Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death
| Autor: | Jérôme Roy, Alexandre Lucas, Marion Laudette, Bijan Ghaleh, Olivier Lairez, Florence Tortosa, Caroline Conte, Yannis Sainte-Marie, Pierre Sicard, Malik Bisserier, Frank Lezoualc'h, Sandrine Pons, Sílvia Paula-Gomes, Loubina Fazal, Jeanne Mialet-Perez, Jérémy Fauconnier |
|---|---|
| Přispěvatelé: | Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), MORNET, Dominique |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Programmed cell death Physiology [SDV]Life Sciences [q-bio] Mitochondrion Biology Mitochondria Heart Mice 03 medical and health sciences chemistry.chemical_compound Membrane Microdomains [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system Ca2+/calmodulin-dependent protein kinase medicine Animals Guanine Nucleotide Exchange Factors Humans Myocytes Cardiac cyclic AMP Cells Cultured ComputingMilieux_MISCELLANEOUS Heart Failure Mice Knockout reactive oxygen species ischemia reperfusion injury calcium Cell Death medicine.disease Rats [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system Cell biology mitochondria 030104 developmental biology Animals Newborn chemistry Mitochondrial permeability transition pore Second messenger system Cardiology and Cardiovascular Medicine VDAC1 Reperfusion injury Nicotinamide adenine dinucleotide phosphate |
| Zdroj: | Circulation Research Circulation Research, American Heart Association, 2017, 120 (4), pp.645-657. ⟨10.1161/CIRCRESAHA.116.309859⟩ Circulation Research, 2017, 120 (4), pp.645-657. ⟨10.1161/CIRCRESAHA.116.309859⟩ |
| ISSN: | 0009-7330 1524-4571 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|