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.

Fig. 1 ∣. Lactate—waste and fuel.

a, Lactate is half of glucose, whereas pyruvate is more oxidized. b, Lactate as waste. Glycolytic flux from glucose to pyruvate generates NADH from NAD at the GAPDH reaction. NADH’s electrons can be transported into mitochondria via the malate–aspartate or glycerol phosphate shuttles, regenerating cytosolic NAD. Alternatively, NADH can be used by LDH to reduce pyruvate to lactate, which is secreted as waste. c, Lactate as fuel. The reactions are the same, but the direction of LDH flux is reversed. The resulting extra NADH electrons are transported into mitochondria. GAP, glyceraldehyde 3-phosphate.

Fig. 2 ∣. Redox buffering by circulating lactate and pyruvate.

a, Traditional perspective. Glycolytic flux exceeds pyruvate and lactate exchange between the cell and the circulation. Intracellular metabolic reactions (glycolytic flux and transport of NADH’s electrons into mitochondria) determine the cellular NADH/NAD ratio and thereby the cellular lactate/pyruvate ratio. b, Redox buffering perspective. Exchange in pyruvate and lactate between cells and the circulation is more rapid than glycolysis. These MCT-catalysed exchange reactions determine the cellular lactate/pyruvate ratio and thereby the cellular NADH/NAD ratio. In cases in which excessive NADH begins to build up, net uptake of pyruvate and excretion of lactate alleviates the redox imbalance. GLUT, glucose transporter.

Fig. 3 ∣. Whole-body lactate homeostasis.

At the tissue level, lactate exchange with the circulation allows for independent operation of glycolysis and the TCA cycle. At the organismal level, however, lactate production (largely via glycolysis) and consumption (largely via the TCA cycle) must balance to maintain lactate homeostasis. Some tissues, such as kidney and muscle, both produce and consume circulating lactate.

Fig. 4 ∣. Production and consumption of 3C units.

At the organismal level, 3C-unit production (largely via glycolysis) and consumption (largely via PDH) must balance to maintain lactate homeostasis. Bidirectional connections indicate that the metabolites can interconvert (typically with energy input, for example, via glycolysis or gluconeogenesis).