Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals

Cell. 2018 Oct 4;175(2):502-513.e13. doi: 10.1016/j.cell.2018.08.040. Epub 2018 Sep 20.


Acetate is a major nutrient that supports acetyl-coenzyme A (Ac-CoA) metabolism and thus lipogenesis and protein acetylation. However, its source is unclear. Here, we report that pyruvate, the end product of glycolysis and key node in central carbon metabolism, quantitatively generates acetate in mammals. This phenomenon becomes more pronounced in the context of nutritional excess, such as during hyperactive glucose metabolism. Conversion of pyruvate to acetate occurs through two mechanisms: (1) coupling to reactive oxygen species (ROS) and (2) neomorphic enzyme activity from keto acid dehydrogenases that enable function as pyruvate decarboxylases. Further, we demonstrate that de novo acetate production sustains Ac-CoA pools and cell proliferation in limited metabolic environments, such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. By virtue of de novo acetate production being coupled to mitochondrial metabolism, there are numerous possible regulatory mechanisms and links to pathophysiology.

Keywords: dehydrogenase; flux analysis; glycolysis; lipogenesis; metabolomics; mitochondria; pyruvate; reactive oxygen species; stable isotope tracing; thiamine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Citrate (pro-S)-Lyase / physiology
  • Acetates / metabolism*
  • Acetyl Coenzyme A / biosynthesis
  • Acetyl Coenzyme A / metabolism
  • Acetylation
  • Animals
  • Female
  • Glucose / metabolism*
  • Glycolysis / physiology
  • Lipogenesis / physiology
  • Male
  • Mammals / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Oxidoreductases
  • Pyruvate Decarboxylase / physiology
  • Pyruvic Acid / metabolism*
  • Reactive Oxygen Species / metabolism


  • Acetates
  • Reactive Oxygen Species
  • Acetyl Coenzyme A
  • Pyruvic Acid
  • Oxidoreductases
  • ATP Citrate (pro-S)-Lyase
  • Pyruvate Decarboxylase
  • Glucose