De novo acetate production is coupled to central carbon metabolism in mammals

Abstract

In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient whose source has been unclear. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.peer-reviewed)

Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers

“…Conversely, we did not detect enrichment of citrate, malate, or succinate in the nuclear fraction (Figure S2C). Nuclei can utilize 13 C-pyruvate for histone acetylation (Liu et al, 2018), and we observed robust histone acetylation in the nuclear fraction and not the cytosolic fraction, further confirming the purity of the nuclear preparations ( Figure S2C). As an internal control, the cytosolic fraction was also subjected to protease digestion to demonstrate the removal of proteins and enzyme activity after treatment (Figures 2H,S2B,and S2C).…”

“…Pyruvate supplies a significant portion of intracellular acetate required for histone acetylation (Liu et al, 2018). Malin-directed glycogenolysis could provide an additional source for the nuclear pyruvate pool.…”

“…While this method is extremely powerful at dissecting organelle-specific pathways without cytosolic interference, we cannot determine the fractional contributions of metabolites from other sources. For example, nuclear pyruvate production is likely a combination of nuclear glycogen breakdown, transport of cytosolic pyruvate into the nucleus, and acetate from glycolysis or fatty acid oxidation (Bulusu et al, 2017;Gao et al, 2016;Liu et al, 2018). Additionally, these pools are likely to shift subject to environmental stress or malignant transformation.…”

UK5099 inhibits macrophage activation independent of mitochondrial pyruvate carrier mediated metabolism

“…Although Mpc depletion resulted in less intercellular citrate, cytosolic acetyl-CoA can be compensated by accumulated pyruvate. Further, pyruvate can be catalyzed into acetate, and in turn to acetyl-CoA in cytosol [27]. Indeed, we found that Mpc depletion blocks the entry of pyruvate into the mitochondria and leads to more pyruvate release.…”

Higher glucose availability augments the metabolic responses of the C2C12 myotubes to exercise-like electrical pulse stimulation

“…During increased energy demand or restricted TCA cycle function, all of the pyruvate-derived acetyl-CoA might have not successfully entered the TCA cycle and thus the excess can be hydrolyzed to acetate and released into the circulation (42,43). Acetate can be produced from pyruvate via enzymatic and non-enzymatic reactions including pyruvate dehydrogenase (PDH) and reactive oxygen species (ROS) (44), respectively, and PDH activity (45) and ROS levels ( 16) are increased by exercise and/or myotube contractions. In addition, hyperactive glucose metabolism and nutritional excess have been related to incomplete metabolism and excretion of metabolites, which lead to promoted conversion of pyruvate to acetate (44).…”