Objective The need for mitochondria in the body is ubiquitous yet the shapes these organelles take vary widely across tissues and change rapidly in response to nutrient availability. How and why this occurs is not well understood. Therefore, we propose an interdisciplinary research program that will investigate the molecular basis and metabolic regulation of mitochondrial morphology. Mitochondrial morphology is defined by opposing events of fission and fusion, which must be tightly controlled. We discovered that accelerated mitochondrial fission impairs cardiac metabolism and causes heart failure in mice, revealing an intriguing link between mitochondrial dynamics and metabolism. Seeking to understand how metabolic signals drive mitochondrial fission, we will characterize the inner membrane protein MTP18, whose fission activity is controlled by the PI3K nutrient-signalling pathway. First, we will define the interactome of MTP18 to discover the molecular components of the inner membrane fission machinery. Second, we will investigate the how mitochondrial fission is regulated by PI3K nutrient-signalling pathway the heart, liver, and kidney. We will determine whether cardiac dysfunction, liver cancer, and kidney failure caused by over-active PI3K signalling in the mouse can be rescued by blunting the downstream activity of MTP18 and re-balancing mitochondrial dynamics. Third, we will determine the disease relevance of mitochondrial fission in humans. For the first time, mitochondrial morphology from patient-derived cells will be evaluated in automated, high content screens to identify human mutations that drive imbalanced mitochondrial dynamics in a truly unbiased manner. Genome-wide RNAi screens in these cells will reveal novel modulators of mitochondrial dynamics. Taken together, this work aims to understand the metabolic pathways that control mitochondrial morphology and to develop a new technology to identify yet unknown modulators of mitochondrial dynamics. Fields of science medical and health sciencesbasic medicineanatomy and morphologynatural sciencesbiological sciencescell biologycell signalingnatural sciencesbiological sciencescell biologycell metabolismnatural sciencesbiological sciencesmolecular biologymolecular neuroscience Keywords Mitochondrial dynamics metabolism Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2016-STG - ERC Starting Grant Call for proposal ERC-2016-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Host institution CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS Net EU contribution € 1 375 000,00 Address RUE MICHEL ANGE 3 75794 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations 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 € 1 375 000,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS France Net EU contribution € 1 375 000,00 Address RUE MICHEL ANGE 3 75794 Paris See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations 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 € 1 375 000,00