Lactate: the ugly duckling of energy metabolism (Rabinowitz, 2020)

[SNT Gatchaman]

Lactate: the ugly duckling of energy metabolism
Rabinowitz JD, Enerbäck S

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.

PubMed Link | PubMed PDF | Nature Metabolism PDF

 

[SNT Gatchaman]

In the absence of lactate, glycolysis must operate in lockstep with the TCA cycle, such that every glycolysis-produced NADH and pyruvate is cleared by mitochondrial metabolism. Correspondingly, cells would need to break down glucose via glycolysis to generate energy from carbohydrate. Lactate’s fundamental role is to uncouple these pathways.

Despite PDK's importance, manifested by the existence of four different kinase isozymes, its physiological purpose remains unclear.

Given the particularly tight control of circulating lactate levels, a novel regulatory system for lactate homeostasis is likely to exist.

Circulating lactate can also enter the faeces and thereby feed the microbiome. A quantitative understanding of the importance and regulation of microbiome-mediated lactate clearance merits further investigation.