title: Dimethyl α-ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathy.
abstract: It has been a longstanding problem to identify specific and efficient pharmacological modulators of autophagy. Recently, we found that depletion of acetyl-coenzyme A (AcCoA) induced autophagic flux, while manipulations designed to increase cytosolic AcCoA efficiently inhibited autophagy. Thus, the cell permeant ester dimethyl α-ketoglutarate (DMKG) increased the cytosolic concentration of α-ketoglutarate, which was converted into AcCoA through a pathway relying on either of the 2 isocitrate dehydrogenase isoforms (IDH1 or IDH2), as well as on ACLY (ATP citrate lyase). DMKG inhibited autophagy in an IDH1-, IDH2- and ACLY-dependent fashion in vitro, in cultured human cells. Moreover, DMKG efficiently prevented autophagy induced by starvation in vivo, in mice. Autophagy plays a maladaptive role in the dilated cardiomyopathy induced by pressure overload, meaning that genetic inhibition of autophagy by heterozygous knockout of Becn1 suppresses the pathological remodeling of heart muscle responding to hemodynamic stress. Repeated administration of DMKG prevents autophagy in heart muscle responding to thoracic aortic constriction (TAC) and simultaneously abolishes all pathological and functional correlates of dilated cardiomyopathy: hypertrophy of cardiomyocytes, fibrosis, dilation of the left ventricle, and reduced contractile performance. These findings indicate that DMKG may be used for therapeutic autophagy inhibition.
authors.affiliation: Equipe 11 labelisée par la Ligue Nationale contre le Cancer; INSERM U1138; Centre de Recherche des Cordeliers; Paris, France; Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy; Villejuif, France; Université Paris Descartes/Paris 5; 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; Paris, France; Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy; Villejuif, France; Université Paris Descartes/Paris 5; Paris, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Pietrocola
authors.affiliation: Department of Internal Medicine (Cardiology); University of Texas Southwestern Medical Center; Dallas, TX USA.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Institute of Molecular Biosciences; University of Graz; 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 USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: Institute of Molecular Biosciences; University of Graz; Graz, Austria.
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; Paris, France; Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy; Villejuif, France; Université Paris Descartes/Paris 5; Paris, France; Pôle de Biologie; Hôpital Européen Georges Pompidou; Paris, France.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D006984:Hypertrophy; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology
chemical_list: D007656:Ketoglutaric Acids; C541783:dimethyl alpha-ketoglutarate
keywords: acetyl-coenzyme A; dilated cardiopathy; macroautophagy