Regulation of autophagy by cytosolic acetyl-coenzyme A

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / chemistry*
  • Adenosine Triphosphate / chemistry
  • Animals
  • Autophagy*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Cytosol / enzymology*
  • Cytosol / metabolism
  • E1A-Associated p300 Protein / chemistry
  • Gene Expression Regulation, Enzymologic*
  • Green Fluorescent Proteins / metabolism
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Ketoglutaric Acids / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Mitochondria / metabolism
  • RNA, Small Interfering / metabolism


  • Ketoglutaric Acids
  • RNA, Small Interfering
  • dimethyl alpha-ketoglutarate
  • Green Fluorescent Proteins
  • Acetyl Coenzyme A
  • Adenosine Triphosphate
  • E1A-Associated p300 Protein
  • EP300 protein, human