Monocarboxylate transporters in the brain and in cancer

Abstract

Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1–4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1–4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

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

“…Cognitive impairment due to decreased energy metabolism was also found in the pathophysiology of Alzheimer disease in rats. Indeed, decreased lactate content accompanied by reduced MCT2 expression was demonstrated in the cerebral cortex and hippocampus in a rat model of the disease 61. Changes in rat MCT expression were also observed in response to oxygen deprivation, for instance, due to ischemic stroke 62.…”

“…With respect to cognitive functions, it could be demonstrated in rat models that downregulation of MCT1, but also MCT4, in glial cells, and/or MCT2 in neurons prevented learning and long‐term memory formation 61. Cognitive impairment due to decreased energy metabolism was also found in the pathophysiology of Alzheimer disease in rats.…”

“…Although it remains unknown whether these symptoms were direct effects of MCT1 deficiency in the CNS or were caused by repeated ketoacidosis, an involvement of MCT1 or other MCTs is not unreasonable. The brain is highly dependent on continuous energy supply and disturbed shuttling of energy substrates between the different brain cell types may have detrimental consequences for the highly complex and tightly regulated brain physiology and energy homeostasis 61. Most studies investigating diseases of the CNS and/or the peripheral nervous system and the relevance of MCTs were performed in rodent models.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Con se quently, this meta bolic pref er ence was pro posed to re sult in glu cose spar ing near blood ves sels, thus im prov ing glu cose de liv ery to dis tant hy poxic/ gly colytic tu mor ar eas. In the sym bio sis, higher glu cose avail abil ity is a meta bolic re ward for gly colytic can cer cells that con sume glu cose and pro duce lac tate [72]. For ox ida tive can cer cells, us ing lac tate pref er en tially to glu cose pro vides a sub tler meta bolic ad van tage.…”

“…For ox ida tive can cer cells, us ing lac tate pref er en tially to glu cose pro vides a sub tler meta bolic ad van tage. The ox ida tive path way of lac tate com prises lac tate up take in a process pri mar ily fa cil i tated by MCT1, a mono car boxy late trans porter with a high affin ity for lac tate [72], the con ver sion of lac tate and NAD to lac tate, NADH and H by lac tate de hy dro ge nase B (LDHB), and the mi to chon dr ial use of pyru vate [5] and NADH (im ported into mi to chon dria through the malate as par tate shut tle) [73]. Im por tantly, other au thors have re ported that LDHB can also re side in the mi to chon dria of some can cer cell lines, where they would gen er ate pyru vate and NADH from lac tate to di rectly fuel the TCA cy cle and the elec tron trans port chain, re spec tively [74,75].…”