@article{57d2045d6d414192be7253e05e2ebce4,
title = "Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals",
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.",
keywords = "dehydrogenase, flux analysis, glycolysis, lipogenesis, metabolomics, mitochondria, pyruvate, reactive oxygen species, stable isotope tracing, thiamine",
author = "Xiaojing Liu and Cooper, {Daniel E.} and Cluntun, {Ahmad A.} and Warmoes, {Marc O.} and Steven Zhao and Reid, {Michael A.} and Juan Liu and Lund, {Peder J.} and Mariana Lopes and Garcia, {Benjamin A.} and Wellen, {Kathryn E.} and Kirsch, {David G.} and Locasale, {Jason W.}",
note = "Funding Information: We acknowledge support from the NIH (awards R01CA193256 and R00 CA16899 to J.W.L.; T32 CA093240 to D.E.C.; R35 CA197616 to D.G.K.; R01CA174761 to KEW; R01GM110174 to B.A.G.; T32CA009140 to P.J.L.; F99CA222741 to S.Z.), the American Cancer Society ( TBE434120 to J.W.L.; TBE130927 to M.A.R.), FAPESP ( 2017/15835-1 to M.L.), and the King Abdullah International Medical Research Center under the Ministry of National Guard Health graduate fellowship (to A.A.C). We thank Dr. Anthony Ribeiro (NMR facility at Duke University) for help with spectroscopy measurements and Dr. Clementina Mesaros (University of Pennsylvania) for helpful advice on the 18 O 2 tracing assay. We also thank members of the Locasale lab for helpful discussions. J.W.L. is especially grateful for discussions on unpublished work with Eyal Gottlieb and Zach Schug about the importance of acetate that laid the groundwork for this study. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = oct,
day = "4",
doi = "10.1016/j.cell.2018.08.040",
language = "English",
volume = "175",
pages = "502--513.e13",
journal = "Cell",
issn = "0092-8674",
number = "2",
}