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         headline:A cardiac mitochondrial cAMP signaling pathway regulates calcium accumulation, permeability transition and cell death
         description:Although cardiac cytosolic cyclic 3′,5′-adenosine monophosphate (cAMP) regulates multiple processes, such as beating, contractility, metabolism and apoptosis, little is known yet on the role of this second messenger within cardiac mitochondria. Using cellular and subcellular approaches, we demonstrate here the local expression of several actors of cAMP signaling within cardiac mitochondria, namely a truncated form of soluble AC (sACt) and the exchange protein directly activated by cAMP 1 (Epac1), and show a protective role for sACt against cell death, apoptosis as well as necrosis in primary cardiomyocytes. Upon stimulation with bicarbonate (HCO3−) and Ca2+, sACt produces cAMP, which in turn stimulates oxygen consumption, increases the mitochondrial membrane potential (ΔΨm) and ATP production. cAMP is rate limiting for matrix Ca2+ entry via Epac1 and the mitochondrial calcium uniporter and, as a consequence, prevents mitochondrial permeability transition (MPT). The mitochondrial cAMP effects involve neither protein kinase A, Epac2 nor the mitochondrial Na+/Ca2+ exchanger. In addition, in mitochondria isolated from failing rat hearts, stimulation of the mitochondrial cAMP pathway by HCO3− rescued the sensitization of mitochondria to Ca2+-induced MPT. Thus, our study identifies a link between mitochondrial cAMP, mitochondrial metabolism and cell death in the heart, which is independent of cytosolic cAMP signaling. Our results might have implications for therapeutic prevention of cell death in cardiac pathologies.
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      headline:A cardiac mitochondrial cAMP signaling pathway regulates calcium accumulation, permeability transition and cell death
      description:Although cardiac cytosolic cyclic 3′,5′-adenosine monophosphate (cAMP) regulates multiple processes, such as beating, contractility, metabolism and apoptosis, little is known yet on the role of this second messenger within cardiac mitochondria. Using cellular and subcellular approaches, we demonstrate here the local expression of several actors of cAMP signaling within cardiac mitochondria, namely a truncated form of soluble AC (sACt) and the exchange protein directly activated by cAMP 1 (Epac1), and show a protective role for sACt against cell death, apoptosis as well as necrosis in primary cardiomyocytes. Upon stimulation with bicarbonate (HCO3−) and Ca2+, sACt produces cAMP, which in turn stimulates oxygen consumption, increases the mitochondrial membrane potential (ΔΨm) and ATP production. cAMP is rate limiting for matrix Ca2+ entry via Epac1 and the mitochondrial calcium uniporter and, as a consequence, prevents mitochondrial permeability transition (MPT). The mitochondrial cAMP effects involve neither protein kinase A, Epac2 nor the mitochondrial Na+/Ca2+ exchanger. In addition, in mitochondria isolated from failing rat hearts, stimulation of the mitochondrial cAMP pathway by HCO3− rescued the sensitization of mitochondria to Ca2+-induced MPT. Thus, our study identifies a link between mitochondrial cAMP, mitochondrial metabolism and cell death in the heart, which is independent of cytosolic cAMP signaling. Our results might have implications for therapeutic prevention of cell death in cardiac pathologies.
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            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:D Liu
      affiliation:
            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:A Varin
      affiliation:
            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:V Nicolas
      affiliation:
            name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay
            address:
               name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:D Courilleau
      affiliation:
            name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay
            address:
               name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:P Mateo
      affiliation:
            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:C Caubere
      affiliation:
            name:INSERM I2MC, UMR 1048, Université Paul Sabatier
            address:
               name:INSERM I2MC, UMR 1048, Université Paul Sabatier, Toulouse, France
               type:PostalAddress
            type:Organization
      name:P Rouet
      affiliation:
            name:INSERM I2MC, UMR 1048, Université Paul Sabatier
            address:
               name:INSERM I2MC, UMR 1048, Université Paul Sabatier, Toulouse, France
               type:PostalAddress
            type:Organization
      name:A-M Gomez
      affiliation:
            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:G Vandecasteele
      affiliation:
            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:R Fischmeister
      affiliation:
            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
            name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay
            address:
               name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      name:C Brenner
      affiliation:
            name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay
            address:
               name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
            name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay
            address:
               name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:INSERM I2MC, UMR 1048, Université Paul Sabatier, Toulouse, France
      name:INSERM I2MC, UMR 1048, Université Paul Sabatier, Toulouse, France
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
      name:UMS–IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France

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