Role of the MICU1-MCU interaction in the Mitochondrial Ca2+ Regulation during ischemia-reperfusion injury – MitoCaRe

We will combine innovative live fluorescent imaging microscopy, proteomic analyses and in vivo model of myocardial infarction up to the translational level in isolated human cardiomyocytes from non-failing and failing patients.

Our first results suggest an alteration of mitochondrial Ca2+ uptake in the early post-ischemic reperfusion, followed by a deleterious remodeling of the uniporter composition at long term.

We are currently pursuing our investigation of the underlying mechanims to develop new drugs.

Brun et al., Archives of Cardiovasc Dis Supp 2021, doi.org/10.1016/j.acvdsp.2021.04.126

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.