title: Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan.
abstract: Healthy aging depends on removal of damaged cellular material that is in part mediated by autophagy. The nutritional status of cells affects both aging and autophagy through as-yet-elusive metabolic circuitries. Here, we show that nucleocytosolic acetyl-coenzyme A (AcCoA) production is a metabolic repressor of autophagy during aging in yeast. Blocking the mitochondrial route to AcCoA by deletion of the CoA-transferase ACH1 caused cytosolic accumulation of the AcCoA precursor acetate. This led to hyperactivation of nucleocytosolic AcCoA-synthetase Acs2p, triggering histone acetylation, repression of autophagy genes, and an age-dependent defect in autophagic flux, culminating in a reduced lifespan. Inhibition of nutrient signaling failed to restore, while simultaneous knockdown of ACS2 reinstated, autophagy and survival of ach1 mutant. Brain-specific knockdown of Drosophila AcCoA synthetase was sufficient to enhance autophagic protein clearance and prolong lifespan. Since AcCoA integrates various nutrition pathways, our findings may explain diet-dependent lifespan and autophagy regulation.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schroeder
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Andryushkova
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pendl
authors.affiliation: Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Albertstrasse 19, 79104 Freiburg, Germany; Department of Dermatology, University Freiburg Medical Center, Hauptstrasse 7, 79104 Freiburg, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Küttner
authors.affiliation: Institute for Biology/Genetics, Freie Universität, Takustraße 6, 14195 Berlin, Germany; NeuroCure, Charité, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Bhukel
authors.affiliation: INSERM U848, Pavillon de Recherche 1, 94805 Villejuif, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Pavillon de Recherche 1, 94805 Villejuif, France; Université Paris Sud, Faculté de Médecine, 63 Rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mariño
authors.affiliation: INSERM U848, Pavillon de Recherche 1, 94805 Villejuif, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Pavillon de Recherche 1, 94805 Villejuif, France; Université Paris Sud, Faculté de Médecine, 63 Rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Pietrocola
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria; Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Harger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Tarek
authors.initials: T
authors.lastname: Moustafa
authors.affiliation: Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Albertstrasse 19, 79104 Freiburg, Germany; Department of Dermatology, University Freiburg Medical Center, Hauptstrasse 7, 79104 Freiburg, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Sprenger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jany
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Büttner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Didac
authors.initials: D
authors.lastname: Carmona-Gutierrez
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ruckenstuhl
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Ring
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Wieland
authors.initials: W
authors.lastname: Reichelt
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schimmel
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Tina
authors.initials: T
authors.lastname: Leeb
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Moser
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schatz
authors.affiliation: Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University Graz, Auenbruggerplatz 29, 8036 Graz, Austria.
authors.forename: Lars-Peter
authors.initials: LP
authors.lastname: Kamolz
authors.affiliation: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., Leonhardstraße 59, 8010 Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., Leonhardstraße 59, 8010 Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Sinner
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Sedej
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Fröhlich
authors.affiliation: Department of Anatomy, Cell, and Developmental Biology, Eotvos Lorand University, Egyetem tér 1-3, 1053 Budapest, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Juhasz
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., Leonhardstraße 59, 8010 Graz, Austria.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.affiliation: Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Albertstrasse 19, 79104 Freiburg, Germany; Department of Dermatology, University Freiburg Medical Center, Hauptstrasse 7, 79104 Freiburg, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Institute for Biology/Genetics, Freie Universität, Takustraße 6, 14195 Berlin, Germany; NeuroCure, Charité, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sigrist
authors.affiliation: INSERM U848, Pavillon de Recherche 1, 94805 Villejuif, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Pavillon de Recherche 1, 94805 Villejuif, France; Université Paris Sud, Faculté de Médecine, 63 Rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France; Equipe 11 Labellisée Ligue Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 15 Rue de l'École de Médecine, 75006 Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 20 Rue Leblanc, 75908 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006 Paris, France. Electronic address: kroemer@orange.fr.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria. Electronic address: frank.madeo@uni-graz.at.
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
mesh_terms: D000105:Acetyl Coenzyme A / Q000096:biosynthesis; D000107:Acetylation; D000375:Aging; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000201:enzymology; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D006657:Histones / Q000378:metabolism; D008136:Longevity; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C114830:ATG7 protein, S cerevisiae; D029721:Drosophila Proteins; D006657:Histones; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D000105:Acetyl Coenzyme A; C413542:GPI13 protein, S cerevisiae; D017853:Phosphotransferases (Alcohol Group Acceptor); D003066:Coenzyme A Ligases; D000071193:Autophagy-Related Protein 7