Myocardial infarction remains a frequent and disabling disease with still no therapeutic strategy to mitigate the risk of developing heart failure. The mitochondrial Ca2+ uniporter represents the key structure which controls Ca2+ entry inside mitochondria and therefore a relevant target upstream of the mitochondrial Ca2+ overload to modulate not only cell death but also mitochondrial bioenergetics and Ca2+ homeostasis. The PI recently identified the interaction site between the Ca2+-sensing regulator MICU1, with MCU, the pore forming protein of the uniporter, required to control the Ca2+ flux and in fine cell survival. Based on this evidence, we postulate that a loss of mitochondrial Ca2+ uptake regulation by MICU1 would be the key trigger of mitochondrial Ca2+ overload-induced cell death during ischemia-reperfusion. In this project, we aim at determining the molecular mechanisms controlling the MICU1-MCU interaction during ischemia-reperfusion in order to mimic the regulation of MCU by MICU1 as a new therapeutic target in mitochondrial Ca2+ overload diseases, such as myocardial infarction. Our hypothesis will be tested through three original tasks from molecular to whole animal scale, up to the translational level in human cells: Task 1: Decipher the mechanistic role of the MICU1-MCU interaction during ischemia-reperfusion (IR) Task 2: Examine the modulation of the MICU1/MCU interaction during IR Task 3: Investigate the medical relevance of MICU1 mimicking as a therapeutic strategy We believe that the MitoCaRe research program will provide new potential protective molecules against mitochondrial Ca2+ overload-induced pathologies such as myocardial infarction and stroke, which could further be extended to the neuromuscular degenerative diseases field.