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 LeebClaudia 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

Research output: Contribution to journalArticle

139 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)431-444
Number of pages14
JournalCell Metabolism
Volume19
Issue number3
DOIs
Publication statusPublished - Mar 4 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    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., ... Madeo, F. (2014). Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme A stimulates autophagy and prolongs lifespan. Cell Metabolism, 19(3), 431-444. https://doi.org/10.1016/j.cmet.2014.02.010