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Lactate: the ugly duckling of energy metabolism

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.

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Fig. 1: Lactate—waste and fuel.
Fig. 2: Redox buffering by circulating lactate and pyruvate.
Fig. 3: Whole-body lactate homeostasis.
Fig. 4: Production and consumption of 3C units.

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Acknowledgements

S.E. is supported by the Swedish Research Council (2019-00773, 2018-02537), The Knut and Alice Wallenberg Foundation, Sahlgrenska’s University Hospital (LUA-ALF) and Novo Nordisk Foundation. J.D.R. is supported by NIH Pioneer award 1DP1DK113643, Diabetes Research Center grant P30 DK019525 and Pfizer, Inc.

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J.R. and S.E. equally conceived the idea, selected content and wrote the manuscript.

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Correspondence to Joshua D. Rabinowitz or Sven Enerbäck.

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J.D.R. is a cofounder and stockholder in VL54 and Raze Therapeutics, and an advisor and stockholder in Agios Pharmaceuticals, Kadmon Pharmaceuticals, Bantam Pharmaceuticals, Colorado Research Partners, Rafael Pharmaceuticals and L.E.A.F. Pharmaceuticals. S.E. declares no competing interests.

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Rabinowitz, J.D., Enerbäck, S. Lactate: the ugly duckling of energy metabolism. Nat Metab 2, 566–571 (2020). https://doi.org/10.1038/s42255-020-0243-4

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