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SHR Neuro Cancer Cardio Lipid Metab Microb
Eisenberg, T; Schroeder, S; Andryushkova, A; Pendl, T; Küttner, V; Bhukel, A; Mariño, G; Pietrocola, F; Harger, A; Zimmermann, A; Moustafa, T; Sprenger, A; Jany, E; Büttner, S; Carmona-Gutierrez, D; Ruckenstuhl, C; Ring, J; Reichelt, W; Schimmel, K; Leeb, T; Moser, C; Schatz, S; Kamolz, LP; Magnes, C; Sinner, F; Sedej, S; Fröhlich, KU; Juhasz, G; Pieber, TR; Dengjel, J; Sigrist, SJ; Kroemer, G; Madeo, F.
Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan.
Cell Metab. 2014; 19(3):431-444
Doi: 10.1016/j.cmet.2014.02.010
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- Co-authors Med Uni Graz
- Fuchs Aleksandra
- Harger Alexandra
- Kamolz Lars-Peter
- Moser Claudia
- Moustafa Tarek
- Pieber Thomas
- Sedej Simon
- Sinner Frank Michael
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- 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. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- 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 -