Regulator Of Iron Homeostasis Research Articles

Mitochondrial Aconitase ACO2 Links Iron Homeostasis with Tumorigenicity in Non-Small Cell Lung Cancer.

FeS cluster-associated proteins including ACO2, mNT (encoded by CISD1), and IRP1 (encoded by ACO1) are part of an "ACO2-Iron Axis" that regulates iron homeostasis and is a determinant of a particularly aggressive subset of NSCLC.

Hepcidin as a Potential Biomarker for the Diagnosis of Anemia.

There are several blood-based markers to assess iron stores, but they all have some limitations. Hepcidin, a low-molecular-weight peptide hormone, is produced mainly by the liver. It is the main regulator of iron homeostasis by preventing iron release into plasma from absorptive enterocytes and macrophages. This review aims to critically assess existing data on potential role of hepcidin in diagnosis, particularly the (pre) analytical implications of the hepcidin measurement. There is a well-known causative correlation between hepcidin and iron deficiency. Therefore, hepcidin is considered as a promising marker in the assessment of iron status, particularly in patients with a diagnostic dilemma, such as patients with chronic renal disease and infants. The clinical implications of this peptide hormone in diagnosis of other diseases have been expanded in the recent studies, including elevated hepcidin levels in neoplastic diseases, sepsis, and inflammation. The potential role of hepcidin in diagnosis is controversial in the various types of iron deficiency because data are conflicting (as in anaemia of chronic disease) or limited (as in infants), whereas in the case of hereditary haemochromatosis, it has been proposed that hepcidin may be used for stratification of molecular testing, or to improve the frequency of phlebotomy, however, this issue still needs to be investigated. Due to lack of a clinically approved test, the medical application of this peptide as a biomarker in diagnosis is restricted. Recently, assays have been developed to determine hepcidin levels in serum and urine, facilitating the future use of hepcidin in research and clinical practice.

Cytochrome P450 1B1: A Key Regulator of Ocular Iron Homeostasis and Oxidative Stress.

Cytochrome P450 (CYP) 1B1 belongs to the superfamily of heme-containing monooxygenases. Unlike other CYP enzymes, which are highly expressed in the liver, CYP1B1 is predominantly found in extrahepatic tissues, such as the brain, and ocular tissues including retina and trabecular meshwork. CYP1B1 metabolizes exogenous chemicals such as polycyclic aromatic hydrocarbons. CYP1B1 also metabolizes endogenous bioactive compounds including estradiol and arachidonic acid. These metabolites impact various cellular and physiological processes during development and pathological processes. We previously showed that CYP1B1 deficiency mitigates ischemia-mediated retinal neovascularization and drives the trabecular meshwork dysgenesis through increased levels of oxidative stress. However, the underlying mechanisms responsible for CYP1B1-deficiency-mediated increased oxidative stress remain largely unresolved. Iron is an essential element and utilized as a cofactor in a variety of enzymes. However, excess iron promotes the production of hydroxyl radicals, lipid peroxidation, increased oxidative stress, and cell damage. The retinal endothelium is recognized as a major component of the blood–retinal barrier, which controls ocular iron levels through the modulation of proteins involved in iron regulation present in retinal endothelial cells, as well as other ocular cell types including trabecular meshwork cells. We previously showed increased levels of reactive oxygen species and lipid peroxidation in the absence of CYP1B1, and in the retinal vasculature and trabecular meshwork, which was reversed by administration of antioxidant N-acetylcysteine. Here, we review the important role CYP1B1 expression and activity play in maintaining retinal redox homeostasis through the modulation of iron levels by retinal endothelial cells. The relationship between CYP1B1 expression and activity and iron levels has not been previously delineated. We review the potential significance of CYP1B1 expression, estrogen metabolism, and hepcidin–ferroportin regulatory axis in the local regulation of ocular iron levels.

Minireview: Chromatin-based regulation of iron homeostasis in plants

Plants utilize delicate mechanisms to effectively respond to changes in the availability of nutrients such as iron. The responses to iron status involve controlling gene expression at multiple levels. The regulation of iron deficiency response by a network of transcriptional regulators has been extensively studied and recent research has shed light on post-translational control of iron homeostasis. Although not as considerably investigated, an increasing number of studies suggest that histone modification and DNA methylation play critical roles during iron deficiency and contribute to fine-tuning iron homeostasis in plants. This review will focus on the current understanding of chromatin-based regulation on iron homeostasis in plants highlighting recent studies in Arabidopsis and rice. Understanding iron homeostasis in plants is vital, as it is not only relevant to fundamental biological questions, but also to agriculture, biofortification, and human health. A comprehensive overview of the effect and mechanism of chromatin-based regulation in response to iron status will ultimately provide critical insights in elucidating the complexities of iron homeostasis and contribute to improving iron nutrition in plants.

The critical role of ferritinophagy in human disease.

Ferritinophagy is a type of autophagy mediated by nuclear receptor activator 4 (NCOA4), which plays a role in inducing ferroptosis by regulating iron homeostasis and producing reactive oxygen species in cells. Under physiological conditions, ferritinophagy maintains the stability of intracellular iron by regulating the release of free iron. Studies have demonstrated that ferritinophagy is necessary to induce ferroptosis; however, under pathological conditions, excessive ferritinophagy results in the release of free iron in large quantities, which leads to lipid peroxidation and iron-dependent cell death, known as ferroptosis. Ferritinophagy has become an area of interest in recent years. We here in review the mechanism of ferritinophagy and its association with ferroptosis and various diseases to provide a reference for future clinical and scientific studies.

MliR, a novel MerR-like regulator of iron homeostasis, impacts metabolism, membrane remodeling, and cell adhesion in the marine Bacteroidetes Bizionia argentinensis.

The MerR family is a group of transcriptional activators with conserved N-terminal helix-turn-helix DNA binding domains and variable C-terminal effector binding regions. In most MerR proteins the effector binding domain (EBD) contains a cysteine center suited for metal binding and mediates the response to environmental stimuli, such as oxidative stress, heavy metals or antibiotics. We here present a novel transcriptional regulator classified in the MerR superfamily that lacks an EBD domain and has neither conserved metal binding sites nor cysteine residues. This regulator from the psychrotolerant bacteria Bizionia argentinensis JUB59 is involved in iron homeostasis and was named MliR (MerR-like iron responsive Regulator). In silico analysis revealed that homologs of the MliR protein are widely distributed among different bacterial species. Deletion of the mliR gene led to decreased cell growth, increased cell adhesion and filamentation. Genome-wide transcriptomic analysis showed that genes associated with iron homeostasis were downregulated in mliR-deletion mutant. Through nuclear magnetic resonance-based metabolomics, ICP-MS, fluorescence microscopy and biochemical analysis we evaluated metabolic and phenotypic changes associated with mliR deletion. This work provides the first evidence of a MerR-family regulator involved in iron homeostasis and contributes to expanding our current knowledge on relevant metabolic pathways and cell remodeling mechanisms underlying in the adaptive response to iron availability in bacteria.

Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo.

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

The mechanisms of ferroptosis and its role in alzheimer's disease.

Alzheimer’s disease (AD) accounts for two-thirds of all dementia cases, affecting 50 million people worldwide. Only four of the more than 100 AD drugs developed thus far have successfully improved AD symptoms. Furthermore, these improvements are only temporary, as no treatment can stop or reverse AD progression. A growing number of recent studies have demonstrated that iron-dependent programmed cell death, known as ferroptosis, contributes to AD-mediated nerve cell death. The ferroptosis pathways within nerve cells include iron homeostasis regulation, cystine/glutamate (Glu) reverse transporter (system xc−), glutathione (GSH)/glutathione peroxidase 4 (GPX4), and lipid peroxidation. In the regulation pathway of AD iron homeostasis, abnormal iron uptake, excretion and storage in nerve cells lead to increased intracellular free iron and Fenton reactions. Furthermore, decreased Glu transporter expression leads to Glu accumulation outside nerve cells, resulting in the inhibition of the system xc− pathway. GSH depletion causes abnormalities in GPX4, leading to excessive accumulation of lipid peroxides. Alterations in these specific pathways and amino acid metabolism eventually lead to ferroptosis. This review explores the connection between AD and the ferroptosis signaling pathways and amino acid metabolism, potentially informing future AD diagnosis and treatment methodologies.

Regulation of plant iron homeostasis by abscisic acid: a review

Iron (Fe) is an important trace element involved in many important plant physiological and metabolic processes such as photosynthesis, respiration and nitrogen metabolism. Plants maintain iron homeostasis through absorption, transporting, storage and redistribution of iron. Iron metabolism is strictly regulated in plants. Iron regulatory transcription factors and iron transporters constitute the regulatory network of plant iron absorption and transport in plants. Ferritin and iron transporter jointly regulate the response to excess iron in plants. In recent years, important progress has been made in understanding how abscisic acid (ABA) regulates iron metabolism in plants. ABA may be used as a signal to regulate the absorption, transportation and reuse of Fe, or to relieve the symptoms of iron stress by regulating the oxidative stress responses in plants. In order to gain deeper insights into the crosstalk of ABA and iron metabolism in plants, this review summarized the mechanisms of iron absorption and transport and metabolic regulatory network in plants, as well as the mechanisms of ABA in regulating iron metabolism. The relationship between ABA and FER-like iron deficiency-induced transcription factor (FIT), iron-regulated transporter 1 (IRT1), and oxidative stress of iron deficiency were highlighted, and future research directions were prospected.

Codon-optimized FAM132b gene therapy prevents dietary obesity by blockading adrenergic response and insulin action

FAM132b (myonectin) has been identified as a muscle-derived myokine with exercise and has hormone activity in circulation to regulate iron homeostasis and lipid metabolism via unknown receptors. Here, we aim to explore the potential of adeno-associated virus to deliver FAM132b in vivo to develop a gene therapy against obesity. Adeno-associated virus AAV9 were engineered to induce overexpression of FAM132b with two mutations, A136T and P159A. Then, AAV9 was delivered into high-fat diet mice through tail vein, and glucose homeostasis and obesity development of mice were observed. Methods of structural biology were used to predict the action site or receptor of the FAM132b mutant. Treatment of high-fat diet-fed mice with AAV9 improved glucose intolerance and insulin resistance, and resulted in reductions in body weight, fat depot, and adipocyte size. Codon-optimized FAM132b (coFAM132b) reduced the glycemic response to epinephrine (EPI) in the whole body and increased the lipolytic response to EPI in adipose tissues. However, FAM132b knockdown by shRNA significantly increased the glycemic response to EPI in vivo and reduced adipocyte response to EPI and adipose tissue browning. Structural analysis predicted that the FAM132b mutant with A136T and P159A may form a weak bond with β2 adrenergic receptor (ADRB2) and may have more affinity for insulin and insulin-receptor complexes. Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating the adrenergic response and insulin action. Both structural biological analysis and in vivo experiments suggest that the adrenergic response and insulin action are most likely blockaded by FAM132b mutants.

BACH1 Expression Is Promoted by Tank Binding Kinase 1 (TBK1) in Pancreatic Cancer Cells to Increase Iron and Reduce the Expression of E-Cadherin.

BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species and promotes metastasis of various cancers including pancreatic ductal adenocarcinoma (PDAC). However, it is not clear how BACH1 is regulated in PDAC cells. Knockdown of Tank binding kinase 1 (TBK1) led to reductions of BACH1 mRNA and protein amounts in AsPC−1 human PDAC cells. Gene expression analysis of PDAC cells with knockdown of TBK1 or BACH1 suggested the involvement of TBK1 and BACH1 in the regulation of iron homeostasis. Ferritin mRNA and proteins were both increased upon BACH1 knockdown in AsPC−1 cells. Flow cytometry analysis showed that AsPC−1 cells with BACH1 knockout or knockdown contained lower labile iron than control cells, suggesting that BACH1 increased labile iron by repressing the expression of ferritin genes. We further found that the expression of E-cadherin was upregulated upon the chelation of intracellular iron content. These results suggest that the TBK1-BACH1 pathway promotes cancer cell metastasis by increasing labile iron within cells.

Iron homeostasis of liver-gut axis alleviates inflammation caused by dietary cottonseed meal through dietary Fe2+ supplementation in juvenile grass carp (Ctenopharyngodon idellus)

This study aimed to explore whether Fe2+ supplementation can improve the ability of grass carp to tolerate a high content of dietary cottonseed meal (CSM) and, if so, to uncover the potential regulation mechanism involved. Soybean and rapeseed meals were used as the main protein materials for the feed diet low in free gossypol (LFG) while CSM predominated in the diet high in free gossypol (HFG). In two other treatments, amounts of FeSO4•7H2O were supplemented in HFG diets to configure an HFG + Fe1 diet (containing supplementary 400 mg/kg of Fe2+) and an HFG + Fe2 diet (800 mg/kg of Fe2+). The experimental diets were randomly assigned to 12 cages, in triplicate, for an 8-week feeding trial. The results showed that fish fed the HFG diet had lower levels of PER (P < 0.05) than that fed the LFG diet. The greatest values for FBW, WGR, SGR, PER, and FCR were recorded in the HFG + Fe2 group, all differing significantly from the HFG group (P < 0.05). Meanwhile, the HFG + Fe2 diet conspicuously improved the lipid-deposition induced by HFG (P < 0.05). Fish fed the HFG diet showed lower levels of iron contents both in their blood (P > 0.05) and liver (P < 0.05) than did the LFG group, whereas the HFG + Fe2 diet increased them (P < 0.05) to maintain iron homeostasis by up-regulating hepcidin (P < 0.05) and down-regulating fpn1 mRNA (P < 0.05). The HFG + Fe2 diet also down-regulated the expression level of il-1β, and increased that of two anti-inflammatory cytokines, il-11 and tgf-β1, all of which differed significantly from those of the LFG group (P < 0.05). Compared with the LFG group, mRNA expression levels of jam-a and claudin-b in the HFG group were inhibited significantly (P < 0.05), but increasing the Fe2+ supplementation up-regulated expression levels of intestinal tight junctions, such as zo-1, zo-2, jam-a, occludin, claudin b, and claudin c. Altogether then, the inclusion of dietary Fe2+ supplementation (1–2:1 ratio of extra iron to free gossypol) augmented the tolerance to the high content of dietary CSM in grass carp by alleviating the intestinal inflammatory and restoring intestinal barrier function through iron homeostasis regulation.

IRONMAN peptide interacts with OsHRZ1 and OsHRZ2 to maintain Fe homeostasis in rice.

IRONMAN (IMA) is a family of small peptides which positively regulate plant responses under Fe deficiency. However, the molecular mechanism by which OsIMA1 and OsIMA2 regulate Fe homeostasis in rice is unclear. Here, we reveal that OsIMA1 and OsIMA2 interact with the potential Fe sensors, OsHRZ1 (HAEMERYTHRIN MOTIF-CONTAINING REALLY INTERESTING NEW GENE (RING) AND ZINC-FINGER PROTEIN 1) and OsHRZ2. OsIMA1 and OsIMA2 contain a conserved 17 amino acid C-terminal region which is responsible for the interactions with OsHRZ1 and OsHRZ2. Plants overexpressing OsIMA1 (OsIMA1ox) show increased Fe concentration in seeds and reduced fertility, as observed in the hrz1-2 loss-of-function mutant plants. Moreover, the expression patterns of Fe deficiency inducible genes in the OsIMA1ox plants are the same as those in hrz1-2. Co-expression assays suggest that OsHRZ1 and OsHRZ2 promote the degradation of OsIMA1 proteins. As the interaction partners of OsHRZ1, the OsPRI (POSITIVE REGULATOR OF IRON HOMEOSTASIS) proteins also interact with OsHRZ2. The conserved C-terminal region of four OsPRIs contributes to the interactions with OsHRZ1 and OsHRZ2. An artificial IMA (aIMA) derived from the C-terminal of OsPRI1 can be also degraded by OsHRZ1. Moreover, aIMA overexpressing rice plants accumulate more Fe without reduction of fertility. This work establishes the link between OsIMAs and OsHRZs, and develops a new strategy for Fe fortification in rice.

Fluctuating selection on bacterial iron regulation in the mammalian gut

Iron is critical in host-microbe interactions, and its availability is tightly regulated in the mammalian gut. Antibiotics and inflammation can perturb iron availability in the gut, which could alter host-microbe interactions. Here, we show that an adaptive allele of iscR, a major regulator of iron homeostasis of Escherichia coli, is under fluctuating selection in the mouse gut. Invivo competitions in immune-competent, immune-compromised, and germ-free mice reveal that the selective pressure on an iscR mutant E.coli is modulated by the presence of antibiotics, the microbiota, and the immune system. Invitro assays show that iron availability is an important mediator of the iscR allele fitness benefits or costs. We identify Lipocalin-2, a host's immune protein that prevents bacterial iron acquisition, as a major host mechanism underlying fluctuating selection of iscR. Our results provide a remarkable example of strong fluctuating selection acting on bacterial iron regulation in the mammalian gut.

The role of mitochondria in the recovery of neurons after injury.

The role of mitochondria in the recovery of neurons after injury.

OsIRO3 negatively regulates Fe homeostasis by repressing the expression of OsIRO2.

Iron (Fe) is crucial for crop productivity and quality. However, Fe deficiency is prevalent worldwide, particularly in alkaline soil. Plants have evolved sophisticated mechanisms to withstand Fe-deficient conditions. Oryza sativa IRON-RELATED BHLH TRANSCRIPTION FACTOR 3 (OsIRO3/OsbHLH63) has been identified as a negative regulator of Fe deficiency response signaling; however, the underlying mechanism remains unclear. In the present study, we constructed two iro3 mutants, which developed leaves with necrotic lesions under Fe-deficient conditions. Loss-of-function of OsIRO3 caused upregulation of Fe deficiency-associated genes in the root. Fe concentration measurements showed that the iro3 mutants had increased shoot Fe concentration only under Fe-deficient conditions. Further analysis revealed that OsIRO3 directly regulated the expression of IRON-RELATED BHLH TRANSCRIPTION FACTOR 2 (OsIRO2), which encodes a positive regulator of the Fe uptake system. Further investigation demonstrated that OsIRO3 interacted with POSITIVE REGULATOR OF IRON HOMEOSTASIS 1(OsPRI1) and OsPRI2, and. OsIRO3 repressed their transcription activation towards OsIRO2. OsIRO3 contains an EAR motif, which recruits the TOPLESS/TOPLESS-RELATED (OsTPL/OsTPRs) corepressors. Mutation of the EAR motif attenuated the repression ability of OsIRO3. This work sheds light on the molecular mechanism by which OsIRO3 modulates Fe homeostasis in rice.

Iron, Neuroinflammation and Neurodegeneration.

Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation.

Iron-Induced Hepatocarcinogenesis—Preventive Effects of Nutrients

The liver is a primary organ that stores body iron, and plays a central role in the regulation of iron homeostasis. Hepatic iron overload (HIO) is a prevalent feature among patients with chronic liver diseases (CLDs), including alcoholic/nonalcoholic liver diseases and hepatitis C. HIO is suggested to promote the progression toward hepatocellular carcinoma because of the pro-oxidant nature of iron. Iron metabolism is tightly regulated by various factors, such as hepcidin and ferroportin, in healthy individuals to protect the liver from such deteriorative effects. However, their intrinsic expressions or functions are frequently compromised in patients with HIO. Thus, various nutrients have been reported to regulate hepatic iron metabolism and protect the liver from iron-induced damage. These nutrients are beneficial in HIO-associated CLD treatment and eventually prevent iron-mediated hepatocarcinogenesis. This mini-review aimed to discuss the mechanisms and hepatocarcinogenic risk of HIO in patients with CLDs. Moreover, nutrients that hold the potential to prevent iron-induced hepatocarcinogenesis are summarized.

Effects of Moderate Consumption of Red Wine on Hepcidin Levels in Patients with Type 2 Diabetes Mellitus.

Iron overload is often associated with type 2 diabetes (T2D), indicating that hepcidin, the master regulator of iron homeostasis, might be involved in diabetes pathogenesis. Alcohol consumption may also result in increased body iron stores. However, the moderate consumption of wine with meals might be beneficial in T2D. This effect has been mainly attributed to both the ethanol and the polyphenolic compounds in wine. Therefore, we examined the effects of red wine on hepcidin in T2D patients and non-diabetic controls. The diabetic patients (n = 18) and age- and BMI-matched apparently healthy controls (n = 13) were men, aged 40–65 years, non-smoking, with BMI < 35 kg/m2. Following a 2-week alcohol-free period, both groups consumed 300 mL of red wine for 3 weeks. The blood samples for the iron status analysis were taken at the end of each period. The red wine intake resulted in a decrease in serum hepcidin in both the diabetic subjects (p = 0.045) and controls (p = 0.001). The levels of serum ferritin also decreased after wine in both groups, reaching statistical significance only in the control subjects (p = 0.017). No significant alterations in serum iron, transferrin saturation, or soluble transferrin receptors were found. The suppression of hepcidin, a crucial iron-regulatory hormone and acute-phase protein, in T2D patients and healthy controls, is a novel biological effect of red wine. This may deepen our understanding of the mechanisms of the cardiometabolic effects of wine in T2D.

P1597: THE DYNAMIC INTERACTION BETWEEN INFLAMMATION AND IRON SENSORS IN MALARIA-INDUCED ANEMIA

Background: Severe malarial anemia (SMA) is a complication developed during Plasmodium infection. It is often associated with increased rates of malaria-related morbidity and mortality, especially in children and pregnant women. Hence, it is fundamental to investigate new parameters to prevent this lethality. Aims: The occurrence of ineffective erythropoiesis, caused by a dysregulated erythropoietin (EPO)-erythropoietin receptor (EPOR) signaling pathway, is one of the main features of SMA. Therefore, to gain new insights into the pathogenesis of SMA, our study aims to better understand the dynamic interaction between erythropoiesis and inflammation in mice exposed to single or multiple infections, mimicking what occurs in endemic regions. Methods: Erythroid cell differentiation and immune cells activation were evaluated by flow cytometry. Changes in iron metabolism were assessed by the differences in expression of genes regulating iron homeostasis by qRT-PCR. Results: Flow cytometry analyses suggested that additional exposure to the parasite enhances erythropoiesis. Comparing infected with reinfected mice, we observed a faster erythropoietic response, induced by the bone marrow. It was also found that reinfected mice presented an earlier and robust immune response activation, as developing innate immune memory. Due to the fundamental role of iron in erythropoiesis and immune response activation, the expression of iron sensors, like HFE, was analyzed, detecting a strict correlation between disease severity and multiple infections exposure. The action of HFE in the pathogenesis of SMA and its role on the immune response activation, elicited to combat malaria, was also investigated. Preliminary data shows that when HFE knockout mice were infected with the parasite, their anemic profile improves. Summary/Conclusion: These reveals HFE as a potential target for drug therapy during hemolytic disorders, such as malaria infection.