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Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity

Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cy...

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Autores principales: Laudette, Marion, Sainte-Marie, Yannis, Cousin, Grégoire, Bergonnier, Dorian, Belhabib, Ismahane, Brun, Stéphanie, Formoso, Karina, Laib, Loubna, Tortosa, Florence, Bergoglio, Camille, Marcheix, Bertrand, Borén, Jan, Lairez, Olivier, Fauconnier, Jérémy, Lucas, Alexandre, Mialet-Perez, Jeanne, Moro, Cédric, Lezoualc’h, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410846/
https://www.ncbi.nlm.nih.gov/pubmed/34471096
http://dx.doi.org/10.1038/s41419-021-04113-9
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author Laudette, Marion
Sainte-Marie, Yannis
Cousin, Grégoire
Bergonnier, Dorian
Belhabib, Ismahane
Brun, Stéphanie
Formoso, Karina
Laib, Loubna
Tortosa, Florence
Bergoglio, Camille
Marcheix, Bertrand
Borén, Jan
Lairez, Olivier
Fauconnier, Jérémy
Lucas, Alexandre
Mialet-Perez, Jeanne
Moro, Cédric
Lezoualc’h, Frank
author_facet Laudette, Marion
Sainte-Marie, Yannis
Cousin, Grégoire
Bergonnier, Dorian
Belhabib, Ismahane
Brun, Stéphanie
Formoso, Karina
Laib, Loubna
Tortosa, Florence
Bergoglio, Camille
Marcheix, Bertrand
Borén, Jan
Lairez, Olivier
Fauconnier, Jérémy
Lucas, Alexandre
Mialet-Perez, Jeanne
Moro, Cédric
Lezoualc’h, Frank
author_sort Laudette, Marion
collection PubMed
description Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cyclase in cardiomyocytes. cAMP further induced exchange protein directly activated by cyclic AMP 1 (Epac1) activation, which was upregulated in the myocardium of obese patients. Epac1 enhanced the activity of a key enzyme regulating mitochondrial FA uptake, carnitine palmitoyltransferase 1. Consistently, pharmacological or genetic Epac1 inhibition prevented lipid overload, increased FA oxidation (FAO), and protected against mitochondrial dysfunction in cardiomyocytes. In addition, analysis of Epac1 phosphoproteome led us to identify two key mitochondrial enzymes of the the β-oxidation cycle as targets of Epac1, the long-chain FA acyl-CoA dehydrogenase (ACADL) and the 3-ketoacyl-CoA thiolase (3-KAT). Epac1 formed molecular complexes with the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), which phosphorylated ACADL and 3-KAT at specific amino acid residues to decrease lipid oxidation. The Epac1-CaMKII axis also interacted with the α subunit of ATP synthase, thereby further impairing mitochondrial energetics. Altogether, these findings indicate that Epac1 disrupts the balance between mitochondrial FA uptake and oxidation leading to lipid accumulation and mitochondrial dysfunction, and ultimately cardiomyocyte death.
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spelling pubmed-84108462021-09-22 Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity Laudette, Marion Sainte-Marie, Yannis Cousin, Grégoire Bergonnier, Dorian Belhabib, Ismahane Brun, Stéphanie Formoso, Karina Laib, Loubna Tortosa, Florence Bergoglio, Camille Marcheix, Bertrand Borén, Jan Lairez, Olivier Fauconnier, Jérémy Lucas, Alexandre Mialet-Perez, Jeanne Moro, Cédric Lezoualc’h, Frank Cell Death Dis Article Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cyclase in cardiomyocytes. cAMP further induced exchange protein directly activated by cyclic AMP 1 (Epac1) activation, which was upregulated in the myocardium of obese patients. Epac1 enhanced the activity of a key enzyme regulating mitochondrial FA uptake, carnitine palmitoyltransferase 1. Consistently, pharmacological or genetic Epac1 inhibition prevented lipid overload, increased FA oxidation (FAO), and protected against mitochondrial dysfunction in cardiomyocytes. In addition, analysis of Epac1 phosphoproteome led us to identify two key mitochondrial enzymes of the the β-oxidation cycle as targets of Epac1, the long-chain FA acyl-CoA dehydrogenase (ACADL) and the 3-ketoacyl-CoA thiolase (3-KAT). Epac1 formed molecular complexes with the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), which phosphorylated ACADL and 3-KAT at specific amino acid residues to decrease lipid oxidation. The Epac1-CaMKII axis also interacted with the α subunit of ATP synthase, thereby further impairing mitochondrial energetics. Altogether, these findings indicate that Epac1 disrupts the balance between mitochondrial FA uptake and oxidation leading to lipid accumulation and mitochondrial dysfunction, and ultimately cardiomyocyte death. Nature Publishing Group UK 2021-09-01 /pmc/articles/PMC8410846/ /pubmed/34471096 http://dx.doi.org/10.1038/s41419-021-04113-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Laudette, Marion
Sainte-Marie, Yannis
Cousin, Grégoire
Bergonnier, Dorian
Belhabib, Ismahane
Brun, Stéphanie
Formoso, Karina
Laib, Loubna
Tortosa, Florence
Bergoglio, Camille
Marcheix, Bertrand
Borén, Jan
Lairez, Olivier
Fauconnier, Jérémy
Lucas, Alexandre
Mialet-Perez, Jeanne
Moro, Cédric
Lezoualc’h, Frank
Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
title Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
title_full Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
title_fullStr Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
title_full_unstemmed Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
title_short Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
title_sort cyclic amp-binding protein epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410846/
https://www.ncbi.nlm.nih.gov/pubmed/34471096
http://dx.doi.org/10.1038/s41419-021-04113-9
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