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Mechanisms of Phosphate Transport

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 25127

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Prof. Dr. Victor Sorribas

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Department of Biochemistry and Molecular and Cellular Biology, Molecular Toxicology Lab., University of Zaragoza, Zaragoza, Spain

Special Issue Information

Dear Colleagues,

The International Journal of Molecular Science (IJMS, ISSN 1422-0067) has decided to publish an issue on the field of inorganic phosphate transport. This is an excellent, well-deserved opportunity because inorganic phosphate is involved not only in many physiological processes (buffer, macromolecule component, signal transduction, energy store, etc.) but also in the pathophysiology of processes caused by either the deprivation (hypophosphatemia), excess (hyperphosphatemia), or dysregulation (precipitation with calcium, deposition) of phosphate.

Over the last thirty years, in-depth knowledge on the identification of new Pi transporters and the corresponding molecular mechanisms of sodium–phosphate cotransport has been compiled. The study of interactions with associated proteins, of the hormonal and non-hormonal regulation of Pi transport, of transport-independent (paracellular) intestinal Pi absorption, and of toxicity during hyperphosphemia are just a few pending areas of research waiting to be studied in greater detail. Similarly, there is strong evidence that new Pi transporters exist, some of them functioning independently of sodium.

The Special Issue, “Mechanisms of phosphate transport”, of the International Journal of Molecular Science is intended to include original research papers and reviews about various aspects of the molecular and cellular biology of Pi transport. Studies on the molecular mechanisms of regulation and phosphate sensing and signaling are also welcomed, and pathophysiological studies that include the molecular mechanisms of diseases related to Pi dysregulation will also be considered.

Prof. Dr. Victor Sorribas
Guest Editor

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Keywords

Pi
Transporter
NaPi
PiT1
PiT2
Slc34
Slc20
Phosphatonins
Pi homeostasis
PTH

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Published Papers (7 papers)

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Research

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23 pages, 3861 KiB

Open AccessArticle

Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells

by Marco Antonio Lacerda-Abreu, Thais Russo-Abrahão, Nathália Rocco-Machado, Daniela Cosentino-Gomes, Claudia Fernanda Dick, Luiz Fernando Carvalho-Kelly, Michelle Tanny Cunha Nascimento, Thaís Cristino Rocha-Vieira and José Roberto Meyer-Fernandes

Int. J. Mol. Sci. 2021, 22(18), 10096; https://doi.org/10.3390/ijms221810096 - 18 Sep 2021

Cited by 5 | Viewed by 2426

Abstract

According to the growth rate hypothesis (GRH), tumour cells have high inorganic phosphate (Pi) demands due to accelerated proliferation. Compared to healthy individuals, cancer patients present with a nearly 2.5-fold higher Pi serum concentration. In this work, we show that an increasing concentration of Pi had the opposite effect on Pi-transporters only in MDA-MB-231 when compared to other breast cell lines: MCF-7 or MCF10-A (non-tumoural breast cell line). Here, we show for the first time that high extracellular Pi concentration mediates ROS production in TNBC (MDA-MB-231). After a short-time exposure (1 h), Pi hyperpolarizes the mitochondrial membrane, increases mitochondrial ROS generation, impairs oxygen (O₂) consumption and increases PKC activity. However, after 24 h Pi-exposure, the source of H₂O₂ seems to shift from mitochondria to an NADPH oxidase enzyme (NOX), through activation of PKC by H₂O₂. Exogenous-added H₂O₂ modulated Pi-transporters the same way as extracellular high Pi, which could be reversed by the addition of the antioxidant N-acetylcysteine (NAC). NAC was also able to abolish Pi-induced Epithelial-mesenchymal transition (EMT), migration and adhesion of MDA-MB-231. We believe that Pi transporters support part of the energy required for the metastatic processes stimulated by Pi and trigger Pi-induced H₂O₂ production as a signalling response to promote cell migration and adhesion. Full article

(This article belongs to the Special Issue Mechanisms of Phosphate Transport)

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14 pages, 1053 KiB

Open AccessArticle

Probiotic Activity of Staphylococcus epidermidis Induces Collagen Type I Production through FFaR2/p-ERK Signaling

by Indira Putri Negari, Sunita Keshari and Chun-Ming Huang

Int. J. Mol. Sci. 2021, 22(3), 1414; https://doi.org/10.3390/ijms22031414 - 31 Jan 2021

Cited by 13 | Viewed by 4406

Abstract

Collagen type I is a key structural component of dermis tissue and is produced by fibroblasts and the extracellular matrix. The skin aging process, which is caused by intrinsic or extrinsic factors, such as natural aging or free radical exposure, greatly reduces collagen expression, thereby leading to obstructed skin elasticity. We investigated the effective fermentation of Cetearyl isononanoate (CIN), a polyethylene glycol (PEG) analog, as a carbon source with the skin probiotic bacterium Staphylococcus epidermidis (S.epidermidis) or butyrate, as their fermentation metabolites could noticeably restore collagen expression through phosphorylated extracellular signal regulated kinase (p-ERK) activation in mouse fibroblast cells and skin. Both the in vitro and in vivo knockdown of short-chain fatty acid (SCFA) or free fatty acid receptor 2 (FFaR2) considerably blocked the probiotic effect of S. epidermidis on p-ERK-induced collagen type I induction. These results demonstrate that butyric acid (BA) in the metabolites of fermenting skin probiotic bacteria mediates FFaR2 to induce the synthesis of collagen through p-ERK activation. We hereby imply that metabolites from the probiotic S. epidermidis fermentation of CIN as a potential carbon source could restore impaired collagen in the dermal extracellular matrix (ECM), providing integrity and elasticity to skin. Full article

(This article belongs to the Special Issue Mechanisms of Phosphate Transport)

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21 pages, 1471 KiB

Open AccessArticle

Modulation of Intestinal Phosphate Transport in Young Goats Fed a Low Phosphorus Diet

by Joie L. Behrens, Nadine Schnepel, Kathrin Hansen, Karin Hustedt, Marion Burmester, Stefanie Klinger, Gerhard Breves and Alexandra S. Muscher-Banse

Int. J. Mol. Sci. 2021, 22(2), 866; https://doi.org/10.3390/ijms22020866 - 16 Jan 2021

Cited by 3 | Viewed by 2109

Abstract

The intestinal absorption of phosphate (P_i) takes place transcellularly through the active NaPi-cotransporters type IIb (NaPiIIb) and III (PiT1 and PiT2) and paracellularly by diffusion through tight junction (TJ) proteins. The localisation along the intestines and the regulation of P_i absorption differ between species and are not fully understood. It is known that 1,25-dihydroxy-vitamin D₃ (1,25-(OH)₂D₃) and phosphorus (P) depletion modulate intestinal P_i absorption in vertebrates in different ways. In addition to the apical uptake into the enterocytes, there are uncertainties regarding the basolateral excretion of P_i. Functional ex vivo experiments in Ussing chambers and molecular studies of small intestinal epithelia were carried out on P-deficient goats in order to elucidate the transepithelial P_i route in the intestine as well as the underlying mechanisms of its regulation and the proteins, which may be involved. The dietary P reduction had no effect on the duodenal and ileal P_i transport rate in growing goats. The ileal PiT1 and PiT2 mRNA expressions increased significantly, while the ileal PiT1 protein expression, the mid jejunal claudin-2 mRNA expression and the serum 1,25-(OH)₂D₃ levels were significantly reduced. These results advance the state of knowledge concerning the complex mechanisms of the P_i homeostasis in vertebrates. Full article

(This article belongs to the Special Issue Mechanisms of Phosphate Transport)

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Review

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12 pages, 615 KiB

Open AccessReview

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight

by Lucile Figueres, Sarah Beck-Cormier, Laurent Beck and Joanne Marks

Int. J. Mol. Sci. 2021, 22(11), 5701; https://doi.org/10.3390/ijms22115701 - 27 May 2021

Cited by 8 | Viewed by 3565

Abstract

Phosphate homeostasis is essential for health and is achieved via interaction between the bone, kidney, small intestine, and parathyroid glands and via intricate processes involving phosphate transporters, phosphate sensors, and circulating hormones. Numerous genetic and acquired disorders are associated with disruption in these processes and can lead to significant morbidity and mortality. The role of the kidney in phosphate homeostasis is well known, although it is recognized that the cellular mechanisms in murine models and humans are different. Intestinal phosphate transport also appears to differ in humans and rodents, with recent studies demonstrating a dominant role for the paracellular pathway. The existence of phosphate sensing has been acknowledged for decades; however, the underlying molecular mechanisms are poorly understood. At least three phosphate sensors have emerged. PiT2 and FGFR1c both act as phosphate sensors controlling Fibroblast Growth Factor 23 secretion in bone, whereas the calcium-sensing receptor controls parathyroid hormone secretion in response to extracellular phosphate. All three of the proposed sensors are expressed in the kidney and intestine but their exact function in these organs is unknown. Understanding organ interactions and the mechanisms involved in phosphate sensing requires significant research to develop novel approaches for the treatment of phosphate homeostasis disorders. Full article

(This article belongs to the Special Issue Mechanisms of Phosphate Transport)

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20 pages, 2433 KiB

Open AccessReview

Molecular Mechanisms of Phosphate Sensing, Transport and Signalling in Streptomyces and Related Actinobacteria

by Juan Francisco Martín and Paloma Liras

Int. J. Mol. Sci. 2021, 22(3), 1129; https://doi.org/10.3390/ijms22031129 - 23 Jan 2021

Cited by 49 | Viewed by 6229

Abstract

Phosphorous, in the form of phosphate, is a key element in the nutrition of all living beings. In nature, it is present in the form of phosphate salts, organophosphates, and phosphonates. Bacteria transport inorganic phosphate by the high affinity phosphate transport system PstSCAB, and the low affinity PitH transporters. The PstSCAB system consists of four components. PstS is the phosphate binding protein and discriminates between arsenate and phosphate. In the Streptomyces species, the PstS protein, attached to the outer side of the cell membrane, is glycosylated and released as a soluble protein that lacks its phosphate binding ability. Transport of phosphate by the PstSCAB system is drastically regulated by the inorganic phosphate concentration and mediated by binding of phosphorylated PhoP to the promoter of the PstSCAB operon. In Mycobacterium smegmatis, an additional high affinity transport system, PhnCDE, is also under PhoP regulation. Additionally, Streptomyces have a duplicated low affinity phosphate transport system encoded by the pitH1–pitH2 genes. In this system phosphate is transported as a metal-phosphate complex in simport with protons. Expression of pitH2, but not that of pitH1 in Streptomyces coelicolor, is regulated by PhoP. Interestingly, in many Streptomyces species, three gene clusters pitH1–pstSCAB–ppk (for a polyphosphate kinase), are linked in a supercluster formed by nine genes related to phosphate metabolism. Glycerol-3-phosphate may be transported by the actinobacteria Corynebacterium glutamicum that contains a ugp gene cluster for glycerol-3-P uptake, but the ugp cluster is not present in Streptomyces genomes. Sugar phosphates and nucleotides are used as phosphate source by the Streptomyces species, but there is no evidence of the uhp gene involved in the transport of sugar phosphates. Sugar phosphates and nucleotides are dephosphorylated by extracellular phosphatases and nucleotidases. An isolated uhpT gene for a hexose phosphate antiporter is present in several pathogenic corynebacteria, such as Corynebacterium diphtheriae, but not in non-pathogenic ones. Phosphonates are molecules that contains phosphate linked covalently to a carbon atom through a very stable C–P bond. Their utilization requires the phnCDE genes for phosphonates/phosphate transport and genes for degradation, including those for the subunits of the C–P lyase. Strains of the Arthrobacter and Streptomyces genera were reported to degrade simple phosphonates, but bioinformatic analysis reveals that whole sets of genes for putative phosphonate degradation are present only in three Arthrobacter species and a few Streptomyces species. Genes encoding the C–P lyase subunits occur in several Streptomyces species associated with plant roots or with mangroves, but not in the laboratory model Streptomyces species; however, the phnCDE genes that encode phosphonates/phosphate transport systems are frequent in Streptomyces species, suggesting that these genes, in the absence of C–P lyase genes, might be used as surrogate phosphate transporters. In summary, Streptomyces and related actinobacteria seem to be less versatile in phosphate transport systems than Enterobacteria. Full article

(This article belongs to the Special Issue Mechanisms of Phosphate Transport)

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15 pages, 1849 KiB

Open AccessReview

Noncanonical Sequences Involving NHERF1 Interaction with NPT2A Govern Hormone-Regulated Phosphate Transport: Binding Outside the Box

by Tatyana Mamonova and Peter A. Friedman

Int. J. Mol. Sci. 2021, 22(3), 1087; https://doi.org/10.3390/ijms22031087 - 22 Jan 2021

Cited by 8 | Viewed by 2638

Abstract

Na⁺/H⁺ exchange factor-1 (NHERF1), a multidomain PDZ scaffolding phosphoprotein, is required for the type II sodium-dependent phosphate cotransporter (NPT2A)-mediated renal phosphate absorption. Both PDZ1 and PDZ2 domains are involved in NPT2A-dependent phosphate uptake. Though harboring identical core-binding motifs, PDZ1 and PDZ2 play entirely different roles in hormone-regulated phosphate transport. PDZ1 is required for the interaction with the C-terminal PDZ-binding sequence of NPT2A (-TRL). Remarkably, phosphocycling at Ser²⁹⁰ distant from PDZ1, the penultimate step for both parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) regulation, controls the association between NHERF1 and NPT2A. PDZ2 interacts with the C-terminal PDZ-recognition motif (-TRL) of G Protein-coupled Receptor Kinase 6A (GRK6A), and that promotes phosphorylation of Ser²⁹⁰. The compelling biological puzzle is how PDZ1 and PDZ2 with identical GYGF core-binding motifs specifically recognize distinct binding partners. Binding determinants distinct from the canonical PDZ-ligand interactions and located “outside the box” explain PDZ domain specificity. Phosphorylation of NHERF1 by diverse kinases and associated conformational changes in NHERF1 add more complexity to PDZ-binding diversity. Full article

(This article belongs to the Special Issue Mechanisms of Phosphate Transport)

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12 pages, 1096 KiB

Open AccessReview

The Roles of Sodium-Independent Inorganic Phosphate Transporters in Inorganic Phosphate Homeostasis and in Cancer and Other Diseases

by Marco Antonio Lacerda-Abreu, Thais Russo-Abrahão and Jose Roberto Meyer-Fernandes

Int. J. Mol. Sci. 2020, 21(23), 9298; https://doi.org/10.3390/ijms21239298 - 6 Dec 2020

Cited by 11 | Viewed by 2906

Abstract

Inorganic phosphate (Pi) is an essential nutrient for the maintenance of cells. In healthy mammals, extracellular Pi is maintained within a narrow concentration range of 0.70 to 1.55 mM. Mammalian cells depend on Na⁺/Pi cotransporters for Pi absorption, which have been well studied. However, a new type of sodium-independent Pi transporter has been identified. This transporter assists in the absorption of Pi by intestinal cells and renal proximal tubule cells and in the reabsorption of Pi by osteoclasts and capillaries of the blood–brain barrier (BBB). Hyperphosphatemia is a risk factor for mineral deposition, the development of diseases such as osteoarthritis, and vascular calcifications (VCs). Na⁺-independent Pi transporters have been identified and biochemically characterized in vascular smooth muscle cells (VSMCs), chondrocytes, and matrix vesicles, and their involvement in mineral deposition in the extracellular microenvironment has been suggested. According to the growth rate hypothesis, cancer cells require more phosphate than healthy cells due to their rapid growth rates. Recently, it was demonstrated that breast cancer cells (MDA-MB-231) respond to high Pi concentration (2 mM) by decreasing Na⁺-dependent Pi transport activity concomitant with an increase in Na⁺-independent (H⁺-dependent) Pi transport. This Pi H⁺-dependent transport has a fundamental role in the proliferation and migratory capacity of MDA-MB-231 cells. The purpose of this review is to discuss experimental findings regarding Na⁺-independent inorganic phosphate transporters and summarize their roles in Pi homeostasis, cancers and other diseases, such as osteoarthritis, and in processes such as VC. Full article

(This article belongs to the Special Issue Mechanisms of Phosphate Transport)

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