Unravelling a small non-coding RNA interface between the mitochondrial and nuclear genomes

解开线粒体和核基因组之间的小型非编码RNA界面

• 批准号: 409522241
• 负责人: Dr. Ina Kirmes
• 金额: --
• 依托单位: Queensland Brain Institute
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/409522241?language=en
• 关键词: Unravelling; small; non; coding; RNA

Mitochondria are a remarkable hub of metabolic activity, generating the majority of the cell’s energy through oxidative phosphorylation (OXPHOS). As an ancestral vestige of their bacterial origin, mitochondria retain a small circular genome (mtDNA) that encodes the key genes necessary for the assembly of the OXPHOS enzymatic complexes. The health of the mitochondrial genome is critical for cellular energy production and complex life. Inherited mtDNA lesions result in severe metabolic disease, whereas acquired mtDNA mutations have been proposed to accumulate during the lifetime, contributing to the progressive nature of late-onset degenerative diseases. Cells are able to sense, respond, and counter the pathogenic effects of mtDNA damage by readapting metabolism through nuclear gene expression changes, however the underlying signalling mechanisms between the two genomes are poorly understood. Here, I have discovered that small ncRNAs, in particular microRNAs (miRNAs), act as an interface between the mitochondrial and nuclear genomes, by actively responding to mtDNA molecular lesion in Caenorhabditis elegans. mtDNA damage caused by the tissue-specific expression of the endonuclease PstI in the mitochondria of the body wall muscle in C. elegans induces members of the miR-35 family and miR-71 which were previously found to be upregulated upon oxygen and nutrient shortage as well as during ageing, respectively. Epigenetic signalling mediated by small ncRNAs may offer rapid, reversible, and systemic protective effects. Using a set of state-of-the-art genetic tools that I and my host laboratory have developed for this project, I will determine how small ncRNAs are activated in response to mtDNA damage and whether they can counteract its effects. Furtermore, I will test whether small ncRNAs act to communicate the status of the mitochondrial genome intercellularly.

线粒体是代谢活动的重要中心，通过氧化磷酸化 (OXPHOS) 产生细胞的大部分能量。作为细菌起源的祖先遗迹，线粒体保留了一个小的环状基因组 (mtDNA)，该基因组编码 OXPHOS 酶复合物组装所需的关键基因。线粒体基因组的健康对于细胞能量产生和复杂生命至关重要。遗传性线粒体DNA损伤会导致严重的代谢性疾病，而获得性线粒体DNA突变被认为会在一生中积累，从而导致迟发性退行性疾病的进展。细胞能够通过核基因表达变化重新适应代谢来感知、响应和对抗 mtDNA 损伤的致病效应，然而，两个基因组之间的潜在信号机制尚不清楚。在这里，我发现小 ncRNA，特别是 microRNA (miRNA)，通过主动响应秀丽隐杆线虫的 mtDNA 分子损伤，充当线粒体和核基因组之间的接口。线虫体壁肌肉线粒体中核酸内切酶 PstI 的组织特异性表达引起的 mtDNA 损伤会诱导 miR-35 家族和 miR-71 成员的产生，此前发现这些成员在缺氧和营养缺乏以及衰老过程中分别上调。由小 ncRNA 介导的表观遗传信号可能提供快速、可逆和系统性的保护作用。使用我和我的宿主实验室为该项目开发的一套最先进的遗传工具，我将确定小型 ncRNA 如何响应 mtDNA 损伤而被激活，以及它们是否可以抵消其影响。此外，我将测试小 ncRNA 是否能够在细胞间传达线粒体基因组的状态。