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

线粒体是代谢活动的重要枢纽，通过氧化磷酸化（OXPHOS）产生细胞的大部分能量。作为其细菌起源的祖先遗迹，线粒体保留了编码组装OXPHOS酶复合物所必需的关键基因的小的环状基因组（mtDNA）。线粒体基因组的健康对于细胞能量生产和复杂生命至关重要。遗传性mtDNA损伤导致严重的代谢性疾病，而获得性mtDNA突变已被提出在一生中积累，有助于晚发型退行性疾病的进行性。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损伤的致病作用，然而对两个基因组之间的潜在信号传导机制知之甚少。在这里，我发现，小ncRNA，特别是microRNA（miRNA），作为线粒体和核基因组之间的接口，通过积极响应线粒体DNA分子损伤秀丽隐杆线虫。线粒体DNA的损伤是由组织特异性表达的内切酶Pst I引起的。elegans诱导miR-35家族和miR-71的成员，先前发现它们分别在氧气和营养缺乏时以及在衰老期间上调。由小ncRNA介导的表观遗传信号可能提供快速、可逆和全身性的保护作用。使用我和我的宿主实验室为这个项目开发的一套最先进的遗传工具，我将确定小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是否在细胞间传递线粒体基因组的状态。

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.