Showing papers on "Monocarboxylate transporter published in 2008"
TL;DR: Low thyroid hormone transport across the blood-brain barrier contributes to the neurological deficits observed in affected patients with MCT8 mutations, and the high microvessel expression of OATP14 in rodent compared with human brain may contribute to the relatively mild phenotype observed in Mct8-null mice.
Abstract: Thyroid hormones require transport across cell membranes to carry out their biological functions. The importance of transport for thyroid hormone signaling was highlighted by the discovery that inactivating mutations in the human monocarboxylate transporter-8 (MCT8) (SLC16A2) cause severe psychomotor retardation due to thyroid hormone deficiency in the central nervous system. It has been reported that Mct8 expression in the mouse brain is restricted to neurons, leading to the model that organic ion transporter polypeptide-14 (OATP14, also known as OATP1C1/SLCO1C1) is the primary thyroid hormone transporter at the blood-brain barrier, whereas MCT8 mediates thyroid hormone uptake into neurons. In contrast to these reports, we report here that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human, mouse, and rat. In addition, OATP14 mRNA and protein are strongly enriched in mouse and rat cerebral microvessels but not in human microvessels. In rat, Mct8 and ...
264 citations
TL;DR: The increased expression of Monocarboxylate transporters suggests an important role in CRC, which might justify their use, especially MCT1 and MCT4, as targets in CRC drug therapy.
Abstract: Tumour cells are known to be highly glycolytic, thus producing high amounts of lactic acid. Monocarboxylate transporters (MCTs), by promoting the efflux of the accumulating acids, constitute one of the most important mechanisms in the maintenance of tumour intracellular pH. Since data concerning MCT expression in colorectal carcinomas (CRC) are scarce and controversial, the present study aimed to assess the expressions of MCT1, 2, and 4 in a well characterized series of CRC and assess their role in CRC carcinogenesis. CRC samples (126 cases) were analyzed for MCT1, MCT2, and MCT4 immunoexpression and findings correlated with clinico-pathological parameters. Expression of all MCT isoforms in tumour cells was significantly increased when compared to adjacent normal epithelium. Remarkably, there was a significant gain of membrane expression for MCT1 and MCT4 and loss of plasma membrane expression for MCT2 in tumour cells. Plasma membrane expression of MCT1 was directly related to the presence of vascular invasion. This is the larger study on MCT expression in CRC and evaluates for the first time its clinico-pathological significance. The increased expression of these transporters suggests an important role in CRC, which might justify their use, especially MCT1 and MCT4, as targets in CRC drug therapy.
230 citations
TL;DR: Thyroid hormone (TH) is essential for the proper development of numerous tissues, notably the brain, and several transporter families have been identified, but only monocarboxylate transporter (MCT)8, MCT10 and organic anion-transporting polypeptide (OATP)1C1 demonstrate a high degree of specificity towards TH.
Abstract: Thyroid hormone (TH) is essential for the proper development of numerous tissues, notably the brain. TH acts mostly intracellularly, which requires transport by TH transporters across the plasma membrane. Although several transporter families have been identified, only monocarboxylate transporter (MCT)8, MCT10 and organic anion-transporting polypeptide (OATP)1C1 demonstrate a high degree of specificity towards TH. Recently, the biological importance of MCT8 has been elucidated. Mutations in MCT8 are associated with elevated serum T3 levels and severe psychomotor retardation, indicating a pivotal role for MCT8 in brain development. MCT8 knockout mice lack neurological damage, but mimic TH abnormalities of MCT8 patients. The exact pathophysiological mechanisms in MCT8 patients remain to be elucidated fully. Future research will probably identify novel TH transporters and disorders based on TH transporter defects.
219 citations
TL;DR: The existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN is confirmed, and lactate derived from astroCytes forms part of the central chemosensory stimulus for ventilation in this nucleus.
Abstract: The astrocyte-neuronal lactate-shuttle hypothesis posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 microM alpha-cyano-4-hydroxy-cinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT) 2 but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 microM 4-CIN significantly reduced the magnitude of the acidosis in neurons but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-D-glucose analog in neurons but did not alter the uptake rate of this 2-deoxy-D-glucose analog in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates.
102 citations
TL;DR: The MCT proteins have the typical twelve transmembrane-spanning domain (TMD) topology of membrane transporter proteins, and their structure–function relationship is discussed, especially in relation to the future impact of the single nucleotide polymorphism (SNP) databases and, given their ability to transport pharmacologically relevant compounds, the potential impact for pharmacogenomics.
Abstract: 1. The monocarboxylate transporter (MCT, SLC16) family comprises 14 members, of which to date only MCT1-4 have been shown to carry monocarboxylates, transporting important metabolic compounds such as lactate, pyruvate and ketone bodies in a proton-coupled manner. The transport of such compounds is fundamental for metabolism, and the tissue locations, properties and regulation of these isoforms is discussed. 2. Of the other members of the MCT family, MCT8 (a thyroid hormone transporter) and TAT1 (an aromatic amino acid transporter) have been characterized more recently, and their physiological roles are reviewed herein. The endogenous substrates and functions of the remaining members of the MCT family await elucidation. 3. The MCT proteins have the typical twelve transmembrane-spanning domain (TMD) topology of membrane transporter proteins, and their structure-function relationship is discussed, especially in relation to the future impact of the single nucleotide polymorphism (SNP) databases and, given their ability to transport pharmacologically relevant compounds, the potential impact for pharmacogenomics.
86 citations
TL;DR: Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations.
Abstract: Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T3 levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T3 and T4 uptake, T3 metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T3, immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T3 uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of ...
85 citations
TL;DR: A hypothetical model in which the effective movement of H+ into the bulk cytosol is increased by CAII, thus slowing the dissipation of the H+ gradient across the cell membrane, which drives MCT1 activity is presented.
83 citations
TL;DR: By genome-wide ex vivo mRNA expression studies using mouse islets and an extensive panel of other tissues, the future challenge is to explore the physiological/pathological relevance and study conditions under which the phenotypically disallowed state in the beta-cell is breached.
Abstract: A differentiated β-cell results not only from cell-specific gene expression, but also from cell-selective repression of certain housekeeping genes. Indeed, to prevent insulin toxicity, β-cells should handle insulin stores carefully, preventing exocytosis under conditions when circulating insulin is unwanted. Some ubiquitously expressed proteins would significantly jeopardize this safeguard, when allowed to function in β-cells. This is illustrated by two studied examples. First, low- K m hexokinases are disallowed as their high affinity for glucose would, when expressed, significantly lower the threshold for glucose-induced β-cell function and cause hypoglycaemia, as happens in patients with β-cell tumours. Thus the β-cell phenotype means not only expression of glucokinase but also absence of low- K m hexokinases. Secondly, the absence of MCTs (monocarboxylic acid transporters) in β-cells explains the pyruvate paradox (pyruvate being an excellent substrate for mitochondrial ATP production, yet not stimulating insulin release when added to β-cells). The relevance of this disallowance is underlined in patients with exercise-induced inappropriate insulin release: these have gain-of-function MCT1 promoter mutations and loss of the pyruvate paradox. By genome-wide ex vivo mRNA expression studies using mouse islets and an extensive panel of other tissues, we have started to identify in a systematic manner other specifically disallowed genes. For each of those, the future challenge is to explore the physiological/pathological relevance and study conditions under which the phenotypically disallowed state in the β-cell is breached.
75 citations
TL;DR: It is hypothesize that disruption of Mct3 leads to a potentially reversible decrease in subretinal space pH, thereby reducing the magnitude of the light suppressible photoreceptor current.
Abstract: To meet the high-energy demands of photoreceptor cells, the outer retina metabolizes glucose through glycolytic and oxidative pathways, resulting in large-scale production of lactate and CO2. Mct3,...
66 citations
TL;DR: Molecular analysis of the monocarboxylate transporter 8 gene showed that the patient was hemizygous for a novel missense mutation P537L, which highlights the importance of determining thyroid hormone levels, especially triiodothyronine, in infants with severe neonatal hypotonia.
Abstract: Monocarboxylate transporter 8 acts as a specific cell membrane transporter for thyroxine and especially triiodothyronine into target cells. It is expressed in brain neurons and in many other tissues. The monocarboxylate transporter 8 gene resides on chromosome Xq13.2. An 11-month-old male infant was referred because of severe hypotonia from early life and global developmental delay. Thyroid-function tests showed normal thyrotropin levels and the characteristic for the disorder, including high serum triiodothyronine and low thyroxine concentrations. Molecular analysis of the monocarboxylate transporter 8 gene showed that the patient was hemizygous for a novel missense mutation P537L. This case highlights the importance of determining thyroid hormone levels, especially triiodothyronine, in infants with severe neonatal hypotonia.
53 citations
TL;DR: It is suggested that pyruvate at this time is used for energy production, consistent with memory inhibition by dinitrophenol, and D-lactate acts as an astrocytic metabolic inhibitor rather than as an inhibitor of neuronal L- lactate uptake, as has occasionally been suggested.
TL;DR: MCT8 gene deficiency results in deviant myelinization and general atrophy, which is substantiated by the MR spectroscopy findings of increased choline and myoinositol levels and decreased N-acetyl aspartate.
Abstract: Context: In monocarboxylate transporter 8 (MCT8) gene deficiency, a syndrome combining thyroid and neurological abnormalities, the central nervous system has not yet been characterized by magnetic resonance (MR) spectroscopy. Objective: We studied whether the degree of dysmyelinization in MCT8 gene deficiency according to MR imaging (MRI) is coupled with abnormalities in brain metabolism. Design: MRI and MR spectroscopy of the brain were performed twice in two MCT8 gene deficiency patients, for the first time at age 8-10 months and for the second time at age 17-28 months. The results were compared with those obtained in controls of a similar age. Results: Compared with controls, young children with MCT8 show choline and myoinositol level increases and N-acetyl aspartate decreases in supraventricular gray and white matter, phenomena associated with the degree of dysmyelinization according to MRI. Conclusion: MCT8 gene deficiency results in deviant myelinization and general atrophy, which is substantiated by the MR spectroscopy findings of increased choline and myoinositol levels and decreased N-acetyl aspartate. The observations suggest that different mutations in the MCT8 gene lead to differences in the severity of the clinical spectrum, dysmyelinization, and MR spectroscopy-detectable changes in brain metabolism.
TL;DR: It is observed for the first time that activation of PPARalpha in rats by clofibrate treatment or fasting increased hepatic mRNA concentration of MCT1.
TL;DR: The cellular localization of transporters suggests the involvement of SMCT in the uptake of filtrated lactate and ketone bodies and that of MCTs in the transport of monocarboxylate metabolites between tubular cells and circulation, but the different distribution patterns do not support the notion of a functional linkage between SMCT and MCT1/MCT2.
Abstract: Expression analysis of transporters selective for monocarboxylates such as lactate and ketone bodies in the kidney contributes to understanding the renal energy metabolism. Distribution and expression intensity of a sodium-dependent monocarboxylate transporter (SMCT) and proton-coupled monocarboxylate transporters (MCT) were examined in the mouse kidney. In situ hybridization survey detected significant mRNA expressions of SMCT and MCT-1, 2, 5, 8, 9, 10, and 12. Among these, signals for SMCT, MCT2 and MCT8 were predominant; transcripts of SMCT were restricted to the cortex and the outer stripe of outer medulla, while those of MCT2 and MCT8 gathered in the inner stripe of outer medulla and the cortex, respectively. Immunohistochemically, SMCT was present at the brush border in S2 and S3 of proximal tubules, suggesting the active uptake of luminal monocarboxylates here. MCT1 and MCT2 immunoreactivities were respectively found baso-laterally in S1 and thick ascending limbs of Henle’s loop. The cellular localization of transporters suggests the involvement of SMCT in the uptake of filtrated lactate and ketone bodies and that of MCTs in the transport of monocarboxylate metabolites between tubular cells and circulation, but the different distribution patterns do not support the notion of a functional linkage between SMCT and MCT1/MCT2.
TL;DR: The present immunohistochemical study suggests that peripheral nerves depend on monocarboxylates as a major energy source and that MCT1 in the perineurium is responsible for the supply of monOCarboxyates to nerve fibers and Schwann cells.
Abstract: Peripheral nerves express GLUT1 in both endoneurial blood vessels and the perineurium and utilize glucose as a major energy substrate, as does the brain. However, under conditions of a reduced utilization of glucose, the brain is dependent upon monocarboxylates such as ketone bodies and lactate, being accompanied by an elevated expression of a monocarboxylate transporter (MCT1) in the blood-brain barrier. The present immunohistochemical study aimed to examine the expression of MCT1 in the peripheral nerves of mice. MCT1 immunoreactivity was found in the perineurial sheath and colocalized with GLUT1, while the endoneurial blood vessels expressed GLUT1 only. An intense expression of MCT1 in the perineurium was confirmed by Western blot and in situ hybridization analyses. Ultrastructurally, the MCT1 and GLUT1 immunoreactivities in the thick perineurium showed an intensity gradient decreasing towards the innermost layer. In neonates, the MCT1 immunoreactivity in the perineurium was intense, while the GLUT1 immunoreactivity was faint or absent. These findings suggest that peripheral nerves depend on monocarboxylates as a major energy source and that MCT1 in the perineurium is responsible for the supply of monocarboxylates to nerve fibers and Schwann cells.
TL;DR: Investigation of the distribution of the monocarboxylate transporter MCT2 in the cortex of normal adult human brain using an immunohistochemical approach supports a putative role for MCT1 in adjustment of energy supply to levels of activity.
TL;DR: This work identifies Sln as a novel LKB1-interacting protein using Drosophila melanogaster genetic modifier screening and proposes Sln is an important downstream target of L KB1.
Abstract: Silnoon (Sln) is a monocarboxylate transporter (MCT) that mediates active transport of metabolic monocarboxylates such as butyrate and lactate. Here, we identify Sln as a novel LKB1-interacting protein using Drosophila melanogaster genetic modifier screening. Sln expression does not affect cell cycle progression or cell size but specifically enhances LKB1-dependent apoptosis and tissue size reduction. Conversely, down-regulation of Sln suppresses LKB1-dependent apoptosis, implicating Sln as a downstream mediator of LKB1. The kinase activity of LKB1 induces apical trafficking of Sln in polarized cells, and LKB1-dependent Sln trafficking is crucial for triggering apoptosis induced by extracellular butyrate. Given that LKB1 functions to control both epithelial polarity and cell death, we propose Sln is an important downstream target of LKB1.
TL;DR: MCT1 plays a pivotal role in the control of basal proton‐driven lactate flux in astrocytes while basigin is only partly involved, most likely via its interaction with MCT1.
Abstract: Lactate release by astrocytes is postulated to be of importance for neuroenergetics but its regulation is poorly understood. Basigin, a chaperone protein for specific monocarboxylate transporters (MCTs), represents a putatively important regulatory element for lactate fluxes. Indeed, basigin knockdown by RNA interference in primary cultures of astrocytes partially reduced both proton-driven lactate influx and efflux. But more strikingly, enhancement of lactate efflux induced by glutamate was prevented while the effect of sodium azide was significantly reduced by treatment of cultured astrocytes with anti-basigin small interfering RNA. Enhancement of glucose utilization was unaffected under the same conditions. Basal lactate uptake and release were significantly reduced by MCT1 knockdown, even more so than with basigin knockdown, whereas glutamate-driven or sodium azide-induced enhancement of lactate release was not inhibited by either MCT1, 2, or 4 small interfering RNAs. In conclusion, MCT1 plays a pivotal role in the control of basal proton-driven lactate flux in astrocytes while basigin is only partly involved, most likely via its interaction with MCT1. In contrast, basigin appears to critically regulate the enhancement of lactate release caused by glutamate (or sodium azide) but via an effect on another unidentified transporter at least present in astrocytes in vitro.
TL;DR: The hypothesis that E regulates basal and IIH‐associated patterns of DVC MCT2 and neuronal glucose transporter gene expression and that caudal fourth ventricular (CV4) lactate infusion exerts divergent effects on blood glucose levels and DVC energy transducer gene profiles in hypoglycemic E‐ vs. oil (O)‐implanted ovariectomized rats is investigated.
Abstract: The monocarboxylate, lactate, is produced by astrocytic glycolysis and is trafficked to neurons as a substrate fuel for aerobic respiration. This molecule is a critical monitored metabolic variable in hindbrain detection of cellular energy imbalance, because diminished uptake and/or oxidative catabolism of lactate in this part of the brain activates neural mechanisms that increase systemic glucose availability. Lactate-sensitive chemosensory neurons occur in the hindbrain dorsal vagal complex (DVC). Estradiol (E) enhances expression of the neuronal monocarboxylate transporter MCT2 in the DVC during insulin-induced hypoglycemia (IIH), evidence that this hormone may promote local lactate utilization during systemic glucose shortages. We investigated the hypothesis that E regulates basal and IIH-associated patterns of DVC MCT2 and neuronal glucose transporter gene expression and that caudal fourth ventricular (CV4) lactate infusion exerts divergent effects on blood glucose levels and DVC energy transducer gene profiles in hypoglycemic E- vs. oil (O)-implanted ovariectomized (OVX) rats. Insulin-induced decrements in circulating glucose were significantly augmented by lactate, albeit to a greater extent in the presence of E. DVC MCT2, GLUT3, GLUT4, glucokinase (GCK), and sulfonylurea receptor-1 (SUR1) mRNA levels did not differ between saline-injected OVX + E and OVX + O rats. IIH elevated MCT2 and GLUT3 gene profiles in both E- and O-implanted groups, but up-regulation of MCT2 transcripts was reversed by CV4 lactate infusion during hypoglycemia in E- but not O-implanted animals. DVC GLUT4 and GK mRNA were decreased by insulin alone in OVX + O but not OVX + E, but were suppressed by lactate plus insulin treatment in the latter group. Expression of the SUR1 subunit of the energy-dependent potassium channel K(ATP) was significantly decreased by IIH in both E- and O-treated rats and further suppressed in response to lactate delivery during hypoglycemia in OVX + E. These data reveal that E does not control baseline DVC substrate fuel transporter or energy transducer gene profiles or local MCT2, GLUT3, or SUR1 transcriptional responses to IIH but prevents IIH-associated decreases in GLUT4 and GCK mRNA in this brain site. The results also show that, in the presence of E, intensifying effects of CV4 lactate infusion on hypoglycemia are correlated with reversal of IIH enhancement of DVC MCT2 gene expression, augmented IIH inhibition of SUR1 transcripts, and reductions in GLUT4 and GCK mRNA levels relative to baseline. This work implies that IIH may enhance specific neuronal lactate and glucose transport mechanisms in the female rat DVC and that, in the presence of E, caudal hindbrain lactate repletion may normalize neuronal lactate but not glucose internalization by local neurons. The results also suggest that putative IIH-associated reductions in K(ATP)-mediated regulation of membrane voltage in this brain site may be causally related to diminished glucose availability.
TL;DR: A highly predictive regression model, including waist circumference, citrate synthase activity, and percentage of type 1 fibers, was found to explain the highly variable MCT1 response to weight loss in the obese group and appears linked both to changes in oxidative parameters and toChanges in visceral adipose tissue content.
Abstract: The effects of weight loss on skeletal muscle lactate transporter [monocarboxylate transporter (MCT)] expression in obese subjects were investigated to better understand how lactate transporter met...
TL;DR: The results of functional divergence analysis provided statistical evidences for shifted evolutionary rate and/or changes of amino acid property after gene duplication and showed that strong functional constraints must impose on the N- and C-terminal domains of vertebrate MCTs.
TL;DR: The transient decrease of extracellular SUC observed during epileptiform activity suggested that the function of the synaptic target recognizing protonated succinate monocarboxylate may vary under different (patho)physiological conditions.
Abstract: Succinate (SUC), a citrate (CIT) cycle intermediate, and carbenoxolone (CBX), a gap junction inhibitor, were shown to displace [3H]gamma-hydroxybutyrate ([3H]GHB), which is specifically bound to sites present in synaptic membrane subcellular fractions of the rat forebrain and the human nucleus accumbens. Elaboration on previous work revealed that acidic pH-induced specific binding of [3H]SUC occurs, and it has been shown to have a biphasic displacement profile distinguishing high-affinity (K(i,SUC) = 9.1 +/- 1.7 microM) and low-affinity (K(i,SUC) = 15 +/- 7 mM) binding. Both high- and low- affinity sites were characterized by the binding of GHB (K(i,GHB) = 3.9 +/- 0.5 microM and K(i,GHB) = 5.0 +/- 2.0 mM) and lactate (LAC; K(i,LAC) = 3.9 +/- 0.5 microM and K(i,LAC) = 7.7 +/- 0.9 mM). Ligands, including the hemiester ethyl-hemi-SUC, and the gap junction inhibitors flufenamate, CBX, and the GHB binding site-selective NCS-382 interacted with the high-affinity site (in microM: K(i,EHS) = 17 +/- 5, K(i,FFA) = 24 +/- 13, K(i,CBX) = 28 +/- 9, K(i,NCS-382) = 0.8 +/- 0.1 microM). Binding of the Na+,K+-ATPase inhibitor ouabain, the proton-coupled monocarboxylate transporter (MCT)-specific alpha-cyano-hydroxycinnamic acid (CHC), and CIT characterized the low-affinity SUC binding site (in mM: K(i,ouabain) = 0.13 +/- 0.05, K(i,CHC) = 0.32 +/- 0.07, K(i,CIT) = 0.79 +/- 0.20). All tested compounds inhibited [3H]SUC binding in the human nucleus accumbens and had K(i) values similar to those observed in the rat forebrain. The binding process can clearly be recognized as different from synaptic and mitochondrial uptake or astrocytic release of SUC, GHB, and/or CIT by its unique GHB selectivity. The transient decrease of extracellular SUC observed during epileptiform activity suggested that the function of the synaptic target recognizing protonated succinate monocarboxylate may vary under different (patho)physiological conditions. Furthermore, we put forward a hypothesis on the synaptic activity-regulated signaling between astrocytes and neurons via SUC protonation.
TL;DR: Evidence is provided that in Drosophila melanogaster a signaling network controlled by the LKB1 tumor suppressor regulates trafficking of an Sln/dMCT1 monocarboxylate transporter to the plasma membrane, which enables cells to import additional energy sources such as lactate and butyrate, enhancing the repertoire of fuels they can use to power vital activities.
Abstract: A question preoccupying many researchers is how signal transduction pathways control metabolic processes and energy production. A study by Jang et al. (Jang, C., G. Lee, and J. Chung. 2008. J. Cell Biol. 183:11–17) provides evidence that in Drosophila melanogaster a signaling network controlled by the LKB1 tumor suppressor regulates trafficking of an Sln/dMCT1 monocarboxylate transporter to the plasma membrane. This enables cells to import additional energy sources such as lactate and butyrate, enhancing the repertoire of fuels they can use to power vital activities.
TL;DR: Both protein kinases A and C, whose effects are mediated by cytoskeleton, negatively regulate the endogenous lactate transporter of Xenopus oocyte, suggesting that these kinases may have a role in the control of cytosolic pyruvate/lactate pool in the oocyte.
Abstract: Carbon flux in Xenopus laevis oocyte is glycogenic and an endogenous monocarboxylate transporter is responsible for intracellular lactate uptake. The aim of the present study was to determine if direct activation of protein kinases C and A modulates the activity of lactate transporter, as well as to investigate the possible role of cytoskeleton in these regulatory phenomena. The modulation was studied in isolated Xenopus oocytes of stage V-VI by measuring (14)C-lactate uptake, both in the absence and in the presence of cytoskeletal-perturbing toxins. We found that the basal lactate transporter activity depends on the integrity of the cytoskeleton since it is partially inhibited by cytoskeleton disorganisation. Both PKA and PKC activation caused a significant decrease in transport activity and this decrease could be blocked by specific protein kinase inhibitors. The evidenced effects were not additive. Transport inhibition was annulled by agents that destabilize actin filaments or microtubules. We conclude that both protein kinases A and C, whose effects are mediated by cytoskeleton, negatively regulate the endogenous lactate transporter of Xenopus oocyte, suggesting that these kinases may have a role in the control of cytosolic pyruvate/lactate pool in the oocyte.
TL;DR: The findings from the current study suggest that MCTs would involve in establishing adequate microenvironment for sperm maturation and storage in the epididymis, eventually leading to maintenance of male fertility.
Abstract: In the present study, real-time PCR was performed to evaluated expression of several isoforms of monocarboxylate transporters(MCTs) and two known MCT regulatory proteins, basigin (Bsg) and embigin, in the epididymis of the male reproductive tract during postnatal development. In addition, ERα�-mediated regulation of MCT1 expression in the epididymis was determined with estrogen receptor(ER) α� knockout(α�ERKO) mice by immunohistochemistry. Results from the current study demonstrated differential expression of MCT isoform(MCT 1, 2, 3, 4, and 8), Bsg, and embigin mRNAs in rat epididymis according to postnatal age and epididymal region. In addition, immunohistochemical study of MCT1 revealed the limited localization of MCT1 at apical area of corpus and caudal epididymis. The present study also showed that expression of MCT1 was not directly regulated by ERα�. The findings from the current study suggest that MCTs would involve in establishing adequate microenvironment for sperm maturation and storage in the epididymis, eventually leading to maintenance of male fertility.