Nucleocytosolic Depletion of the Energy Metabolite Acetyl-Coenzyme A Stimulates Autophagy and Prolongs Lifespan

被引：230

作者：

Eisenberg, Tobias ^{[1
]}

Schroeder, Sabrina ^{[1
]}

Andryushkova, Aleksandra ^{[1
]}

Pendl, Tobias ^{[1
]}

Kuettner, Victoria ^{[2
,3
]}

Bhukel, Anuradha ^{[4
,5
]}

Marino, Guillermo ^{[6
,7
,8
]}

Pietrocola, Federico ^{[6
,7
,8
]}

Harger, Alexandra ^{[1
,9
]}

Zimmermann, Andreas ^{[1
]}

Moustafa, Tarek ^{[1
]}

Sprenger, Adrian ^{[2
,3
]}

Jany, Evelyne ^{[1
]}

Buettner, Sabrina ^{[1
]}

Carmona-Gutierrez, Didac ^{[1
]}

Ruckenstuhl, Christoph ^{[1
]}

Ring, Julia ^{[1
]}

Reichelt, Wieland ^{[1
]}

Schimmel, Katharina ^{[1
]}

Leeb, Tina ^{[1
]}

Moser, Claudia ^{[1
]}

Schatz, Stefanie ^{[1
]}

Kamolz, Lars-Peter ^{[10
]}

Magnes, Christoph ^{[11
]}

Sinner, Frank ^{[9
,11
]}

Sedej, Simon ^{[12
]}

Froehlich, Kai-Uwe ^{[1
]}

Juhasz, Gabor ^{[13
]}

Pieber, Thomas R. ^{[11
]}

Dengjel, Joern ^{[2
,3
]}

Sigrist, Stephan J. ^{[4
,5
]}

Kroemer, Guido ^{[6
,7
,8
,14
,15
,16
]}

Madeo, Frank ^{[1
]}

机构：

[1] Graz Univ, Inst Mol Biosci, A-8010 Graz, Austria

[2] Univ Freiburg, Freiburg Inst Adv Studies FRIAS, D-79104 Freiburg, Germany

[3] Univ Freiburg, Med Ctr, Dept Dermatol, D-79104 Freiburg, Germany

[4] Free Univ Berlin, Inst Biol Genet, D-14195 Berlin, Germany

[5] NeuroCure, D-10117 Berlin, Germany

[6] INSERM U848, F-94805 Villejuif, France

[7] Inst Gustave Roussy, F-94805 Villejuif, France

[8] Univ Paris 11, Fac Med, F-94270 Le Kremlin Bicetre, France

[9] Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, A-8036 Graz, Austria

[10] Med Univ Graz, Dept Surg, Div Plast Aesthet & Reconstruct Surg, A-8036 Graz, Austria

[11] Joanneum Res Forschungsgesellschaft mbH, HEALTH Inst Biomed & Hlth Sci, A-8010 Graz, Austria

[12] Med Univ Graz, Dept Cardiol, A-8036 Graz, Austria

[13] Eotvos Lorand Univ, Dept Anat Cell & Dev Biol, H-1053 Budapest, Hungary

[14] Ctr Rech Cordeliers, INSERM U1138, Equipe Labellisee Ligue Contre Canc 11, F-75006 Paris, France

[15] Hop Europe Georges Pompidou, AP HP, Pole Biol, F-75908 Paris, France

[16] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France

来源：

CELL METABOLISM | 2014年 / 19卷 / 03期

基金：

奥地利科学基金会; 欧洲研究理事会;

关键词：

MOLECULAR-MECHANISM; YEAST; SPERMIDINE; LONGEVITY; PATHWAYS; INDUCTION; EXTENSION;

D O I：

10.1016/j.cmet.2014.02.010

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：431 / 444

页数：14

共 52 条

[1]

Autophagy is required for extension of yeast chronological life span by rapamycin [J].