Showing papers on "Monocarboxylate transporter published in 2022"

Gene therapy targeting the blood–brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency

Abstract: Abstract A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan–Herndon–Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased tri-iodothyronine (T3) levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

AAV9-MCT8 delivery at juvenile stage ameliorates neurological and behavioral deficits in a mouse model of MCT8-deficiency.

Abstract: BACKGROUND Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous, but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased T3 brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. METHODS The potential of intravenous delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/- double knockout (dKO) mouse model of AHDS, which unlike MCT8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. RESULTS Systemic intravenous delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive function at P120-P140, . Thiswhich was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus and parietal cortex). Effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/rT3 ratio and in liver deiodinase 1 expression. CONCLUSION Intravenous administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term a beneficial effect predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.

Monocarboxylate Transporter 1 (MCT1) Mediates Succinate Export in the Retina

Abstract: Succinate is exported by the retina and imported by eyecup tissue. The transporters mediating this process have not yet been identified. Recent studies showed that monocarboxylate transporter 1 (MCT1) can transport succinate across plasma membranes in cardiac and skeletal muscle. Retina and retinal pigment epithelium (RPE) both express multiple MCT isoforms including MCT1. We tested the hypothesis that MCTs facilitate retinal succinate export and RPE succinate import.We assessed retinal succinate export and eyecup succinate import in short-term ex vivo culture using gas chromatography-mass spectrometry. We tested the dependence of succinate export and import on pH, proton ionophores, conventional MCT substrates, and the MCT inhibitors AZD3965, AR-C155858, and diclofenac.Succinate exits retinal tissue through MCT1 but does not enter the RPE through MCT1 or any other MCT. Intracellular succinate levels are a contributing factor that determines if an MCT1-expressing tissue will export succinate.MCT1 facilitates export of succinate from retinas. An unidentified, non-MCT transporter facilitates import of succinate into RPE.

Distinct Actions of the Thyroid Hormone Transporters Mct8 and Oatp1c1 in Murine Adult Hippocampal Neurogenesis

Abstract: Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in Allan-Herndon-Dudley Syndrome, a severe form of psychomotor retardation, while inactivating mutations in another TH transporter, organic anion transporting polypeptide 1c1 (OATP1C1), are linked to juvenile neurodegeneration. These diseases point to essential roles for TH transporters in CNS function. We recently defined the presence of Mct8 in adult hippocampal progenitors and mature granule cell neurons and unraveled cell-autonomous and indirect requirements for Mct8 in adult hippocampal neurogenesis. Here, we investigated whether Oatp1c1 is involved in the hippocampal neurogenic process in concert with Mct8. We detected Oatp1c1 gene expression activity and transcripts in subsets of progenitors, neurons and niche cells in the dentate gyrus. Absence of Oatp1c1 resulted in increased neuroblast and reduced immature neuron numbers in 6-month-old Oatp1c1ko and Mct8/Oatp1c1 double knockout (M/Odko) mice. Reduced EdU-label retention in Mct8ko and M/Odko mice confirmed the impact of Mct8 on neuron formation. In contrast, no significant effect of Oatp1c1 loss on granule cell neuron production and anxiety-like behavior in the open field arena were seen. Together, our results reinforce that distinct actions of each TH transporter are required at multiple stages to ensure proper adult hippocampal neurogenesis.

Monocarboxylate transporter functions and neuroprotective effects of valproic acid in experimental models of amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate derivative, is a known antiepileptic drug and a histone deacetylase inhibitor.To investigate whether monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) are altered in ALS cell and mouse models, a cellular uptake study, quantitative real time polymerase chain reaction and western blot parameters were used. Similarly, whether VPA provides a neuroprotective effect in the wild-type (WT; hSOD1WT) and ALS mutant-type (MT; hSOD1G93A) NSC-34 motor neuron-like cell lines was determined through the cell viability assay.[3H]VPA uptake was dependent on time, pH, sodium and concentration, and the uptake rate was significantly lower in the MT cell line than the WT cell line. Interestingly, two VPA transport systems were expressed, and the VPA uptake was modulated by SMCT substrates/inhibitors in both cell lines. Furthermore, MCT1 and SMCT1 expression was significantly lower in motor neurons of ALS (G93A) model mice than in those of WT mice. Notably, VPA ameliorated glutamate- and hydrogen peroxide-induced neurotoxicity in both the WT and MT ALS cell lines.Together, the current findings demonstrate that VPA exhibits a neuroprotective effect regardless of the dysfunction of an MCT in ALS, which could help develop useful therapeutic strategies for ALS.

Whole-brain neuronal MCT2 lactate transporter expression links metabolism to human brain structure and function

Abstract: Brain activity is constrained by local availability of chemical energy, which is generated through compartmentalized metabolic processes. By analyzing data of whole human brain gene expression, we characterize the spatial distribution of seven glucose and monocarboxylate membrane transporters that mediate astrocyte–neuron lactate shuttle transfer of energy. We found that the gene coding for neuronal MCT2 is the only gene enriched in cerebral cortex where its abundance is inversely correlated with cortical thickness. Coexpression network analysis revealed that MCT2 was the only gene participating in an organized gene cluster enriched in K+ dynamics. Indeed, the expression of KATP subunits, which mediate lactate increases with spiking activity, is spatially coupled to MCT2 distribution. Notably, MCT2 expression correlated with fluorodeoxyglucose positron emission tomography task-dependent glucose utilization. Finally, the MCT2 messenger RNA gradient closely overlaps with functional MRI brain regions associated with attention, arousal, and stress. Our results highlight neuronal MCT2 lactate transporter as a key component of the cross-talk between astrocytes and neurons and a link between metabolism, cortical structure, and state-dependent brain function.

Monocarboxylate transporter functions and neuroprotective effects of valproic acid in experimental models of amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate derivative, is a known antiepileptic drug and a histone deacetylase inhibitor.To investigate whether monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) are altered in ALS cell and mouse models, a cellular uptake study, quantitative real time polymerase chain reaction and western blot parameters were used. Similarly, whether VPA provides a neuroprotective effect in the wild-type (WT; hSOD1WT) and ALS mutant-type (MT; hSOD1G93A) NSC-34 motor neuron-like cell lines was determined through the cell viability assay.[3H]VPA uptake was dependent on time, pH, sodium and concentration, and the uptake rate was significantly lower in the MT cell line than the WT cell line. Interestingly, two VPA transport systems were expressed, and the VPA uptake was modulated by SMCT substrates/inhibitors in both cell lines. Furthermore, MCT1 and SMCT1 expression was significantly lower in motor neurons of ALS (G93A) model mice than in those of WT mice. Notably, VPA ameliorated glutamate- and hydrogen peroxide-induced neurotoxicity in both the WT and MT ALS cell lines.Together, the current findings demonstrate that VPA exhibits a neuroprotective effect regardless of the dysfunction of an MCT in ALS, which could help develop useful therapeutic strategies for ALS.

Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology.

Abstract: Due to increased reliance on glycolysis, which produces lactate, monocarboxylate transporters (MCTs) are often upregulated in cancer. MCT4 is associated with the export of lactic acid from cancer cells under hypoxia, so inhibition of MCT4 may lead to cytotoxic levels of intracellular lactate. In addition, tumor-derived lactate is known to be immunosuppressive, so MCT4 inhibition may be of interest for immuno-oncology. At the outset, no potent and selective MCT4 inhibitors had been reported, but a screen identified a triazolopyrimidine hit, with no close structural analogues. Minor modifications to the triazolopyrimidine were made, alongside design of a constrained linker and broad SAR exploration of the biaryl tail to improve potency, physical properties, PK, and hERG. The resulting clinical candidate 15 (AZD0095) has excellent potency (1.3 nM), MCT1 selectivity (>1000×), secondary pharmacology, clean mechanism of action, suitable properties for oral administration in the clinic, and good preclinical efficacy in combination with cediranib.

Cortical Dysplasia in Rats Provokes Neurovascular Alterations, GLUT1 Dysfunction, and Metabolic Disturbances That Are Sustained Post-Seizure Induction

Abstract: Focal cortical dysplasia (FCD) is associated with blood-brain barrier (BBB) dysfunction in patients with difficult-to-treat epilepsy. However, the underlying cellular and molecular factors in cortical dysplasia (CD) associated with progressive neurovascular challenges during the pro-epileptic phase, post-seizure, and during epileptogenesis remain unclear. We studied the BBB function in a rat model of congenital (in utero radiation-induced, first hit) CD and longitudinally examined the cortical brain tissues at baseline and the progressive neurovascular alterations, glucose transporter-1 (GLUT1) expression, and glucose metabolic activity at 2, 15, and 30 days following a second hit using pentylenetetrazole-induced seizure. Our study revealed through immunoblotting, immunohistochemistry, and biochemical analysis that (1) altered vascular density and prolongation of BBB albumin leakages in CD rats continued through 30 days post-seizure; (2) CD brain tissues showed elevated matrix metalloproteinase-9 levels at 2 days post-seizure and microglial overactivation through 30 days post-seizure; (3) BBB tight junction protein and GLUT1 levels were decreased and neuronal monocarboxylate transporter-2 (MCT2) and mammalian target of rapamycin (mTOR) levels were increased in the CD rat brain: (4) ATPase activity is elevated and a low glucose/high lactate imbalance exists in CD rats; and (5) the mTOR pathway is activated and MCT2 levels are elevated in the presence of high lactate during glucose starvation in vitro. Together, this study suggests that BBB dysfunction, including decreased GLUT1 expression and metabolic disturbance, may contribute to epileptogenesis in this CD rat model through multiple mechanisms that could be translated to FCD therapy in medically refractory epilepsy.

Imaging of lactate metabolism in retinal Müller cells with a FRET nanosensor

Abstract: Müller cells, the glial cells of the retina, provide metabolic support for photoreceptors and inner retinal neurons, and have been proposed as source of the significant lactate production of this tissue. To better understand the role of lactate in retinal metabolism, we expressed a lactate and a glucose nanosensor in organotypic mouse retinal explants cultured for 14 days, and used FRET imaging in acute vibratome sections of the explants to study metabolite flux in real time. Pharmacological manipulation with specific monocarboxylate transporter (MCT) inhibitors and immunohistochemistry revealed the functional expression of MCT2 and MCT4 in Müller cells. The introduction of nanosensors to measure key metabolites at the cellular level may contribute to a better understanding of heretofore poorly understood issues in retinal metabolism.

Structural aspects of the glucose and monocarboxylate transporters involved in the Warburg effect

Abstract: Cancer cells shift their glucose catabolism from aerobic respiration to lactic fermentation even in the presence of oxygen, and this is known as the “Warburg effect”. To accommodate the high glucose demands and to avoid lactate accumulation, the expression levels of human glucose transporters (GLUTs) and human monocarboxylate transporters (MCTs) are elevated to maintain metabolic homeostasis. Therefore, inhibition of GLUTs and/or MCTs provides potential therapeutic strategies for cancer treatment. Here, we summarize recent advances in the structural characterization of GLUTs and MCTs, providing a comprehensive understanding of their transport and inhibition mechanisms to facilitate further development of anticancer therapies.

Sodium phenylbutyrate rescues thyroid hormone transport in brain endothelial-like cells.

Abstract: BACKGROUND Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease leading to a severe developmental delay due to a lack of thyroid hormones during critical stages of human brain development. Some MCT8-deficient patients are not as severely affected than others. Previously, we hypothesized that these patients' mutations do not affect the functionality but destabilize the MCT8 protein leading to a diminished number of functional MCT8 molecules at the cell surface. METHODS We have already demonstrated that the chemical chaperone sodium phenylbutyrate (NaPB) rescues the function of these mutants by stabilizing their protein expression in an overexpressing cell system. Here we expand our previous work and used iPSC-derived brain microvascular endothelial-like cells (iBMECs) as a physiologically relevant cell model of human origin to test for NaPB responsiveness. Effects on mutant MCT8 expression and function were tested by Western blotting and radioactive uptake assays. RESULTS We found that NaPB rescues decreased mutant MCT8 expression and restores transport function in iBMECs carrying patient's mutation MCT8-P321L. Furthermore, we identified MCT10 as an alternative TH transporter in iBMECs that contributes to T3 uptake, the biological active thyroid hormone. Our results indicate an upregulation of MCT10 after NaPB treatment. In addition, we detected an increase in T4 uptake after NaPB treatment that was not mediated by rescued MCT8 but an unidentified T4 transporter. CONCLUSION We demonstrate that NaPB is suitable to stabilize a pathogenic missense mutation in a human-derived cell model. Furthermore, it activates thyroid hormone transport independent of MCT8. Both options fuel future studies to investigate repurposing the FDA-approved drug NaPB in selected cases of MCT8 deficiency.

Lactate-induced effects on bovine granulosa cells are mediated via PKA signaling

Abstract: Abstract l -lactate acts as a signaling molecule in bovine granulosa cells (GCs). The initiated alterations depend on the transport of l -lactate into the cells via monocarboxylate transporters. In the present study, we further elucidated the intracellular actions of l -lactate and tested whether the PKA signaling pathway is involved. Therefore, we treated cultured bovine GCs with l -lactate and PKA inhibitors H-89 and KT5720, and with an activator of PKA, 6-Bnz-cAMP. l -lactate treatment resulted in decreased estradiol production and downregulation of CYP19A1 , FSHR , and LHCGR as well as in the upregulation of the markers of early luteinization PTX3 , RGS2 , and VNN2 . These specific l -lactate effects were almost completely abolished by pre-treatment of the GCs with both inhibitors of PKA signaling. In addition, also the l -lactate-induced upregulation of LDHA and of the monocarboxylate transporters SLC16A1 and SLC16A7 was abolished after PKA inhibition. An activation of the PKA with 6-Bnz-cAMP revealed similar effects on the gene expression like l -lactate alone. In summary, the presented data demonstrate that l -lactate-induced effects on GCs are mediated via PKA signaling thus supporting the role of l -lactate as signaling molecule during the folliculo-luteal transition.

Increased RNA Transcription of Energy Source Transporters in Circulating White Blood Cells of Aged Mice

Abstract: Circulating white blood cells (WBC) contribute toward maintenance of cerebral metabolism and brain function. Recently, we showed that during aging, transcription of metabolism related genes, including energy source transports, in the brain significantly decreased at the hippocampus resulting in impaired neurological functions. In this article, we investigated the changes in RNA transcription of metabolism related genes (glucose transporter 1 [Glut1], Glut3, monocarboxylate transporter 4 [MCT4], hypoxia inducible factor 1-α [Hif1-α], prolyl hydroxylase 3 [PHD3] and pyruvate dehydrogenase kinase 1 [PDK1]) in circulating WBC and correlated these with brain function in mice. Contrary to our expectations, most of these metabolism related genes in circulating WBC significantly increased in aged mice, and correlation between their increased RNA transcription and impaired neurological functions was observed. Bone marrow mononuclear transplantation into aged mice decreased metabolism related genes in WBC with accelerated neurogenesis in the hippocampus. In vitro analysis revealed that cell-cell interaction between WBC and endothelial cells via gap junction is impaired with aging, and blockade of the interaction increased their transcription in WBC. Our findings indicate that gross analysis of RNA transcription of metabolism related genes in circulating WBC has the potential to provide significant information relating to impaired cell-cell interaction between WBC and endothelial cells of aged mice. Additionally, this can serve as a tool to evaluate the change of the cell-cell interaction caused by various treatments or diseases.

Uptake and Advanced Therapy of Butyrate in Inflammatory Bowel Disease

Abstract: The pathogenesis and refractory nature of inflammatory bowel disease (IBD) are related to multiple factors, including genetic factors, environmental factors, and abnormalities in gut microbial diversity, which lead to decreased levels of short-chain fatty acids (SCFAs). Among SCFAs, butyrate plays an important role in mucosal barrier maintenance, serves as an energy source in intestinal epithelial cells (IECs), and exhibits anti-inflammatory effects; therefore, it is a particularly important factor in gut homeostasis. Changes in gut microbiota and butyrate levels affect the outcomes of drug therapy for IBD. Butyrate is mainly absorbed in the large intestine and is transported by monocarboxylate transporter 1 (MCT1) and sodium-coupled monocarboxylate transporter 1 (SMCT1). During gut inflammation, butyrate utilization and uptake are impaired in IECs. Dysbiosis and low abundance of butyrate affect fecal microbiota transplantation and anticancer immunotherapy. Although butyrate administration has been reported as a treatment for IBD, its effects remain controversial. In this review, we discuss butyrate absorption and metabolism in patients with IBD and their relationship with drug therapy.

Inhibition of monocarboxylate transporters (MCT) 1 and 4 reduces exercise capacity in mice

Abstract: The concept of lactate shuttle is widely accepted in exercise physiology. Lactate transport is mediated by monocarboxylate transporters (MCT), which enable cells to take up and release lactate. However, the role of lactate during exercise has not yet been fully elucidated. In this study, we investigated the effects of lactate transport inhibition on exercise capacity and metabolism in mice. Here, we demonstrated that MCT1 inhibition by α‐cyano‐4‐hydroxycinnamate administration (4‐CIN, 200 mg/g of body weight) reduced the treadmill running duration at 20 m/min. The administration of 4‐CIN increased the blood lactate concentration immediately after exercise. With matched exercise duration, the muscle lactate concentration was higher while muscle glycogen content was lower in 4‐CIN‐administered mice. Further, we showed that MCT4 inhibition by bindarit administration (50 mg/kg of body weight) reduced the treadmill running duration at 40 m/min. Bindarit administration increased the muscle lactate but did not alter the blood lactate and glucose concentrations, as well as muscle glycogen content, immediately after exercise. A negative correlation was observed between exercise duration at 40 m/min and muscle lactate concentration immediately after exercise. Our results suggest that lactate transport via MCT1 and MCT4 plays a pivotal role in sustaining exercise.

Monocarboxylate Transporter 1 May Benefit Cerebral Ischemia via Facilitating Lactate Transport From Glial Cells to Neurons

Abstract: Monocarboxylate transporter 1 (MCT1) is expressed in glial cells and some populations of neurons. MCT1 facilitates astrocytes or oligodendrocytes (OLs) in the energy supplement of neurons, which is crucial for maintaining the neuronal activity and axonal function. It is suggested that MCT1 upregulation in cerebral ischemia is protective to ischemia/reperfusion (I/R) injury. Otherwise, its underlying mechanism has not been clearly discussed. In this review, it provides a novel insight that MCT1 may protect brain from I/R injury via facilitating lactate transport from glial cells (such as, astrocytes and OLs) to neurons. It extensively discusses (1) the structure and localization of MCT1; (2) the regulation of MCT1 in lactate transport among astrocytes, OLs, and neurons; and (3) the regulation of MCT1 in the cellular response of lactate accumulation under ischemic attack. At last, this review concludes that MCT1, in cerebral ischemia, may improve lactate transport from glial cells to neurons, which subsequently alleviates cellular damage induced by lactate accumulation (mostly in glial cells), and meets the energy metabolism of neurons.

Editorial: Lactate as a Major Signaling Molecule for Homeostasis

Abstract: L-lactate metabolism was first investigated in exercise physiology since it was considered as a waste product of glycolysis due to oxygen deficiency. Since the 1980s’, several studies showed that lactate is an essential metabolic fuel and signaling molecule (Brooks, 2020). Then, the interest for lactate has extended to a growing number of disciplines, from physiology to pathology and exercise is now viewed as a metabolic trigger for tissues adaptation. Lactate is transported by the monocarboxylate transporters (MCTs) family which present a ubiquitous tissue distribution but lactate can additionally activate the hydroxycarboxylic acid receptor 1 (HCAR1) also known as G protein-coupled receptor 81 (GPR81). In most tissues and cell types, lactate entry is mediated by MCT1 or MCT2 and related to oxidative capacity whereas MCT4 would be mainly involved in lactate output. The basic knowledge on lactate is that it could be a metabolic substrate or exchange molecule for muscle (Brooks), or brain (Pellerin, 2010), that MCTs content vary with training (Dubouchaud et al., 2000), nutritional status (Lambert et al., 2003; Pierre et al., 2007), cellular activity or intracellular signaling (Pérez-Escuredo et al., 2016) and diseases (Py et al., 2001). This Research Topic provides an update about the knowledge of lactate roles and mechanisms of action. Durand et al., focused on blood lactate kinetics in response to exercise. Their findings showed that the longer the recovery period, the better is the quality of models to describe lactate exchange and removal abilities. In the brain, exercise allows to increase lactate release, favoring hippocampal metabolism and especially mitochondrial biogenesis (Park et al.) but also mitochondrial efficiency and brain-derived neurotrophic factor biosynthesis (Hu et al.) (Figure 1). The ability of lactate to increase mitochondrial biogenesis has been previously described in skeletal muscle. The present studies demonstrated that lactate and oxidative metabolism could play an important role in the physiology of other tissues. Indeed, the effects of exercise on hippocampal mitochondria number and function highlight the role of lactate in mediating memory processes and, in turn, physical performance. Lactate is a mediator of neuronastrocyte dialogue since astrocytes provide lactate to neuron as an energetic substrate. Horvat et al. have provided evidence of this relationship with a focus on the lactate-positive feedback mechanism in astrocytes. Astrocytes switch their metabolism to lipid metabolism, enhancing availability of lactate for neuron as a metabolic substrate when ATP needs to be increased. The control and regulation of lactate entry into astrocytes could involve known and unknown transporters. Interestingly, during stressful conditions, such as hypoxia or ischemiareperfusion (I/R), increasing lactate concentration via exogenous lactate perfusion ameliorates the neurological outcome (Roumes et al., 2021). Buscemi et al. have tested the hypothesis that the beneficial effect of lactate in cerebral I/R process could be due to the activation of HCAR1 by Edited and reviewed by: Geoffrey A. Head, Baker Heart and Diabetes Institute, Australia

Intracerebroventricular high doses of TRIAC at juvenile stages improve peripheral hyperthyroidism and mediate thyromimetic effects in limited brain regions in a mouse model of MCT8 deficiency.

Abstract: INTRODUCTION Patients lacking functional Monocarboxylate transporter 8 (MCT8), a highly specific thyroid hormone (TH) transporter, present severe psychomotor disabilities. MCT8 deficiency leads to peripheral hyperthyroidism and brain hypothyroidism, the latter due to impaired transport of TH across brain barriers. Available treatments for patients are limited and aim to overcome the limited TH transport across brain barriers. The use of TH analogues such as 3,3',5-triiodothyroacetic acid (TRIAC) that do not require MCT8 to cross the cellular membranes is considered a potential therapy for MCT8 deficiency. Previous studies have shown that systemic administration of TRIAC at therapeutic doses does not increase TRIAC content in the brain, while intracerebroventricular (ICV) administration of therapeutic doses of TRIAC increases TRIAC content in the brain but does not mediate thyromimetic effects. In view of this, we hypothesise that ICV administration of high doses of TRIAC can mediate thyromimetic effects in the brain without worsening the brain hypothyroidism or peripheral hyperthyroidism of patients. METHODS 400 ng/g of body weight per day of TRIAC were administered ICV to a mouse model of MCT8 deficiency: Mct8-/y and deiodinase 2 (Dio2)-/ - double knockout mice. The effects of this treatment on TH and TRIAC levels/content in blood and tissues were determined by radioimmunoassay and effects on TH-regulated genes were assessed by RT-qPCR in peripheral and central tissues. RESULTS ICV administration of high doses of TRIAC ameliorated the peripheral hyperthyroidism. In the brain, this treatment did not further aggravate brain hypothyroidism and increased TRIAC content in several brain regions; however, only moderate thyromimetic activity was observed in restricted brain areas. CONCLUSION Administration of high doses of TRIAC by ICV delivery at juvenile stages in a mouse model of MCT8 deficiency, is effective in normalising peripheral hyperthyroidism, but exerts minimal thyromimetic activity in the brain.

Genetic and Neurological Deficiencies in the Visual System of mct8 Mutant Zebrafish

Abstract: Thyroid hormones (THs; T3 and T4) enter cells using specific transporters and regulate development and metabolism. Mutation in the TH transporter monocarboxylate transporter 8 (MCT8, SLC16A2) is associated with brain hypothyroidism and neurological impairment. We established mct8 mutant (mct8−/−) zebrafish as a model for MCT8 deficiency, which causes endocrinological, neurological, and behavioral alterations. Here, we profiled the transcriptome of mct8−/− larvae. Among hundreds of differentially expressed genes, the expression of a cluster of vision-related genes was distinct. Specifically, the expression of the opsin 1 medium wave sensitive 2 (opn1mw2) decreased in two mct8 mutants: mct8−/− and mct8−25bp−/− larvae, and under pharmacological inhibition of TH production. Optokinetic reflex (OKR) assays showed a reduction in the number of conjugated eye movements, and live imaging of genetically encoded Ca2+ indicator revealed altered neuronal activity in the pretectum area of mct8−25bp−/− larvae. These results imply that MCT8 and THs regulate the development of the visual system and suggest a mechanism to the deficiencies observed in the visual system of MCT8-deficiency patients.

Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

Abstract: The Allan-Herndon-Dudley syndrome (AHDS) is a severe disease caused by dysfunctional central thyroid hormone transport due to functional loss of the monocarboxylate transporter 8 (MCT8). In this study, we assessed whether mice with concomitant deletion of the thyroid hormone transporters Mct8 and the organic anion transporting polypeptide (Oatp1c1) represent a valid preclinical model organism for the AHDS. We generated and metabolically characterized a new CRISPR/Cas9 generated Mct8/Oatp1c1 double-knockout (dKO) mouse line for the clinical features observed in patients with AHDS. We show that Mct8/Oatp1c1 dKO mice mimic key hallmarks of the AHDS, including decreased life expectancy, central hypothyroidism, peripheral hyperthyroidism, impaired neuronal myelination, impaired motor abilities and enhanced peripheral thyroid hormone action in the liver, adipose tissue, skeletal muscle and bone. We conclude that Mct8/Oatp1c1 dKO mice are a valuable model organism for the preclinical evaluation of drugs designed to treat the AHDS.

Thyroid hormone regulators in human cerebral cortex development

Abstract: Brain development is critically dependent on the timely supply of thyroid hormones. The thyroid hormone transporters are central to the action of thyroid hormones in the brain, facilitating their passage through the blood–brain barrier. Mutations of the monocarboxylate transporter 8 (MCT8) cause the Allan–Herndon–Dudley syndrome, with altered thyroid hormone concentrations in the blood and profound neurological impairment and intellectual deficit. Mouse disease models have revealed interplay between transport, deiodination, and availability of T3 to receptors in specific cells. However, the mouse models are not satisfactory, given the fundamental differences between the mouse and human brains. The goal of the present work is to review human neocortex development in the context of thyroid pathophysiology. Recent developments in single-cell transcriptomic approaches aimed at the human brain make it possible to profile the expression of thyroid hormone regulators in single-cell RNA-Seq datasets of the developing human neocortex. The data provide novel insights into the specific cellular expression of thyroid hormone transporters, deiodinases, and receptors.

Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells

Abstract: In most regions, cancer ranks the second most frequent cause of death following cardiovascular disorders.

Monocarboxylate Transporters: Role and Regulation in Corneal Diabetes

Abstract: Diabetes mellitus (DM) is a group of metabolic diseases that is known to cause structural and functional ocular complications. In the human cornea, DM-related complications affect the epithelium, stroma, and nerves. Monocarboxylate transporters (MCTs) are a family of proton-linked plasma membrane transporters that carry monocarboxylates across plasma membranes. In the context of corneal health and disease, their role, presence, and function are largely undetermined and solely focused on the most common MCT isoforms, 1 through 4. In this study, we investigated the regulation of MCT1, 2, 4, 5, 8, and 10, in corneal DM, using established 3D self-assembled extracellular matrix (ECM) in vitro models. Primary stromal corneal fibroblasts were isolated from healthy (HCFs), type I (T1DMs), and type II (T2DMs) DM donors. Monoculture 3D constructs were created by stimulating stromal cells on transwells with stable vitamin C for two or four weeks. Coculture 3D constructs were created by adding SH-SY5Y neurons at two different densities, 12 k and 500 k, on top of the monocultures. Our data showed significant upregulation of MCT1 at 4 weeks for HCF, T1DM, and T2DM monocultures, as well as the 500 k nerve cocultures. MCT8 was significantly upregulated in HCF and T1DM monocultures and all of the 500 k nerve cocultures. Further, MCT10 was only expressed at 4 weeks for all cocultures and was limited to HCFs and T1DMs in monocultures. Immunofluorescence analysis showed cytoplasmic MCT expression for all cell types and significant downregulation of both MCT2 and MCT4 in HCFs, when compared to T1DMs and T2DMs. Herein, we reveal the existence and modulation of MCTs in the human diabetic cornea in vitro. Changes appeared dependent on neuronal density, suggesting that MCTs are very likely critical to the neuronal defects observed in diabetic keratopathy/neuropathy. Further studies are warranted in order to fully delineate the role of MCTs in corneal diabetes.