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

• Applicant: Dr. Ina Kirmes
• Subject Area: General Genetics and Functional Genome Biology ; Cell Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409522241

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.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Steven Zuryn, Ph.D.