title: Regulation of autophagy by cytosolic acetyl-coenzyme A.
abstract: Acetyl-coenzyme A (AcCoA) is a major integrator of the nutritional status at the crossroads of fat, sugar, and protein catabolism. Here we show that nutrient starvation causes rapid depletion of AcCoA. AcCoA depletion entailed the commensurate reduction in the overall acetylation of cytoplasmic proteins, as well as the induction of autophagy, a homeostatic process of self-digestion. Multiple distinct manipulations designed to increase or reduce cytosolic AcCoA led to the suppression or induction of autophagy, respectively, both in cultured human cells and in mice. Moreover, maintenance of high AcCoA levels inhibited maladaptive autophagy in a model of cardiac pressure overload. Depletion of AcCoA reduced the activity of the acetyltransferase EP300, and EP300 was required for the suppression of autophagy by high AcCoA levels. Altogether, our results indicate that cytosolic AcCoA functions as a central metabolic regulator of autophagy, thus delineating AcCoA-centered pharmacological strategies that allow for the therapeutic manipulation of autophagy.
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mariño
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Pietrocola
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8036 Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Shoaib Ahmad
authors.initials: SA
authors.lastname: Malik
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8036 Graz, Austria.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Andryushkova
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8036 Graz, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schroeder
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8036 Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pendl
authors.affiliation: Institute of Medical Technologies and Health Management, Joanneum Research, 8036 Graz, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Harger
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Mireia
authors.initials: M
authors.lastname: Niso-Santano
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Naoufal
authors.initials: N
authors.lastname: Zamzami
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Scoazec
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France.
authors.forename: Silvère
authors.initials: S
authors.lastname: Durand
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France.
authors.forename: David P
authors.initials: DP
authors.lastname: Enot
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo 33006, Spain.
authors.forename: Álvaro F
authors.initials: ÁF
authors.lastname: Fernández
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martins
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.affiliation: Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France; INSERM U845, 75014 Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Bauvy
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Morselli
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Vacchelli
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Bennetzen
authors.affiliation: Institute of Medical Technologies and Health Management, Joanneum Research, 8036 Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.affiliation: Institute of Medical Technologies and Health Management, Joanneum Research, 8036 Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Sinner
authors.affiliation: Institute of Medical Technologies and Health Management, Joanneum Research, 8036 Graz, Austria; Medical University of Graz, Division of Endocrinology and Metabolism, Department of Internal Medicine, 8036 Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pieber
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo 33006, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Maiuri
authors.affiliation: Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France; INSERM U845, 75014 Paris, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Codogno
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark.
authors.forename: Jens S
authors.initials: JS
authors.lastname: Andersen
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8036 Graz, Austria. Electronic address: frank.madeo@uni-graz.at.
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.affiliation: Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France. Electronic address: kroemer@orange.fr.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000105:Acetyl Coenzyme A / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology* / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007656:Ketoglutaric Acids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D007656:Ketoglutaric Acids; D034741:RNA, Small Interfering; C541783:dimethyl alpha-ketoglutarate; D049452:Green Fluorescent Proteins; D000105:Acetyl Coenzyme A; D000255:Adenosine Triphosphate; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human