Mitochondrial transport of catalytic RNAs and targeting of the organellar transcriptome in human cells.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-01-17 DOI:10.1093/jmcb/mjad051
Paweł Głodowicz, Konrad Kuczyński, Romain Val, André Dietrich, Katarzyna Rolle
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Abstract

Mutations in the small genome present in mitochondria often result in severe pathologies. Different genetic strategies have been explored, aiming to rescue such mutations. A number of these strategies were based on the capacity of human mitochondria to import RNAs from the cytosol and designed to repress the replication of the mutated genomes or to provide the organelles with wild-type versions of mutant transcripts. However, the mutant RNAs present in mitochondria turned out to be an obstacle to therapy and little attention has been devoted so far to their elimination. Here, we present the development of a strategy to knockdown mitochondrial RNAs in human cells using the transfer RNA-like structure of Brome mosaic virus or Tobacco mosaic virus as a shuttle to drive trans-cleaving ribozymes into the organelles in human cell lines. We obtained a specific knockdown of the targeted mitochondrial ATP6 mRNA, followed by a deep drop in ATP6 protein and a functional impairment of the oxidative phosphorylation chain. Our strategy provides a powerful approach to eliminate mutant organellar transcripts and to analyse the control and communication of the human organellar genetic system.

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线粒体运输催化 RNA 和人体细胞内细胞器转录组的靶向。
线粒体中的小基因组发生突变往往会导致严重的病变。人们探索了不同的遗传策略,旨在挽救这种突变。其中一些策略基于人类线粒体从细胞质导入 RNA 的能力,旨在抑制突变基因组的复制,或为细胞器提供突变转录本的野生型版本。然而,线粒体中存在的突变 RNA 是治疗的障碍,迄今为止,人们很少关注如何消除这些突变 RNA。在这里,我们介绍了一种在人体细胞中敲除线粒体 RNA 的策略,该策略利用 Brome mosaic 病毒或烟草花叶病毒的类转移 RNA 结构作为穿梭器,将反式裂解核糖酶驱动到人体细胞系的细胞器中。我们特异性地敲除了目标线粒体 ATP6 mRNA,随后 ATP6 蛋白深度下降,氧化磷酸化链功能受损。我们的策略为消除突变细胞器转录本和分析人类细胞器遗传系统的控制与交流提供了一种强有力的方法。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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