A cardiac mitochondrial cAMP signaling pathway regulates calcium accumulation, permeability transition and cell death.
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 Ca(2+), sACt produces cAMP, which in turn stimulates oxygen consumption, increases the mitochondrial membrane potential (ΔΨm) and ATP production. cAMP is rate limiting for matrix Ca(2+) 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(+)/Ca(2+) exchanger. In addition, in mitochondria isolated from failing rat hearts, stimulation of the mitochondrial cAMP pathway by HCO3(-) rescued the sensitization of mitochondria to Ca(2+)-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.
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
Z
Z
Wang
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
D
D
Liu
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
A
A
Varin
UMS-IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
V
V
Nicolas
UMS-IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
D
D
Courilleau
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
P
P
Mateo
INSERM I2MC, UMR 1048, Université Paul Sabatier, Toulouse, France.
C
C
Caubere
INSERM I2MC, UMR 1048, Université Paul Sabatier, Toulouse, France.
P
P
Rouet
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
A-M
AM
Gomez
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
G
G
Vandecasteele
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.|UMS-IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
R
R
Fischmeister
INSERM UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.|UMS-IPSIT, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
C
C
Brenner
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001639:Bicarbonates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002166:Camptothecin / Q000633:toxicity; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D003609:Dactinomycin / Q000633:toxicity; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D019210:Troponin I / Q000378:metabolism
D001639:Bicarbonates; D020662:Guanine Nucleotide Exchange Factors; C526973:Rapgef3 protein, rat; D019210:Troponin I; D003609:Dactinomycin; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D002118:Calcium; D002166:Camptothecin