Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan

Tobias Eisenberg; Sabrina Schroeder; Aleksandra Andryushkova; Tobias Pendl; Victoria Küttner; Anuradha Bhukel; Guillermo Mariño; Federico Pietrocola; Alexandra Harger; Andreas Zimmermann; Tarek Moustafa; Adrian Sprenger; Evelyne Jany; Sabrina Büttner; Didac Carmona-Gutierrez; Christoph Ruckenstuhl; Julia Ring; Wieland Reichelt; Katharina Schimmel; Tina Leeb; Claudia Moser; Stefanie Schatz; Lars-Peter Kamolz; Christoph Magnes; Frank Sinner; Simon Sedej; Kai-Uwe Fröhlich; Gabor Juhasz; Thomas R Pieber; Jörn Dengjel; Stephan J Sigrist; Guido Kroemer; Frank Madeo

doi:10.1016/j.cmet.2014.02.010

Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan

Cell Metab. 2014 Mar 4;19(3):431-44. doi: 10.1016/j.cmet.2014.02.010.

Authors

Tobias Eisenberg¹, Sabrina Schroeder¹, Aleksandra Andryushkova¹, Tobias Pendl¹, Victoria Küttner², Anuradha Bhukel³, Guillermo Mariño⁴, Federico Pietrocola⁴, Alexandra Harger⁵, Andreas Zimmermann¹, Tarek Moustafa¹, Adrian Sprenger², Evelyne Jany¹, Sabrina Büttner¹, Didac Carmona-Gutierrez¹, Christoph Ruckenstuhl¹, Julia Ring¹, Wieland Reichelt¹, Katharina Schimmel¹, Tina Leeb¹, Claudia Moser¹, Stefanie Schatz¹, Lars-Peter Kamolz⁶, Christoph Magnes⁷, Frank Sinner⁸, Simon Sedej⁹, Kai-Uwe Fröhlich¹, Gabor Juhasz¹⁰, Thomas R Pieber⁸, Jörn Dengjel², Stephan J Sigrist³, Guido Kroemer¹¹, Frank Madeo¹²

Affiliations

¹ Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
² 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.
³ Institute for Biology/Genetics, Freie Universität, Takustraße 6, 14195 Berlin, Germany; NeuroCure, Charité, Charitéplatz 1, 10117 Berlin, Germany.
⁴ 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.
⁵ 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.
⁶ Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University Graz, Auenbruggerplatz 29, 8036 Graz, Austria.
⁷ HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., Leonhardstraße 59, 8010 Graz, Austria.
⁸ 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.
⁹ Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Austria.
¹⁰ Department of Anatomy, Cell, and Developmental Biology, Eotvos Lorand University, Egyetem tér 1-3, 1053 Budapest, Hungary.
¹¹ 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.
¹² Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria. Electronic address: frank.madeo@uni-graz.at.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetyl Coenzyme A / biosynthesis
Acetylation
Aging
Animals
Autophagy*
Autophagy-Related Protein 7
Coenzyme A Ligases / antagonists & inhibitors
Coenzyme A Ligases / genetics
Coenzyme A Ligases / metabolism*
Drosophila / enzymology
Drosophila Proteins / antagonists & inhibitors
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Energy Metabolism
Histones / metabolism
Longevity*
Membrane Proteins / deficiency
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mitochondria / metabolism
Phosphotransferases (Alcohol Group Acceptor) / deficiency
Phosphotransferases (Alcohol Group Acceptor) / genetics
Phosphotransferases (Alcohol Group Acceptor) / metabolism
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins / antagonists & inhibitors
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Up-Regulation

Substances

ATG7 protein, S cerevisiae
Drosophila Proteins
Histones
Membrane Proteins
Saccharomyces cerevisiae Proteins
Acetyl Coenzyme A
GPI13 protein, S cerevisiae
Phosphotransferases (Alcohol Group Acceptor)
Coenzyme A Ligases
Autophagy-Related Protein 7

Abstract

Publication types

MeSH terms

Substances

Grants and funding