Project description DEENESFRITPL Tissue-specific outcomes of mitochondrial malfunction Mitochondria are remarkable organelles that possess their own DNA, responsible for encoding a limited number of proteins synthesised exclusively within the mitochondria. However, most mitochondrial proteins are encoded by nuclear DNA and synthesised in the cytoplasm before being transported into the mitochondria. Funded by the European Research Council, the MISTRANSMITO project aims to explore the interplay between cytoplasmic and mitochondrial protein synthesis and its impact on mitochondrial function. Researchers will investigate tissue-specific effects of mistranslation and associated stress responses through a systems biology approach. Project findings will provide a better understanding of mitochondrial diseases and pave the way for novel interventions. Show the project objective Hide the project objective Objective Mitochondria play a central role in the energy metabolism of our bodies and their defects give rise to a large variety of clinical phenotypes that can affect practically any tissue. The mechanisms for the tissue-specific outcomes of mitochondrial diseases are poorly understood. Mitochondrial energy production relies on two separate protein synthesis machineries, cytoplasmic and mitochondrial, but the mechanisms regulating the concerted actions between the two are largely to be discovered. Defects in either protein synthesis system that lead to accumulation of mistranslated mitochondrial proteins, intrinsic or imported from the cytoplasm, result in stress signals from mitochondria and in adaptive responses within the organelle and the entire cell. My hypothesis is that some of these signals and adaptive mechanisms are tissue-specific. My group will test the hypothesis by 1) generating and characterizing mouse models of cytoplasmic and mitochondrial mistranslation to be able to address our questions in different tissues. 2) We will develop methods for detection of ribosome stalling in mouse tissues to identify the consequences of mistranslation for individual proteins. 3) We will use systems biology approaches to identify stress signal responses to mitochondrial and/or cytoplasmic mistranslation using different tissues of our models, to identify those that are unique or global. 4) Our previous study has identified an interesting candidate responder to mistranslation stress and we will test the role of this factor in knockout animal models and by crossing with the mistranslation mice. I expect to gain important new knowledge of in vivo responses to mistranslation and execution of quality control. This proposal investigates key questions in understanding differential tissue involvement in metabolic defects, and will provide new directions for utilization of tissue-specific adaptations in finding interventions for mitochondrial diseases. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acidsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteins Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-StG-2014 - ERC Starting Grant Call for proposal ERC-2014-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Host institution HELSINGIN YLIOPISTO Net EU contribution € 1 354 507,50 Address YLIOPISTONKATU 3 00014 Helsingin Yliopisto Finland See on map Region Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 354 507,50 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all HELSINGIN YLIOPISTO Finland Net EU contribution € 1 354 507,50 Address YLIOPISTONKATU 3 00014 Helsingin Yliopisto See on map Region Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 354 507,50