Role of the mitochondria-sarcoplasmic reticulum interactions during ischemia-reperfusion and cardioprotection: GSK3ß inhibition as a potential clinical target – CARDIOCARE
According to the World Health Organization, cardiovascular diseases are the leading cause of death worldwide, with the majority due to coronary heart diseases. It is expected that by 2030, almost 23.6 million people will die from coronary heart diseases. Understanding the underlying mechanisms thus represents a great challenge for basic scientists. Despite major progress in experimental reperfusion therapy, virtually no intervention has shown clearly protective effects against ischemia-reperfusion (IR) injury in the clinical setting, indicating that reevaluation of existing or development of new modalities to protect the heart from IR injury is urgently needed. Accumulating evidence indicates that reperfusion caused irreversible myocardial damage, possibly through a form of mitochondrial dysfunction named permeability transition. Although calcium (Ca2+) overload and excessive production of reactive oxygen species in the early minutes of reflow have been shown to trigger a nonspecific high-conductance channel (mitochondrial permeability-transition pore, PTP), its regulation is still unclear during reperfusion.
Mitochondria and sarco/endoplasmic reticulum (SR/ER) have fundamental roles in energy production and Ca2+ transport, which are central in physiopathological functions of the cardiac muscle. Their involvement during myocardial IR begins to be recognized but the underlying mechanisms are not yet well understood. Recently the host lab and others demonstrated that mitochondria-SR/ER interaction sites allow mitochondria to sense SR/ER stress through local delivery of Ca2+ and other signaling entities. We have identified several proteins enriched at the SR/ER-mitochondria interface, including cyclophilin D (CypD) and glycogen synthase kinase 3 beta (GSK3ß), two potential PTP regulators, with functional and structural significance, thus highlighting the emerging role of this region within the cell.
The general objective of this research program is to understand the role and mechanisms of the physical and functional Ca2+ coupling between SR/ER and mitochondria in the regulation of PTP during cardioprotection and to propose GSK3ß inhibition as a new therapeutic for patients ongoing acute myocardial infarction (AMI). Based on our recent study, we hypothesize that decreasing SR/ER-mitochondria Ca2+ transfer by targeting GSK3ß will promote cardioprotection after IR by preventing mitochondrial Ca2+ overload through the reduction of the local Ca2+ transfer from SR/ER to mitochondria. To determine the underlying mechanisms, Ca2+ imaging and proteomics will be conducted in both human and mice isolated cardiomyocytes.
Thanks to the complementarity of the PI expertise with the host lab environment, we believe that this translational project might help to better understand the physiopathology and to identify new molecular targets for the treatment of cardiovascular diseases.
Monsieur Ludovic Gomez (Institut National de la Sante et de la Recherche Medicale)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM Institut National de la Sante et de la Recherche Medicale
Help of the ANR 343,200 euros
Beginning and duration of the scientific project: September 2016 - 36 Months