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

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

Author information

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.

PMID:
24606900
PMCID:
PMC3988959
DOI:
10.1016/j.cmet.2014.02.010
[Indexed for MEDLINE]
Free PMC Article

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