Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.

/pdf/oligodendroglia-metabolically-support-axons-and-contribute-656tll7706.pdf

Oligodendroglia metabolically support axons and contribute to neurodegeneration

The monocarboxylate cotransporter (MCT) family now comprises 14 members, of which only the first four (MCT1-MCT4) have been demonstrated experimentally to catalyse the proton-linked transport of metabolically important monocarboxylates such as lactate, pyruvate and ketone bodies. SLC16A10 (T-type amino-acid transporter-1, TAT1) is an aromatic amino acid transporter whilst the other members await characterization. MCTs have 12 transmembrane domains (TMDs) with intracellular N- and C-termini and a large intracellular loop between TMDs 6 and 7. MCT1 and MCT4 require a monotopic ancillary protein, CD147, for expression of functional protein at the plasma membrane. Lactic acid transport across the plasma membrane is fundamental for the metabolism of and pH regulation of all cells, removing lactic acid produced by glycolysis and allowing uptake by those cells utilizing it for gluconeogenesis (liver and kidney) or as a respiratory fuel (heart and red muscle). The properties of the different MCT isoforms and their tissue distribution and regulation reflect these roles.

The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond.

Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non–tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.

/pdf/targeting-lactate-metabolism-for-cancer-therapeutics-3utsv5c16t.pdf

Targeting lactate metabolism for cancer therapeutics

http://www.jbc.org/content/early/2006/02/01/jbc.M511397200.full.pdf

The Plasma Membrane Lactate Transporter MCT4, but Not MCT1, Is Up-regulated by Hypoxia through a HIF-1α-dependent Mechanism

Monocarboxylate transporters (MCTs) are proton-linked membrane carriers involved in the transport of monocarboxylates such as lactate, pyruvate, as well as ketone bodies. They belong to a larger family of transporters composed of 14 members in mammals based on sequence homologies. MCTs are found in various tissues including the brain where three isoforms, MCT1, MCT2 and MCT4, have been described. Each of these isoforms exhibits a distinct regional and cellular distribution in rodent brain. At the cellular level, MCT1 is expressed by endothelial cells of microvessels, by ependymocytes as well as by astrocytes. MCT4 expression appears to be specific for astrocytes. By contrast, the predominant neuronal monocarboxylate transporter is MCT2. Interestingly, part of MCT2 immunoreactivity is located at postsynaptic sites, suggesting a particular role of monocarboxylates and their transporters in synaptic transmission. In addition to variation in expression during development and upon nutritional modifications, new data indicate that MCT expression is regulated at the translational level by neurotransmitters. Understanding how transport of monocarboxylates is regulated could be of particular importance not only for neuroenergetics but also for areas such as functional brain imaging, regulation of food intake and glucose homeostasis, or for central nervous system disorders such as ischaemia and neurodegenerative diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2005.03168.x

Monocarboxylate transporters in the central nervous system: distribution, regulation and function

CD147 is a broadly expressed plasma membrane glycoprotein containing two immunoglobulin-like domains and a single charge-containing transmembrane domain. Here we use co-immunoprecipitation and chemical cross-linking to demonstrate that CD147 specifically interacts with MCT1 and MCT4, two members of the proton-linked monocarboxylate (lactate) transporter family that play a fundamental role in metabolism, but not with MCT2. Studies with a CD2–CD147 chimera implicate the transmembrane and cytoplasmic domains of CD147 in this interaction. In heart cells, CD147 and MCT1 co-localize, concentrating at the t-tubular and intercalated disk regions. In mammalian cell lines, expression is uniform but cross-linking with anti-CD147 antibodies caused MCT1, MCT4 and CD147, but not GLUT1 or MCT2, to redistribute together into ‘caps’. In MCT-transfected cells, expressed protein accumulated in a perinuclear compartment, whereas co-transfection with CD147 enabled expression of active MCT1 or MCT4, but not MCT2, in the plasma membrane. We conclude that CD147 facilitates proper expression of MCT1 and MCT4 at the cell surface, where they remain tightly bound to each other. This association may also be important in determining their activity and location.

/pdf/cd147-is-tightly-associated-with-lactate-transporters-mct1-30kn7hk5my.pdf

CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression.

Co-localization of immunoglobulin superfamily member CD147 with a monocarboxylate transporter (MCT1)

T cell engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the re-directed T cell response. This class of bispecifics, exemplified by tebentafusp which has recently shown survival benefit in a randomized phase 3 clinical trial1, bind specific target peptides presented by human leukocyte antigen (HLA) on the cell surface via an affinity-enhanced T cell receptor and can redirect T cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T cell activation, while strong affinity of both targeting and effector domains significantly reduces efficacy. Moreover, by optimising the affinity of both parts of the molecule, it is possible to improve the therapeutic window. These results could be effectively modelled based on kinetic proof-reading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark-state. These findings have important implications for the design of anti-CD3 based bispecifics with optimal biophysical parameters for both activity and specificity. Graphical abstract

P Kirk

Papers

CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression.

Co-localization of immunoglobulin superfamily member CD147 with a monocarboxylate transporter (MCT1)

Tuning the potency and therapeutic window of ImmTAC molecules by affinity modulation