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Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death
Open accessAbstract
Rationale: Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood. Objective: To investigate the role of MitEpac1 (mitochondrial exchange protein directly activated by cAMP 1) in ischemia/reperfusion injury. Methods and Results: We show that Epac1 (exchange protein directly activated by cAMP 1) genetic ablation ( Epac1 −/− ) protects against experimental myocardial ischemia/reperfusion injury with reduced infarct size and cardiomyocyte apoptosis. As observed in vivo, Epac1 inhibition prevents hypoxia/reoxygenation–induced adult cardiomyocyte apoptosis. Interestingly, a deleted form of Epac1 in its mitochondrial-targeting sequence protects against hypoxia/reoxygenation–induced cell death. Mechanistically, Epac1 favors Ca 2+ exchange between the endoplasmic reticulum and the mitochondrion, by increasing interaction with a macromolecular complex composed of the VDAC1 (voltage-dependent anion channel 1), the GRP75 (chaperone glucose-regulated protein 75), and the IP3R1 (inositol-1,4,5-triphosphate receptor 1), leading to mitochondrial Ca 2+ overload and opening of the mitochondrial permeability transition pore. In addition, our findings demonstrate that MitEpac1 inhibits isocitrate dehydrogenase 2 via the mitochondrial recruitment of CaMKII (Ca 2+ /calmodulin-dependent protein kinase II), which decreases nicotinamide adenine dinucleotide phosphate hydrogen synthesis, thereby, reducing the antioxidant capabilities of the cardiomyocyte. Conclusions: Our results reveal the existence, within mitochondria, of different cAMP–Epac1 microdomains that control myocardial cell death. In addition, our findings suggest Epac1 as a promising target for the treatment of ischemia-induced myocardial damage.
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“Finally, rap guanine nucleotide exchange factor 3 (RAPGEF3; best known as EPAC1) appears to trigger PTPC opening by increasing mitochondrial Ca2+ levels through interaction with VDAC1, heat shock protein family A (Hsp70) member 9 (HSPA9; best known as GRP75), and inositol 1,4,5-trisphosphate receptor type 1 (ITPR1; best known as IP3R1), and the knockout of Rapgef3 protects mice against myocardial”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [421]
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Metadata
- Authors
- Fazal, L., Laudette, M., Paula-Gomes, S., Pons, S., Conte, C., Tortosa, F., Sicard, P., Sainte-Marie, Y., Bisserier, M., Lairez, O., Lucas, A., Roy, J., Ghaleh, B., Fauconnier, J., Mialet-Perez, J., & Lezoualc’h, F.
- Affiliations
- Inserm (FR)
- From the Inserm, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France (L.F., M.L., S.P.-G., C.C., F.T., P.S., Y.S.-M., M.B., O.L., A.L., J.M.-P., F.L.); Université de Toulouse, France (L.F., M.L., S.P.-G., C.C., F.T., P.S., Y.S.-M., M.B., O.L., A.L., J.M.-P., F.L.); Inserm, U955, Equipe 03, F-94000, Créteil, France (S.P., B.G.), and Inserm, UMR-1046 (J.R., J.F.); and UMR CNRS-9214, PHYMEDEX, Université de Montpellier, France (J.R., J.F.).
- Corresponding author
- Fazal, Loubina
- Laudette, Marion
- ORCID
- Venue
- Circulation Research
- Published
- 2017-02-17
- Volume
- 120
- Issue
- 4
- Pages
- 645-657
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2577171598
- Cited by
- 111
- References
- 42
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 13 · 2023: 11 · 2022: 9 · 2021: 16 · 2020: 12 · 2019: 15 · 2018: 20 · 2017: 5
- FWCI
- 11.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Fondation de France
- Université de Toulouse
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- Epac1, myocardial ischemia-reperfusion injury, cardiomyocyte apoptosis, mitochondrial calcium overload, VDAC1, GRP75, IP3R1, mitochondrial permeability transition pore, IDH2, CaMKII, NADPH production, hypoxia/reoxygenation, mitochondrial targeting sequence
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, Heart Failure, Humans, Male, Mitochondria, Heart, Cell Death, Mice, Knockout, Guanine Nucleotide Exchange Factors, Membrane Microdomains, Myocytes, Cardiac, Mice, Rats
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