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Mol Cell. 2014 Mar 6;53(5):710-25. doi: 10.1016/j.molcel.2014.01.016. Epub 2014 Feb 20.

Regulation of autophagy by cytosolic acetyl-coenzyme A.

Author information

1
Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
2
Institute of Molecular Biosciences, University of Graz, 8036 Graz, Austria.
3
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Institute of Medical Technologies and Health Management, Joanneum Research, 8036 Graz, Austria.
5
Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France.
6
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo 33006, Spain.
7
Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France; INSERM U845, 75014 Paris, France.
8
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark.
9
Institute of Medical Technologies and Health Management, Joanneum Research, 8036 Graz, Austria; Medical University of Graz, Division of Endocrinology and Metabolism, Department of Internal Medicine, 8036 Graz, Austria.
10
Institute of Molecular Biosciences, University of Graz, 8036 Graz, Austria. Electronic address: frank.madeo@uni-graz.at.
11
Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, 94805 Villejuif, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France. Electronic address: kroemer@orange.fr.

Abstract

Acetyl-coenzyme A (AcCoA) is a major integrator of the nutritional status at the crossroads of fat, sugar, and protein catabolism. Here we show that nutrient starvation causes rapid depletion of AcCoA. AcCoA depletion entailed the commensurate reduction in the overall acetylation of cytoplasmic proteins, as well as the induction of autophagy, a homeostatic process of self-digestion. Multiple distinct manipulations designed to increase or reduce cytosolic AcCoA led to the suppression or induction of autophagy, respectively, both in cultured human cells and in mice. Moreover, maintenance of high AcCoA levels inhibited maladaptive autophagy in a model of cardiac pressure overload. Depletion of AcCoA reduced the activity of the acetyltransferase EP300, and EP300 was required for the suppression of autophagy by high AcCoA levels. Altogether, our results indicate that cytosolic AcCoA functions as a central metabolic regulator of autophagy, thus delineating AcCoA-centered pharmacological strategies that allow for the therapeutic manipulation of autophagy.

PMID:
24560926
DOI:
10.1016/j.molcel.2014.01.016
[Indexed for MEDLINE]
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