Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals

Xiaojing Liu, Daniel E. Cooper, Ahmad A. Cluntun, Marc O. Warmoes, Steven Zhao, Michael A. Reid, Juan Liu, Peder J. Lund, Mariana Lopes, Benjamin A. Garcia, Kathryn E. Wellen, David G. Kirsch, Jason W. Locasale

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

Abstract

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. Cells directly produce acetate from pyruvate through two distinct mechanisms, thus providing support for acetyl-CoA pools during times of metabolic deficiency.

Original languageEnglish
Pages (from-to)502-513.e13
JournalCell
Volume175
Issue number2
DOIs
StatePublished - Oct 4 2018

Keywords

  • dehydrogenase
  • flux analysis
  • glycolysis
  • lipogenesis
  • metabolomics
  • mitochondria
  • pyruvate
  • reactive oxygen species
  • stable isotope tracing
  • thiamine

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