Dissecting the role of mitochondrial translation defects in ageing

• Applicant: Professorin Dr. Aleksandra Trifunovic
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2011 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190865702

Although mitochondria have long been anticipated as a perpetrator of ageing, there was little experi-mental evidence to link these changes directly with the cellular pathology of ageing. Recently, we have made a considerable progress in understanding basic role of acquired mtDNA mutations in ageing by generating the mtDNA mutator mice. The creation ofmtDNA-mutator mice has provided the first direct evidence that accelerating mtDNA mutationrate can result in premature ageing, consistent with the view that loss of mitochondrialfunction is a major causal factor in ageing. Furthermore, we have shown that there is no direct connection between increased mtDNA mutation load and elevated ROS production, arguing against a direct role of oxidative stress in the ageing process. Our latest results strongly argue that the observed phenotypes are a direct consequence of the accumulation of mtDNA point mutations. We propose that even though mtDNA mutator mice randomlyaccumulate point mutations, these mutations would have a deleterious impact primarily on the protein-coding genes.The aim of this research proposal is to further test this hypothesis by making, both Caenorhabditis elegans and mouse models that will have increased amount of amino acidsubstitutions in mtDNA protein coding genes without having additional effects on mtDNAmaintenance or integrity and no effect on mtDNA encoded tRNA and rRNA genes. For this, we will use a recently described mitochondrial translation factor GUF1 with a unique functionof a fidelity factor for mitochondrial protein synthesis. Moreover, these will be the first knock -out models in both worms and mice for a mitochondrial translational factor and therefore will broaden our knowledge on this fundamental process. We believe that the suggested project is of great importance from both a basic science and a medical perspective and will provide new insights into the ageing process in general.

• DFG Programme: Research Grants