iron regulatory proteins
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Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 58
Author(s):  
Xiaoqin Zhang ◽  
Xiaogang Li

Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. Ferroptosis has distinct biological and morphology characteristics, such as shrunken mitochondria when compared to other known regulated cell deaths. The regulation of ferroptosis includes different molecular mechanisms and multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling pathways, which are involved in the amino acid metabolism and the activation of GPX4; iron metabolic signaling pathways, which are involved in the regulation of iron import/export and the storage/release of intracellular iron through iron-regulatory proteins (IRPs), and lipid metabolic signaling pathways, which are involved in the metabolism of unsaturated fatty acids in cell membranes. Ferroptosis plays an essential role in the pathology of various kidneys diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), autosomal dominant polycystic kidney disease (ADPKD), and renal cell carcinoma (RCC). Targeting ferroptosis with its inducers/initiators and inhibitors can modulate the progression of kidney diseases in animal models. In this review, we discuss the characteristics of ferroptosis and the ferroptosis-based mechanisms, highlighting the potential role of the main ferroptosis-associated metabolic pathways in the treatment and prevention of various kidney diseases.


2021 ◽  
Vol 12 ◽  
Author(s):  
Meirong Shan ◽  
Xujie Yu ◽  
Yajie Li ◽  
Changning Fu ◽  
Cheng Zhang

Vitamin B6 (VitB6) is a water-soluble vitamin and includes pyridoxine, pyridoxal, pyridoxamine, and their phosphorylated forms. In the current study, we demonstrated that VitB6 could improve lipopolysaccharide (LPS)–induced myocardial injury. We demonstrated that VitB6 can suppress LPS-induced oxidative stress and lipid peroxidation that lead to ferroptosis and apoptosis in vivo and in vitro. Moreover, we found that VitB6 can regulate the expression of iron regulatory proteins, maintaining intracellular iron homeostasis. To confirm that VitB6 could inhibit LPS-induced ferroptosis and apoptosis, we pretreated mice with ferrostatin-1 (Fer-1) and emricasan that efficiently mimicked VitB6 pharmacological effects. This improved the survival rate of mice challenged with a high LPS dose. In addition, VitB6 regulated the expression of LPS-induced apoptosis-related proteins and iron regulatory proteins. It mediated the expression of Nrf2, transcription factor NF-E2–related factor 2, which promoted the expression of antioxidant enzymes and restrained LPS-induced ferroptosis and apoptosis. Overall, our results indicated that VitB6 can be used on novel therapies to relieve LPS-induced myocardial injury.


Author(s):  
James A Votava ◽  
Shannon Reese ◽  
Kathryn M Deck ◽  
Christopher P Nizzi ◽  
Sheila Anderson ◽  
...  

Chronic kidney disease (CKD) involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in Irp1+/+ and Irp1-/- mice we asked if iron regulatory proteins (IRP), the central regulators of cellular iron metabolism and also suppressors of EPO production, contribute to the etiology of anemia in kidney failure. We identified a significant reduction in IRP protein level and RNA binding activity that associated with a loss of the iron uptake protein transferrin receptor 1, increased expression of the iron storage protein subunits H- and L-ferritin, and a low but overall variable level of stainable iron in the obstructed kidney. This reduction in IRP RNA binding activity and ferritin RNA levels suggests the concomitant rise in ferritin expression and iron content in kidney failure is IRP-dependent. In contrast, the reduction in Epo mRNA level in the obstructed kidney was not rescued by genetic ablation of IRP1 suggesting disruption of normal HIF-2a regulation. Furthermore, reduced expression of some HIFa target genes in UUO occurred in the face of increased expression of HIFa proteins and the prolyl hydroxylases (PHD) 2 and PHD1, the latter of which is not known to be HIFa mediated. Our results suggest that the IRP system drives changes in cellular iron metabolism that are associated with kidney failure in UUO but that the impact of IRP on EPO production is overridden by disrupted hypoxia signaling.


GYNECOLOGY ◽  
2021 ◽  
Vol 23 (4) ◽  
pp. 300-306
Author(s):  
Aleksandr S. Dukhanin

The review considers features of iron and folic acid (FA) pharmacokinetics, which affect the effective micronutrient support: molecular mechanisms of absorption and distribution, homeostatic processes of maintaining plasma vitamin and mineral levels by the feedback mechanism, including by regulating the deposition. An important characteristic of ferrokinetics is the presence of unique iron exporter ferroportin which is controlled by a family of iron regulatory proteins. Systemic ferrotherapy and oral rout of iron delivery are distinguished. In general, parenteral iron preparation complexes consist of Fe(III) oxide/hydroxide core stabilized by a carbohydrate polymer shell. Once entering the bloodstream, iron complexes are absorbed by resident macrophages of the reticuloendothelial system of the liver, spleen and bone marrow. Systemic Fe(III) preparations are prodrugs, the active part of which, i.e. iron is released in the lysosomal matrix of phagocytes. Oral iron preparations are divided into those containing bivalent (ferrous) and trivalent (ferric) iron. The article discusses factors determining the differences in the absorption of oral ferrous and ferric iron preparation, the spectrum of side effects, as well as key pharmaceutical approaches to increase the tolerance and adherence of ferrotherapy. These include using preparations containing Fe(II) organic compounds that have a lower dissociation rate than inorganic iron salts as well as slowing down the release of the active Fe(II) pharmaceutical substance from the drug. The review pays special attention to folates as iron synergists and examines the features of FA pharmacokinetics, the molecular basis of synergism, and substantiates the use of combined iron and FA preparations.


Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1365
Author(s):  
Karl Volz

Iron responsive elements (IREs) are mRNA stem-loop targets for translational control by the two iron regulatory proteins IRP1 and IRP2. They are found in the untranslated regions (UTRs) of genes that code for proteins involved in iron metabolism. There are ten “classic” IRE types that define the conserved secondary and tertiary structure elements necessary for proper IRP binding, and there are 83 published “IRE-like” sequences, most of which depart from the established IRE model. Here are structurally-guided discussions regarding the essential features of an IRE and what is important for IRE family membership.


Author(s):  
Yingying Xing ◽  
Ning Xu ◽  
Deepak D Bhandari ◽  
Dmitry Lapin ◽  
Xinhua Sun ◽  
...  

Abstract Acquisition of nutrients from different species is necessary for pathogen colonization. Iron is an essential mineral nutrient for nearly all organisms, but little is known about how pathogens manipulate plant hosts to acquire iron. Here, we report that AvrRps4, an effector protein delivered by Pseudomonas syringae bacteria to plants, interacts with and targets the plant iron sensor protein BRUTUS (BTS) to facilitate iron uptake and pathogen proliferation in Arabidopsis thaliana. Infection of rps4 and eds1 by P. syringae pv. tomato (Pst) DC3000 expressing AvrRps4 resulted in iron accumulation, especially in the plant apoplast. AvrRps4 alleviates BTS-mediated degradation of bHLH115 and ILR3(IAA-Leucine resistant 3), two iron regulatory proteins. In addition, BTS is important for accumulating immune proteins Enhanced Disease Susceptibility1 (EDS1) at both the transcriptional and protein levels upon Pst (avrRps4) infections. Our findings suggest that AvrRps4 targets BTS to facilitate iron accumulation and BTS contributes to RPS4/EDS1-mediated immune responses.


2020 ◽  
Vol 151 (1) ◽  
pp. 235-244
Author(s):  
Vivian Perng ◽  
Chong Li ◽  
Carolyn R Klocke ◽  
Shya E Navazesh ◽  
Danna K Pinneles ◽  
...  

ABSTRACT Background Both iron deficiency and overload may adversely affect neurodevelopment. Objectives The study assessed how changes in early-life iron status affect iron homeostasis and cytoarchitecture of hippocampal neurons in a piglet model. Methods On postnatal day (PD) 1, 30 Hampshire × Yorkshire crossbreed piglets (n = 15/sex) were stratified by sex and litter and randomly assigned to experimental groups receiving low (L-Fe), adequate (A-Fe), or high (H-Fe) levels of iron supplement during the pre- (PD1–21) and postweaning periods (PD22–35). Pigs in the L-Fe, A-Fe, and H-Fe groups orally received 0, 1, and 30 mg Fe · kg weight−1 · d−1 preweaning and were fed a diet containing 30, 125, and 1000 mg Fe/kg postweaning, respectively. Heme indexes were analyzed weekly, and gene and protein expressions of iron regulatory proteins in duodenal mucosa, liver, and hippocampus were analyzed through qRT-PCR and western blot, respectively, on PD35. Hippocampal neurons stained using the Golgi-Cox method were traced and their dendritic arbors reconstructed in 3-D using Neurolucida. Dendritic complexity was quantified using Sholl and branch order analyses. Results Pigs in the L-Fe group developed iron deficiency anemia (hemoglobin = 8.2 g/dL, hematocrit = 20.1%) on PD35 and became stunted during week 5 with lower final body weight than H-Fe group pigs (6.6 compared with 9.6 kg, P < 0.05). In comparison with A-Fe, H-Fe increased hippocampal ferritin expression by 38% and L-Fe decreased its expression by 52% (P < 0.05), suggesting altered hippocampal iron stores. Pigs in the H-Fe group had greater dendritic complexity in CA1/3 pyramidal neurons than L-Fe group pigs as shown by more dendritic intersections with Sholl rings (P ≤ 0.04) and a greater number of dendrites (P ≤ 0.016). Conclusions In piglets, the developing hippocampus is susceptible to perturbations by dietary iron, with deficiency and overload differentially affecting dendritic arborization.


2020 ◽  
Vol 14 (2) ◽  
pp. 88-99
Author(s):  
Mateen A. Khan

Background: Cellular iron uptake, utilization, and storage are tightly controlled through the action of iron regulatory proteins (IRPs). IRPs achieve this control by binding to IREs-mRNA in the 5'- or 3'-end of mRNAs that encode proteins involved in iron metabolism. The interaction of iron regulatory proteins with mRNAs containing an iron responsive element plays a central role in this regulation. The IRE RNA family of mRNA regulatory structures combines absolutely conserved protein binding sites with phylogenetically conserved base pairs that are specific to each IREs and influence RNA/protein stability. Our previous result revealed the binding and kinetics of IRE RNA with IRP1. The aim of the present study is to gain further insight into the differences in protein/RNA stability as a function of pH and ionic strength. Objective: To determine the extent to which the binding affinity and stability of protein/RNA complex was affected by ionic strength and pH. Methods: Fluorescence spectroscopy was used to characterize IRE RNA-IRP protein interaction. Results: Scatchard analysis revealed that the IRP1 protein binds to a single IRE RNA molecule. The binding affinity of two IRE RNA/IRP was significantly changed with the change in pH. The data suggests that the optimum binding of RNA/IRP complex occurred at pH 7.6. Dissociation constant for two IRE RNA/IRP increased with an increase in ionic strength, with a larger effect for FRT IRE RNA. This suggests that numerous electrostatic interactions occur in the ferritin IRE RNA/IRP than ACO2 IRE RNA/IRP complex. Iodide quenching shows that the majority of the tryptophan residues in IRP1 are solvent-accessible, assuming that most of the tryptophan residues contribute to protein fluorescence. Conclusion: The results obtained from this study clearly indicate that IRE RNA/IRP complex is destabilized by the change in pH and ionic strength. These observations suggest that both pH and ion are important for the assembly and stability of the IRE RNA/IRP complex formation.


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