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] Acetate is actively transported to intestinal enteroendocrine cells via MCT, termed Targ (short for Tarag in Mongolian).[3] MCTs are expressed in nearly every kind of cell.[4]
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
editLactate 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".[5]
Clinical significance
editHighly 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".[6][7] The MCTs have been successfully targeted in pre-clinical studies using RNAi[8] 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.[9][10][11]
See also
editMonocarboxylate transporters:
References
edit- ^ 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.
- ^ a b c d 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.
- ^ Jugder, Bat-Erdene; Kamareddine, Layla; Watnick, Paula I. (August 2021). "Microbiota-derived acetate activates intestinal innate immunity via the Tip60 histone acetyltransferase complex". Immunity. doi:10.1016/j.immuni.2021.05.017. PMC 8363570.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Colen, CB, PhD Thesis (2005) http://elibrary.wayne.edu/record=b3043899~S47
- ^ 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.
- ^ 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.