Lactate: a multifunctional signaling molecule

Abstract

Since its discovery in 1780, lactate has long been misunderstood as a waste by-product of anaerobic glycolysis with multiple deleterious effects. Owing to the lactate shuttle concept introduced in the early 1980s, a paradigm shift began to occur. Increasing evidence indicates that lactate is a coordinator of whole-body metabolism. Lactate is not only a readily accessible fuel that is shuttled throughout the body but also a metabolic buffer that bridges glycolysis and oxidative phosphorylation between cells and intracellular compartments. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells and tissues, resulting in diverse biological consequences including decreased lipolysis, immune regulation, anti-inflammation, wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, accounting for its key role in immune modulation and maintenance of homeostasis.

Keywords: Glycolysis; Homeostasis; Lactate; Lactylation; Shuttle; Warburg effect.

Fig. 1.

The metabolism, shuttle, transporters, receptor, and diverse functions (green boxes) of lactate in glycolytic cells. See text for details. GPR81, G-protein coupled receptor 81; HCA1, hydroxycarboxylic acid receptor 1; ECM, extracellular matrix; ARRB2, arrestin beta 2; Gi, inhibitory G protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; MCT, monocarboxylate transporter; GLUT1, glucose transporter 1; NAD, nicotinamide adenine dinucleotide; NADH, reduced form of NAD; LDHA, A form of lactate dehydrogenase (LDH); ETC, electron transport chain; acetyl-CoA, acetyl coenzyme A; FADH2, reduced flavin adenine dinucleotide; TCA, tricarboxylic acid cycle; MAVS, mitochondrial antiviral signaling; RIG-I, retinoic acid-inducible gene 1; dsRNA, double-stranded RNA; IFN, interferon.