Monocarboxylate transporter

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The monocarboxylate transporters, [1] or MCTs, are a family of proton-linked plasma membrane transporters that carry molecules having one carboxylate group (monocarboxylates), such as lactate, pyruvate, and ketones across biological membranes. [2] MCTs are expressed in nearly every kind of cell. [3]

Contents

There are 14 MCTs corresponding to 14 solute carrier  16A transporters, although the cardinal numbers do not match (for example MCT3 is SLC16A8). [2] MCTs 1-4 have been more carefully investigated than MCTs 5-14. [2]

MCTs can be upregulated by PPAR-α, HIF-1α, Nrf2, and AMPK. [2]

Lactate and the Cori cycle

Lactate has long been considered a byproduct resulting from glucose breakdown through glycolysis during anaerobic metabolism. Glycolysis requires the coenzyme NAD+, and reduces it to NADH. As a means of regenerating NAD+ to allow glycolysis to continue, lactate dehydrogenase catalyzes the conversion of pyruvate to lactate in the cytosol, oxidizing NADH to NAD+. Lactate is then transported from the peripheral tissues to the liver. There it is reformed into pyruvate and ultimately to glucose, which can travel back to the peripheral tissues, completing the Cori cycle.

Thus, lactate has traditionally been considered a toxic metabolic byproduct that could give rise to fatigue and muscle pain during anaerobic respiration. Lactate can be thought of essentially as payment for "oxygen debt", defined by Hill and Lupton as the "total amount of oxygen used, after cessation of exercise in recovery there from". [4]

Clinical significance

Highly malignant tumors rely heavily on aerobic glycolysis (metabolism of glucose to lactic acid even under presence of oxygen; Warburg effect) and thus need to efflux lactic acid via MCTs to the tumor micro-environment to maintain a robust glycolytic flux and to prevent the tumor from being "pickled to death". [5] [6] The MCTs have been successfully targeted in pre-clinical studies using RNAi [7] and a small-molecule inhibitor alpha-cyano-4-hydroxycinnamic acid (ACCA; CHC) to show that inhibiting lactic acid efflux is a very effective therapeutic strategy against highly glycolytic malignant tumors. [8] [9] [10]

See also

Monocarboxylate transporters:

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<span class="mw-page-title-main">Monocarboxylate transporter 4</span> Protein-coding gene in the species Homo sapiens

Monocarboxylate transporter 4 (MCT4) also known as solute carrier family 16 member 3 is a protein that in humans is encoded by the SLC16A3 gene.

<span class="mw-page-title-main">PKM2</span> Protein-coding gene in the species Homo sapiens

Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene.

<span class="mw-page-title-main">Monocarboxylate transporter 1</span>

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<span class="mw-page-title-main">Monocarboxylate transporter 2</span> Protein-coding gene in the species Homo sapiens

Monocarboxylate transporter 2 (MCT2) also known as solute carrier family 16 member 7 (SLC16A7) is a protein that in humans is encoded by the SLC16A7 gene. MCT2 is a proton-coupled monocarboxylate transporter. It catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactic acid, branched-chain oxo acids derived from [[leucine, valine, and isoleucine, and the ketone bodies acetoacetate and beta-hydroxybutyrate. It also functions as high-affinity pyruvate transporter.

<span class="mw-page-title-main">Monocarboxylate transporter 3</span> Protein-coding gene in the species Homo sapiens

Monocarboxylate transporter 3 (MCT3) also known as solute carrier family 16 member 8 is a protein that in humans is encoded by the SLC16A8 gene. MCT is a proton-coupled monocarboxylate transporter. It catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate. It also functions as high-affinity pyruvate transporter.

References

  1. ↑ Halestrap AP, Meredith D (2004). "The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond". Pflügers Arch. 447 (5): 619–28. doi:10.1007/s00424-003-1067-2. PMID   12739169. S2CID   15498611.
  2. 1 2 3 4 Felmlee MA, Jones RS, Morris ME (2020). "Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease". Pharmacological Reviews . 72 (2): 466–485. doi:10.1124/pr.119.018762. PMC   7062045 . PMID   32144120.
  3. ↑ Parks, Scott K.; Mueller-Klieser, Wolfgang; Pouysségur, Jacques (2020). "Lactate and Acidity in the Cancer Microenvironment". Annual Review of Cancer Biology. 4: 141–158. doi: 10.1146/annurev-cancerbio-030419-033556 .
  4. ↑ Lupton, H. (1923). "An analysis of the effects of speed on the mechanical efficiency of human muscular movement". J Physiol. 57 (6): 337–53. doi:10.1113/jphysiol.1923.sp002072. PMC   1405479 . PMID   16993578.
  5. ↑ Alfarouk, KO; Shayoub, ME; Muddathir, AK; Elhassan, GO; Bashir, AH (22 July 2011). "Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity)". Cancers. 3 (4): 3002–17. doi: 10.3390/cancers3033002 . PMC   3759183 . PMID   24310356.
  6. ↑ Mathupala SP, Colen CB, Parajuli P, Sloan AE (2007). "Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis (Review)". J Bioenerg Biomembr. 39 (1): 73–77. doi:10.1007/s10863-006-9062-x. PMC   3385854 . PMID   17354062.
  7. ↑ Mathupala SP, Parajuli P, Sloan AE (2004). "Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study". Neurosurgery. 55 (6): 1410–1419. doi:10.1227/01.neu.0000143034.62913.59. PMID   15574223.
  8. ↑ Colen, CB, PhD Thesis (2005) http://elibrary.wayne.edu/record=b3043899~S47
  9. ↑ Colen CB, Seraji-Bozorgzad N, Marples B, Galloway MP, Sloan AE, Mathupala SP (2006). "Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study". Neurosurgery. 59 (6): 1313–1323. doi:10.1227/01.NEU.0000249218.65332.BF. PMC   3385862 . PMID   17277695.
  10. ↑ Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, Monterey MD, Galloway MP, Sloan AE, Mathupala SP (2011). "Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study". Neoplasia. 13 (7): 620–632. doi:10.1593/neo.11134. PMC   3132848 . PMID   21750656.
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