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

Our hypothesis was tested from the molecular level to the animal level, with a translational application to human cells. We combined innovative imaging experiments, proteomic analyses, and in vivo models of myocardial infarction with a translational approach using patient samples—heart and blood cells.

Using this approach, we demonstrate uniporter protein remodeling in the hearts of heart failure patients, leading to an increased MICU1/MCU ratio. This could act as compensation to limit Ca2+ influx into the mitochondria and thus mitochondrial calcium overload; however, it also leads to maladaptation by limiting mitochondrial bioenergetics necessary for proper cardiomyocyte contractile function. Interestingly, we also observed an alteration in the uniporter structure of blood cells from patients after a myocardial infarction.

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

This project has resulted in five publications and literature reviews. We also conducted five public outreach activities on this topic. Furthermore, the results obtained have led to the exploration of new research avenues, for which funding has been secured. Finally, this «Young Researcher« project has enabled the coordinating researcher to develop her own research area, network, and team.

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.