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

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

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

213 Citations (Scopus)

Résumé

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.

langue originale	Anglais
Pages (de - à)	431-444
Nombre de pages	14
journal	Cell Metabolism
Volume	19
Numéro de publication	3
Les DOIs	https://doi.org/10.1016/j.cmet.2014.02.010
état	Publié - 4 mars 2014

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10.1016/j.cmet.2014.02.010

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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

@article{2d2c541bc28d45e48b1033fa01391b32,

title = "Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme A stimulates autophagy and prolongs lifespan",

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.",

author = "Tobias Eisenberg and Sabrina Schroeder and Aleksandra Andryushkova and Tobias Pendl and Victoria K{\"u}ttner and Anuradha Bhukel and Guillermo Mari{\~n}o and Federico Pietrocola and Alexandra Harger and Andreas Zimmermann and Tarek Moustafa and Adrian Sprenger and Evelyne Jany and Sabrina B{\"u}ttner and Didac Carmona-Gutierrez and Christoph Ruckenstuhl and Julia Ring and Wieland Reichelt and Katharina Schimmel and Tina Leeb and Claudia Moser and Stefanie Schatz and Kamolz, {Lars Peter} and Christoph Magnes and Frank Sinner and Simon Sedej and Fr{\"o}hlich, {Kai Uwe} and Gabor Juhasz and Pieber, {Thomas R.} and J{\"o}rn Dengjel and Sigrist, {Stephan J.} and Guido Kroemer and Frank Madeo",

note = "Funding Information: We thank Drs. Jef D. Boeke, Daniel Klionsky, and G{\"u}nther Daum for providing antibodies. We are also grateful for strains provided by Dr. Boeke. We thank Harald Hofbauer for support with quantitative PCR; and Lydia Opriessnig, Christian Pendl, and Birgit Michelitsch for assistance. This work was supported by the Austrian Science Fund FWF (grants T414-B09 and V235-B09 to S.B.; grants LIPOTOX, I1000, P23490-B12, and P24381-B20 to F.M.). T.E. is recipient of an APART fellowship of the Austrian Academy of Sciences at the Institute of Molecular Biosciences, University of Graz. This work was also supported by grants to G.K. from the Ligue Contre le Cancer ({\'E}quipe Labelis{\'e}e), Agence National de la Recherche (ANR), Association Pour la Recherche sur le Cancer (ARC), Canc{\'e}rop{\^o}le Ile-de-France; AXA Chair for Longevity Research, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche M{\'e}dicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the LabEx Immuno-Oncology, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the Paris Alliance of Cancer Research Institutes (PACRI). ",

year = "2014",

month = mar,

day = "4",

doi = "10.1016/j.cmet.2014.02.010",

language = "English",

volume = "19",

pages = "431--444",

journal = "Cell Metabolism",

issn = "1550-4131",

number = "3",

}

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

TY - JOUR

T1 - Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme A stimulates autophagy and prolongs lifespan

AU - Eisenberg, Tobias

AU - Schroeder, Sabrina

AU - Andryushkova, Aleksandra

AU - Pendl, Tobias

AU - Küttner, Victoria

AU - Bhukel, Anuradha

AU - Mariño, Guillermo

AU - Pietrocola, Federico

AU - Harger, Alexandra

AU - Zimmermann, Andreas

AU - Moustafa, Tarek

AU - Sprenger, Adrian

AU - Jany, Evelyne

AU - Büttner, Sabrina

AU - Carmona-Gutierrez, Didac

AU - Ruckenstuhl, Christoph

AU - Ring, Julia

AU - Reichelt, Wieland

AU - Schimmel, Katharina

AU - Leeb, Tina

AU - Moser, Claudia

AU - Schatz, Stefanie

AU - Kamolz, Lars Peter

AU - Magnes, Christoph

AU - Sinner, Frank

AU - Sedej, Simon

AU - Fröhlich, Kai Uwe

AU - Juhasz, Gabor

AU - Pieber, Thomas R.

AU - Dengjel, Jörn

AU - Sigrist, Stephan J.

AU - Kroemer, Guido

AU - Madeo, Frank

N1 - Funding Information: We thank Drs. Jef D. Boeke, Daniel Klionsky, and Günther Daum for providing antibodies. We are also grateful for strains provided by Dr. Boeke. We thank Harald Hofbauer for support with quantitative PCR; and Lydia Opriessnig, Christian Pendl, and Birgit Michelitsch for assistance. This work was supported by the Austrian Science Fund FWF (grants T414-B09 and V235-B09 to S.B.; grants LIPOTOX, I1000, P23490-B12, and P24381-B20 to F.M.). T.E. is recipient of an APART fellowship of the Austrian Academy of Sciences at the Institute of Molecular Biosciences, University of Graz. This work was also supported by grants to G.K. from the Ligue Contre le Cancer (Équipe Labelisée), Agence National de la Recherche (ANR), Association Pour la Recherche sur le Cancer (ARC), Cancéropôle Ile-de-France; AXA Chair for Longevity Research, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the LabEx Immuno-Oncology, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the Paris Alliance of Cancer Research Institutes (PACRI).

PY - 2014/3/4

Y1 - 2014/3/4

N2 - 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.

AB - 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.

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U2 - 10.1016/j.cmet.2014.02.010

DO - 10.1016/j.cmet.2014.02.010

M3 - Article

C2 - 24606900

AN - SCOPUS:84895755121

SN - 1550-4131

VL - 19

SP - 431

EP - 444

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -