potential, increasing production of reactive oxygen species and altering autophagy. Furthermore, the m.4401A>G mutation altered the angiogenesis, evidenced by aberrant wound regeneration and weaken tube formation in mutant cybrids. Our findings provide new insights into the pathophysiology of hypertension arising from mitochondrial tRNA processing defects.