Clinical Implications of Folate Transport in the Central Nervous System

Alam, Camille; Kondo, Misaki; O’Connor, Deborah L.; Bendayan, Reina

doi:10.1016/j.tips.2020.02.004

Cited by 41 publications

(43 citation statements)

References 93 publications

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“…Folate is not biologically active, but it is readily reduced in the intestinal mucosa or liver and converted into tetrahydrofolate (THF) molecules, such as 5-methyl-THF and 5-formy-THF. 5-methylTHF is the predominant form of folate in the blood and its transport in the brain across the BBB is mediated by the folate receptor alpha (FRα/FOLR1), the H + -coupled folate transporter (PCFT/SLC46A1), and the reduced folate carrier (RFC/SLC19A1), but whether the same mechanisms mediate folate transport in neural cells including astrocytes is unclear ( Figure 3.1 ; Alam et al, 2020 ). Furthermore, because there is no dihydrofolate reductase in the brain to catalyze the formation of 5-methyl-THF ( Wu and Pardridge, 1999 ), 5-methylTHF rather than folate is present in the CSF.…”

Section: Mitochondrial Metabolism In Astrocytes and Redox Balancementioning

confidence: 99%

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

et al. 2020

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In the brain, mitochondrial metabolism has been largely associated with energy production, and its dysfunction is linked to neuronal cell loss. However, the functional role of mitochondria in glial cells has been poorly studied. Recent reports have demonstrated unequivocally that astrocytes do not require mitochondria to meet their bioenergetics demands. Then, the question remaining is, what is the functional role of mitochondria in astrocytes? In this work, we review current evidence demonstrating that mitochondrial central carbon metabolism in astrocytes regulates overall brain bioenergetics, neurotransmitter homeostasis and redox balance. Emphasis is placed in detailing carbon source utilization (glucose and fatty acids), anaplerotic inputs and cataplerotic outputs, as well as carbon shuttles to neurons, which highlight the metabolic specialization of astrocytic mitochondria and its relevance to brain function.

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Section: Mitochondrial Metabolism In Astrocytes and Redox Balancementioning

confidence: 99%

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

et al. 2020

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“…Folate antagonists acquire pharmacological activity after being incorporated by folate carrier protein and metabolized, and folate receptors (FOLRs), reduced folate carrier (RFC-1/SLC19A1), and proton-coupled folate transporter (PCFT/SLC26A1) are known as folate carrier proteins [ 14 ]. Thus, we investigated which folate carrier is expressed in the GSC subsets at the mRNA level.…”

Section: Resultsmentioning

confidence: 99%

Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts

Okada

Togashi

Sugai

et al. 2021

IJMS

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Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.

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“…43,44 Taken together, the activation of NRF-1/PGC-1α signaling by PQQ could potentially represent a novel therapeutic approach for several childhood neurological disorders by improving mitochondrial function and enhancing brain folate delivery through RFC. 45…”

Section: Discussionmentioning

confidence: 99%

Nuclear respiratory factor 1 (NRF‐1) upregulates the expression and function of reduced folate carrier (RFC) at the blood‐brain barrier

et al. 2020

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Folates are important for neurodevelopment and cognitive function. Folate transport across biological membranes is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate transport primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems results in suboptimal folate levels in the cerebrospinal fluid (CSF) causing childhood neurological disorders. Our group has reported that upregulation of RFC at the blood-brain barrier (BBB) through interactions with specific transcription factors, that is, vitamin D receptor (VDR) could increase brain folate delivery. This study investigates the role of nuclear respiratory factor 1 (NRF-1) in the regulation of RFC at the BBB. Activation of NRF-1/PGC-1α signaling through treatment with its specific ligand, pyrroloquinoline quinone (PQQ), significantly induced RFC expression and transport activity in hCMEC/D3 cells. In contrast, transfection with NRF-1 or PGC-1α targeting siRNA downregulated RFC functional expression in the same cell system. Applying chromatin immunoprecipitation (ChIP) assay, we further demonstrated that PQQ treatment increased NRF-1 binding to putative NRF-1 binding sites within the SLC19A1 promoter, which encodes for RFC. Additionally, in vivo treatment of wild type mice with PQQ-induced RFC expression in isolated mouse brain capillaries. Together, these findings demonstrate that NRF-1/PGC-1α activation by PQQ upregulates RFC functional expression at the BBB and could potentially enhance brain folate uptake.

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Clinical Implications of Folate Transport in the Central Nervous System

Cited by 41 publications

References 93 publications

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts

Nuclear respiratory factor 1 (NRF‐1) upregulates the expression and function of reduced folate carrier (RFC) at the blood‐brain barrier

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