期刊
CELL METABOLISM
卷 19, 期 3, 页码 431-444出版社
CELL PRESS
DOI: 10.1016/j.cmet.2014.02.010
关键词
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资金
- Austrian Science Fund FWF [T414-B09, V235-B09]
- LIPOTOX [I1000, P23490-B12, P24381-B20]
- APART fellowship of the Austrian Academy of Sciences at the Institute of Molecular Biosciences, University of Graz
- Ligue Contre le Cancer (Equipe Labelisee)
- Agence National de la Recherche (ANR)
- Association Pour la Recherche sur le Cancer (ARC)
- Canceropole Ile-de-France
- AXA Chair for Longevity Research, Institut National du Cancer (INCa)
- Fondation Bettencourt-Schueller
- Fondation de France
- Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Council (ERC)
- LabEx Immuno-Oncology
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- Austrian Science Fund (FWF) [V235] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 23490, V 235] Funding Source: researchfish
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-coenzymeA(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.
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