monocarboxylate transporter
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Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 120
Author(s):  
Katharina Geistlinger ◽  
Jana D. R. Schmidt ◽  
Eric Beitz

(1) Background: Human aquaporin-9 (AQP9) conducts several small uncharged metabolites, such as glycerol, urea, and lactic acid. Certain brain tumors were shown to upregulate AQP9 expression, and the putative increase in lactic acid permeability was assigned to severity. (2) Methods: We expressed AQP9 and human monocarboxylate transporter 1 (MCT1) in yeast to determine the uptake rates and accumulation of radiolabeled l-lactate/l-lactic acid in different external pH conditions. (3) Results: The AQP9-mediated uptake of l-lactic acid was slow compared to MCT1 at neutral and slightly acidic pH, due to low concentrations of the neutral substrate species. At a pH corresponding to the pKa of l-lactic acid, uptake via AQP9 was faster than via MCT1. Substrate accumulation was fundamentally different between AQP9 and MCT1. With MCT1, an equilibrium was reached, at which the intracellular and extracellular l-lactate/H+ concentrations were balanced. Uptake via AQP9 was linear, theoretically yielding orders of magnitude of higher substrate accumulation than MCT1. (4) Conclusions: The selectivity of AQP9 for neutral l-lactic acid establishes an ion trap for l-lactate after dissociation. This may be physiologically relevant if the transmembrane proton gradient is steep, and AQP9 acts as the sole uptake path on at least one side of a polarized cell.


2022 ◽  
Vol 29 (1) ◽  
Author(s):  
Asmita Gyawali ◽  
Sana Latif ◽  
Seung-Hye Choi ◽  
Seung Jae Hyeon ◽  
Hoon Ryu ◽  
...  

Abstract Background 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. Methods 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. Results [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. Conclusions 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.


Author(s):  
Subrina Jesmin ◽  
Takeru Shima ◽  
Mariko Soya ◽  
Kanako Takahashi ◽  
Koki Omura ◽  
...  

A pre-diabetic population has an increased risk of cognitive decline as well as type 2 diabetes mellitus (T2DM). The present study investigated whether the progression of memory dysfunction and dysregulated brain glycogen metabolism is prevented with four months of exercise intervention from the pre-symptomatic stage in T2DM rat model. Memory function and biochemical and molecular profiles were assessed in the pre-symptomatic stage of OLETF rats, a T2DM model, with LETO rats as genetic control. These rats were subjected to light- or moderate-intensity treadmill running for four months with repetition of the same experiments. Significant hippocampal-dependent memory dysfunction was observed in the pre-symptomatic stage of OLETF rats, accompanied by downregulated levels of hippocampal monocarboxylate transporter 2 (MCT2), a neuronal lactate-transporter, without alteration in hippocampal glycogen levels. Four months of light or moderate exercise from the pre-symptomatic stage of T2DM normalized glycemic parameters and also hippocampal molecular normalization through MCT2, glycogen, and brain-derived neurotrophic factor (BDNF) levels with the improvement of memory dysfunction in OLETF rats. A four-month exercise regimen from the pre-symptomatic stage of T2DM at light and moderate intensities contributed to the prevention of the development of T2DM and the progression of cognitive decline with hippocampal lactate-transport and BDNF improvement.


2021 ◽  
Author(s):  
Andreia P Alves ◽  
Sandra M Rocha ◽  
Ana C Mamede ◽  
Marco G Alves ◽  
Pedro F Oliveira ◽  
...  

Abstract Background: The human Amniotic Membrane (hAM) has been studied as a potential therapeutic option in cancer, namely in hepatocellular carcinoma. Previously, our research group evaluated the effect of human Amniotic Membrane Protein Extracts (hAMPE) in cancer therapy, demonstrating that hAMPE inhibit the metabolic activity of human hepatocellular carcinoma cell lines: Hep3B2.1-7, HepG2 and Huh7. Therefore, the aim of this study was to evaluate the effect of hAMPE treatment in glucose metabolism of hepatocellular carcinoma. Methods and Results: Glucose uptake and lactate production was assessed by 1H-NMR, and the expression of several mediators of the glycolytic pathway was evaluated by Western blot or fluorescence. Our results showed that hAMPE treatment increased glucose consumption on Hep3B2.1-7, HepG2, and Huh7 through the increase of GLUT1 in Hep3B2.1-7 and Huh7, and GLUT3 in HepG2 cells. It was observed increased expression of 6-phosphofrutokinase (PFK-1L) in all cell lines, indicating that glucose can be converted to pyruvate. Also, it was verified that glucose seems not to be converted to lactate on HepG2 and Huh7 cells, suggesting that hAMPE treatment may contradict the Warburg effect observed in carcinogenesis. In Hep3B2.1-7, the hAMPE treatment induced an increase in expression of lactate dehydrogenase (LDH) and monocarboxylate transporter isoform 4 (MCT4). Conclusions: Overall, this work highlighted the potential usefulness of hAMPE as anticancer therapy through the modulation of the glycolytic metabolism in human hepatocellular carcinoma.


Author(s):  
Rojan Ipek ◽  
Sevcan Tug Bozdogan ◽  
Mustafa Kömür ◽  
Cetin Okuyaz

AbstractAllan–Herndon–Dudley's syndrome (AHDS) is a rare X-linked recessive disease that causes abnormal serum thyroid function tests, severe hypotonia, intellectual disability, and motor deficit due to a mutation in the monocarboxylate transporter 8, which is a thyroid hormone transporter. A 6-month-old male patient presented to our outpatient clinic with a serious hypotonia complaint. With a preliminary diagnosis of AHDS, a molecular genetic examination was performed. The molecular genetic analysis detected a new previously unidentified variant in the SLC16A2 gene. This case has been presented to report the AHDS, which is a rare cause of hypotonia in patients presenting/consulting with severe hypotonia, global developmental delay, and abnormal thyroid function test results. Besides, a novel pathogenic mutation in the SLC16A2 gene has been described in the present article.


2021 ◽  
Author(s):  
Sivaraj M Sundaram ◽  
Adriana Arrulo Pereira ◽  
Hannes Köpke ◽  
Helge Müller-Fielitz ◽  
Meri De Angelis ◽  
...  

The solute carrier monocarboxylate transporter 8 (MCT8) transports the thyroid hormones thyroxine and tri-iodothyronine (T3) across cell membranes. MCT8 gene deficiency, termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. As no treatment of the neurological symptoms is available yet, 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 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.


2021 ◽  
Author(s):  
Celia M Bisbach ◽  
Daniel T Hass ◽  
James B Hurley

Purpose: Succinate is exported by the retina and imported by eyecup tissue. The transporter(s) 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. Methods: We assessed retinal succinate export and eyecup succinate import in short term ex vivo culture using gas chromatography-mass spectrometry. We test the dependence of succinate export and import on pH, proton ionophores, conventional MCT substrates, and the MCT inhibitors AZD3965, AR-C155858, and diclofenac. Results: Succinate exits retinal tissue through MCT1 but does not enter RPE through MCT1 or any other MCT. Intracellular succinate levels are a contributing factor that determines if an MCT1-expressing tissue will export succinate. Conclusions: MCT1 facilitates export of succinate from retinas. An unidentified, non-MCT transporter facilitates import of succinate into RPE.


2021 ◽  
Author(s):  
Xiao-Hui Liao ◽  
Pablo Avalos ◽  
Shelest Oksana ◽  
Raz Ofan ◽  
Michael Shilo ◽  
...  

Allan-Herndon-Dudley syndrome (AHDS) is a severe X-linked intellectual and psychomotor disability disorder accompanied by abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8), a specific TH transporter widely expressed in the central nervous system. MCT8 gene 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. AAV9-based gene therapy is a promising approach to treat monogenic neurological disorders. Here, the potential of this approach was tested in the well-established double knockout (dKO) Mct8-/y; Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/- mouse model of AHDS, which displays disease-relevant neurological and TH phenotypes. Systemic intravenous delivery of adeno-associated virus serotype 9 (AAV9)-MCT8 at a juvenile stage led to improved locomotor and cognitive function, as well as rescue of T3-brain content and T3-related gene expression. This preclinical study indicates that this gene therapy may improve the neurological symptoms of AHDS patients.


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