title: Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  We show thatEpac1(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 ofEpac1in its mitochondrial-targeting sequence protects against hypoxia/reoxygenation-induced cell death. Mechanistically, Epac1 favors Ca2+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 Ca2+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 (Ca2+/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.
authors.affiliation: 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.).
authors.forename: Loubina
authors.initials: L
authors.lastname: Fazal
authors.affiliation: 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.).
authors.forename: Marion
authors.initials: M
authors.lastname: Laudette
authors.affiliation: 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.).
authors.forename: Sílvia
authors.initials: S
authors.lastname: Paula-Gomes
authors.affiliation: 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.).
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pons
authors.affiliation: 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.).
authors.forename: Caroline
authors.initials: C
authors.lastname: Conte
authors.affiliation: 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.).
authors.forename: Florence
authors.initials: F
authors.lastname: Tortosa
authors.affiliation: 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.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Sicard
authors.affiliation: 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.).
authors.forename: Yannis
authors.initials: Y
authors.lastname: Sainte-Marie
authors.affiliation: 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.).
authors.forename: Malik
authors.initials: M
authors.lastname: Bisserier
authors.affiliation: 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.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Lairez
authors.affiliation: 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.).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lucas
authors.affiliation: 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.).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roy
authors.affiliation: 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.).
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.affiliation: 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.).
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.affiliation: 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.).
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mialet-Perez
authors.affiliation: 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.). Frank.Lezoualch@inserm.fr.
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors
keywords: calcium; cyclic AMP; ischemia reperfusion injury; mitochondria; reactive oxygen species