The monocarboxylate transporter family—Role and regulation

Abstract

SummaryMonocarboxylate transporter (MCT) isoforms 1-4 catalyze the proton-linked transport of monocarboxylates such as L-lactate across the plasma membrane, whereas MCT8 and MCT10 are thyroid hormone and aromatic amino acid transporters, respectively. The importance of MCTs is becoming increasingly evident as their extensive physiological and pathological roles are revealed. MCTs 1-4 play essential metabolic roles in most tissues with their distinct properties, expression profile, and subcellular localization matching the particular metabolic needs of a tissue. Important metabolic roles include energy metabolism in the brain, skeletal muscle, heart, tumor cells, and T-lymphocyte activation, gluconeogenesis in the liver and kidney, spermatogenesis, bowel metabolism of short-chain fatty acids, and drug transport. MCT8 is essential for thyroid hormone transport across the blood-brain barrier. Genetic perturbation of MCT function may be involved in disease states such as pancreatic b-cell malfunction (inappropriate MCT1 expression), chronic fatigue syndromes (impairment of muscle MCT function), and psychomotor retardation (MCT8 mutation). MCT expression can be regulated at both the transcriptional and post-transcriptional levels. Of particular importance is the upregulation of muscle MCT1 expression in response to training and MCT4 expression in response to hypoxia. The latter is mediated by hypoxia inducible factor 1a and often observed in tumor cells that rely almost entirely on glycolysis for their energy provision. The recent discovery of potent and specific MCT1 inhibitors that prevent proliferation of T-lymphocytes confirms that MCTs may be promising pharmacological targets including for cancer chemotherapy.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…In this study, we report that mitochondria deprived from glycolytic fuels stabilize the expression of MCT1 and of its chaperone protein CD147/basigin in human TCs, thus providing a functional complex known to be involved in the transport of monocarboxylic acids (through MCT1) and in the activation of matrix metalloproteinases (through CD147). 11,14,15 Upon glucose starvation, the complex promoted TC migration towards serum and glucose. Our study identifies a functional link between impaired mitochondrial activity and TC migration wherein the mitochondrion acts as a glucose sensor and signals via ROS MCT1-dependent TC escape to a more favorable metabolic environment.…”

“…11,12,14 This basic information, however, is essential for the prediction of treatment sensitivity and resistance as well as for the rational design of combination therapies. In this study, we report that mitochondria deprived from glycolytic fuels stabilize the expression of MCT1 and of its chaperone protein CD147/basigin in human TCs, thus providing a functional complex known to be involved in the transport of monocarboxylic acids (through MCT1) and in the activation of matrix metalloproteinases (through CD147).…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…MCT1, a transporter with moderate substrate affinities, facilitates either influx or efflux of the substrates depending on substrate and H + ‐concentration gradients and is ubiquitously expressed in human tissues 17. It is expressed in tissues that rely on efflux or uptake of energy metabolites based on the energetic profile but also in the gut to support the absorption of short chain fatty acids, such as acetate, propionate, or butyrate 15. In contrast, MCT2 is a high affinity transporter with a more restricted protein expression pattern.…”

“…The concept of metabolic cooperation via lactate shuttling between cell types of the same organ has been described for skeletal muscle, in which highly glycolytic fast‐twitch white muscle fibers extrude lactate via MCT4, which is taken up by oxidative slow‐twitch red muscle fibers by MCT1 ( Figure 3). 15 A rapid exchange of lactate has also been established for different cell types of the brain, known as the astrocyte‐neuron lactate shuttle hypothesis 20. Here, glycolytic astrocytes provide energy via lactate extrusion by MCT1 and MCT4 to oxidative neurons, which express the high affinity uptake transporter MCT2 ( Figure 3).…”

“…The regulation of MCT gene expression has to be tissue‐specific and, if necessary, very rapid in order to enable adaption to changes in activity or different metabolic states. Transcriptional or post‐transcriptional mechanisms of MCT regulation have been identified and summarized in a comprehensive review 15. In line with its expression in highly glycolytic and hypoxic tissues, MCT4 possesses hypoxia response elements within its promoter region and the transcription is upregulated by the hypoxia‐inducible factor (HIF) 1 81.…”