Lactate: the ugly duckling of energy metabolism. Author Joshua Rabinowitz, Sven Enerbäck Publication Year 2020 Type Journal Article Abstract Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactobacilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals. Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and ischaemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate's reputation as a deleterious waste product. In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This reconceptualization of lactate as a fuel-analogous to how Hans Christian Andersen's ugly duckling is actually a beautiful swan-has the potential to reshape the field of energy metabolism. Keywords Animals, Humans, Glucose, Citric Acid Cycle, Lactic Acid, Energy Metabolism, Glycolysis Journal Nat Metab Volume 2 Issue 7 Pages 566-571 Date Published 2020 Jul ISSN Number 2522-5812 DOI 10.1038/s42255-020-0243-4 Alternate Journal Nat Metab PMCID PMC7983055 PMID 32694798 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML