Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease

Abstract

The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1-4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease. SIGNIFICANCE STATEMENT: The 14-member solute carrier family 16 of monocarboxylate transporters (MCTs) plays a fundamental role in maintaining intracellular concentrations of a broad range of important endogenous molecules in health and disease. MCTs 1, 2, and 4 (L-lactate transporters) are overexpressed in cancers and represent a novel therapeutic target in cancer. Recent studies have highlighted the importance of MCTs in glucose, lipid, and hormone homeostasis, including MCT8 in thyroid hormone brain uptake, MCT12 in carnitine transport, and MCT11 in type 2 diabetes.

Fig. 1.

The proposed topology of the MCT family members. CD147, the ancillary protein that associates with MCT1 and MCT4, is also shown. The N and C termini and the large loop between transmembrane domains 6 and 7 show the greatest variation between family members, whereas the TMDs themselves are highly conserved. Adapted from Halestrap and Meredith (2004) and Halestrap (2013a).

Fig. 2.

The phylogenetic tree of human MCT isoforms. Sequence alignments were performed using Clustal Omega, and phylogeny trees were made using interactive Tree Of Life (iTOL). The bar indicates the number of per amino acid residue, with one corresponding to a distance of one substitution per 10 amino acid residues. Adapted from Halestrap (2012).

Fig. 3.

Tissue protein expression of MCT isoforms in humans, based on data compiled by Morris and Felmlee (2008).

Fig. 4.

The proton antenna effect of CAs in the regulation of MCT1/4. CAII/IX, carbonic anhydrase II/IX; GLUT, glucose transporter; H⁺, proton; LDH, lactate dehydrogenase. Adapted from Noor et al., 2018. Created with BioRender.com.

Fig. 5.

A representation of the Warburg Effect by which glycolytic and oxidative cancer cells participate in lactate shuttling. GLUT, glucose transporter; H⁺, proton; LDHA/B, lactate dehydrogenase A/B; TCA, tricarboxylic acid cycle. Created with BioRender.com.