Monocarboxylate transporter

Monocarboxylate transporters,^[1] or MCTs, constitute a family of proton-linked plasma membrane transporters that carry molecules having one carboxylate group (monocarboxylates), such as lactate and pyruvate, across biological membranes.

Lactate and the Cori cycle

Lactate has long been considered a byproduct resulting from glucose breakdown through glycolysis in times of anaerobic metabolism. As a means of regenerating oxidized NAD⁺, lactate dehydrogenase catalyzes the conversion of pyruvate to lactate in the cytosol, oxidizing NADH to NAD⁺, regenerating the necessary substrate needed to continue glycolysis. Lactate is then transported from the peripheral tissues to the liver by means of the Cori Cycle where it is reformed into pyruvate through the reverse reaction using lactate dehydrogenase. By this logic, lactate has traditionally considered a toxic metabolic byproduct that could give rise to fatigue and muscle pain during times of 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’.^[2]

Clinical significance

Highly malignant tumors rely heavily on aerobic glycolysis (metabolism of glucose to lactic acid even under ample tissue 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".^[3] The MCTs have been successfully targeted in pre-clinical studies using RNAi ^[4] 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.^[5][6][7]

References