Iron Storage Capacity Research Articles

Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway.

Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart. A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells. In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1. Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart.

Lamprey--an excellent model for iron metabolism.

After 500 million years of evolution, lamprey is in a natural environment characterized by low temperature and high iron content, and its unique adaptive evolution mode has developed its organizational structure and life mechanism in the process of metamorphosis, which provides a new direction for people to further study the origin and evolution of life. Iron is one of the essential nutrients for the human body and plays an important role in metabolic processes, but when exceeded, it can lead to iron toxicity. For example, the serum iron concentration of pre-metamorphosis larvae is 149 times that of normal males, and the iron content in the liver of juveniles is about 2-3 times that of normal humans. Lamprey has a complete biochemical system to tolerate high concentrations of free iron in the body, and high expression of important genes for iron homeostasis, such as transferrin, ferritin heavy chain, superoxide dismutase, etc., improves iron transport, iron storage and antioxidant capacity. Lamprey has an IRE/IRP regulatory system, which is an important protection mechanism for lamprey to adapt to the high iron content environment in the organization. In addition, lampreys gradually form oral glands during metamorphosis and development, which become the unique iron metabolism organs of lampreys. In this review, we mainly summarize the distribution of iron in various tissues of lamprey and the potential mechanism of adapting to the content of iron in the body, so as to provide a theoretical basis for the subsequent search for the molecular mechanism of iron metabolism.

Analysis of related factors of CRA in lung cancer patients with different serum iron levels: A retrospective cohort study.

Serum iron, an essential component of hemoglobin (Hb) synthesis invivo, is a crucial parameter for evaluating the body's iron storage and metabolism capacity. Iron deficiency leads to reduced Hb synthesis in red blood cells and smaller red blood cell volume, ultimately resulting in iron-deficiency anemia. Although serum iron cannot independently evaluate iron storage or metabolism ability, it can reflect iron concentration invivo and serve as a good predictor of iron-deficiency anemia. Therefore, exploring the influence of different serum iron levels on anemia and diagnosing and treating iron deficiency in the early stages is of great significance for patients with lung cancer. This study aims to explore the related factors of cancer-related anemia (CRA) in lung cancer and construct a nomogram prediction model to evaluate the risk of CRA in patients with different serum iron levels. A single-center retrospective cohort study was conducted, including 1610 patients with lung cancer, of whom 1040 had CRA. The relationship between CRA and its influencing factors was analyzed using multiple linear regression models. Lung cancer patients were divided into two groups according to their serum iron levels: decreased serum iron and normal serum iron. Each group was randomly divided into a training cohort and a validation cohort at a ratio of 7:3. The influencing factors were screened by univariate and multivariate logistic regression analyses, and nomogram models were constructed. The area under the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the models. CRA in lung cancer is mainly related to surgery, chemotherapy, Karnofsky Performance Status (KPS) score, serum iron, C-reactive protein (CRP), albumin, and total cholesterol (p < 0.05). CRA in lung cancer patients with decreased serum iron is primarily associated with albumin, age, and cancer staging, while CRA in lung cancer patients with normal serum iron is mainly related to CRP, albumin, total cholesterol, and cancer staging. The area under the ROC curve of the training cohort and validation cohort for the prediction model of lung cancer patients with decreased serum iron was 0.758 and 0.760, respectively. Similarly, the area under the ROC curve of the training cohort and validation cohort for the prediction model of lung cancer patients with normal serum iron was 0.715 and 0.730, respectively. The calibration curves of both prediction models were around the ideal 45° line, suggesting good discrimination and calibration. DCA showed that the nomograms had good clinical utility. Both models have good reliability and validity and have significant clinical value. They can help doctors better assess the risk of developing CRA in lung cancer patients. CRP is a risk factor for CRA in lung cancer patients with normal serum iron but not in patients with decreased serum iron. Therefore, whether CRP and the inflammatory state represented by CRP will further aggravate the decrease in serum iron levels, thus contributing to anemia, warrants further study.

Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease

BackgroundNonalcoholic fatty liver disease (NAFLD) is associated with disordered lipid and iron metabolism. Our previous study has substantiated the pivotal role of Caveolin-1 (Cav-1) in protecting hepatocytes and mediating iron metabolism in the liver. This study aimed to explore the specific mechanisms underlying the regulation of iron metabolism by Cav-1 in NAFLD.MethodsHepatocyte-specific Cav-1 overexpression mice and knockout mice were used in this study. Cav-1-knockdown of RAW264.7 cells and mouse primary hepatocytes were performed to verify the changes in vitro. Moreover, a high-fat diet and palmitic acid plus oleic acid treatment were utilized to construct a NAFLD model in vivo and in vitro, respectively, while a high-iron diet was used to construct an in vivo iron overload model. Besides, iron concentration, the expression of Cav-1 and iron metabolism-related proteins in liver tissue or serum were detected using iron assay kit, Prussian blue staining, Western blotting, immunofluorescence staining, immunohistochemical staining and ELISA. The related indicators of lipid metabolism and oxidative stress were evaluated by the corresponding reagent kit and staining.ResultsSignificant disorder of lipid and iron metabolism occurred in NAFLD. The expression of Cav-1 was decreased in NAFLD hepatocytes (P < 0.05), accompanied by iron metabolism disorder. Cav-1 enhanced the iron storage capacity of hepatocytes by activating the ferritin light chain/ferritin heavy chain pathway in NAFLD, subsequently alleviating the oxidative stress induced by excess ferrous ions in the liver. Further, CD68+CD163+ macrophages expressing Cav-1 were found to accelerate iron accumulation in the liver, which was contrary to the effect of Cav-1 in hepatocytes. Positive correlations were also observed between the serum Cav-1 concentration and the serum iron-related protein levels in NAFLD patients and healthy volunteers (P < 0.05).ConclusionsThese findings confirm that Cav-1 is an essential target protein that regulates iron and lipid metabolic homeostasis. It is a pivotal molecule for predicting and protecting against the development of NAFLD.

Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy

Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin's E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.

Regulation of Epidermal Ferritin Expression Influences Systemic Iron Homeostasis

Absorption of dietary iron is largely regulated by the liver hormone hepcidin, which is released under conditions of iron overload and inflammation. Although hepcidin-dependent regulation of iron uptake and circulation is well-characterized, recent studies have suggested that the skin may play an important role in iron homeostasis, including transferrin receptor-mediated epidermal iron uptake and direct hepcidin production by keratinocytes. In this study, we characterized direct keratinocyte responses to conditions of high and low iron. We observed potent iron storage capacity by keratinocytes invitro and invivo and the effects of iron on epidermal differentiation and gene expression associated with inflammation and barrier function. In mice, systemic iron was observed to be coupled to epidermal iron content. Furthermore, topical inflammation, as opposed to systemic inflammation, resulted in a primary iron-deficiency phenotype associated with low liver hepcidin. These studies suggest a role for keratinocytes and epidermal iron storage as regulators of iron homeostasis with direct contribution by the cutaneous inflammatory state.

Unraveling the structure and function of bacterioferritin in Candidatus Kuenenia stuttgartiensis: Iron storage sites maintain cellular iron homeostasis

Anammox bacteria rely heavily on iron and have many iron storage sites. However, the biological significance of these iron storage sites has not been clearly defined. In this study, we explored the properties and location of iron storage sites to better understand their cellular function. To do this, the Candidatus Kuenenia stuttgartiensis iron storage protein, bacterioferritin (K.S Bfr), was successfully expressed and purified. In vitro, correctly assembled globulins were observed by transmission electron microscopy. The self-assembled K.S Bfr has active redox and can bind Fe2+ and mineralize it in the protein cavity. In vivo, engineered bacteria with K.S Bfr showed good adaptability to Fe2+, with a survival rate of 78.9% when exposed to 5 mM Fe2+, compared with only 66.0% for wild-type bacteria lacking K.S Bfr. A potential iron regulatory strategy similar to that of Anammox was identified in transcriptomic analysis of engineered bacteria. This system may be controlled by the iron uptake regulator Furto transport Fe2+ via FeoB and store excess Fe2+ in K.S Bfr to maintain cellular homeostasis. K.S Bfr has superior iron storage capacity both intracellularly and in vitro. The discovery of K.S Bfr reveals the storage location of iron-rich nanoparticles, increases our understanding of the adaptability of iron-dependent bacteria to Fe2+, and suggests possible iron regulation strategies in Anammox bacteria.

Hematological Profile of Iron Overload in Rats Administered with Fruit Extract of Mahkota Dewa (Phaleria macrocarpa)

Background: Repeated blood transfusions lead to an accumulation of iron that exceeds the body's iron storage capacity. Free iron is able to catalyze the formation of hydroxyl radicals that cause oxidative damage and cell death. The use of iron chelating medicines for iron chelation therapy is limited by side effects. Mangiferin is a natural bioactive compound with iron chelating and antioxidant activity. Mahkota dewa is a plant native to Indonesia that contains mangiferin. Objectives: The aim of this study was to evaluate the effect of mahkota dewa fruit extract administration on hematological profile of iron overload rats. Material and Methods: Thirty rats were divided into 6 groups: normal rats (N), iron overload rats (IO), iron overload rats rats given deferiprone (D), mangiferin (M), Mahkota dewa fruit extract at a dose of 100 mg/kg BW (PM1), or 200 mg/kg BW (PM2). Rats were given injection of iron sucrose 15 mg every 3-4 days for 8 weeks. At week 8, rats were sacrificed. Hematological analysis was performed in this study. Results: Iron overload condition caused by iron sucrose injection did not cause statistically significant changes in the haematological profile. Likewise, the administration mahkota dewa fruit extract at a dose of 100 or 200 mg/kg BW did not cause changes in the hematological profile. Conclusions: The administration of mahkota dewa fruit extract did not alter hematological profile of iron oveload rats.

Synchrotron‐Based Nano‐X‐Ray Absorption Near‐Edge Structure Revealing Intracellular Heterogeneity of Iron Species in Magnetotactic Bacteria

Magnetotactic bacteria (MTB) sequester iron from the environment to biomineralize magnetite or greigite nanoparticles in magnetosome organelles, though the necessity of intracellular iron storage for the formation process is still in question. Understanding the role of iron storage would make clear the contribution of MTB in geochemical iron cycling and its potential importance during the biosynthesis of application‐relevant magnetic nanoparticles. Herein, how scanning X‐ray fluorescence microscopy (SXFM) and nanoscale X‐ray absorption near‐edge structure (nano‐XANES) mapping can spatially and chemically identify intracellular iron species is reported, creating an opportunity to examine the role of iron storage in magnetite biomineralization at the single‐cell level. Fe K‐edge nano‐XANES measurements of Magnetospirillum gryphiswaldense in varied iron media conditions and iron storage capacity reveal a significant quantity of intracellular iron heterogeneities through a distinction between formed magnetosomes and intracellular iron material. This intracellular iron component is found in both early and late stages of biomineralization. The capabilities of nano‐XANES in providing an experimental advantage in the multidisciplinary field of biomineralization are highlighted.

Possible Protective Role of Deferoxamine in Ameliorating Osteoporosis in a Rat Model of Liver Cirrhosis via Iron Metabolism Regulation

Abstract Background Liver cirrhosis is considered the terminal stage of many hepatic diseases of different etiologies. Liver cirrhosis was associated with increased incidence rates of some extrahepatic manifestations such as osteoporosis. Regardless of the liver disease etiology, the presence of cirrhosis implies a twofold risk of bone fractures higher than non-cirrhotic patients. The liver is the main storage depot for iron and is the primary organ that is responsible for clearing excess iron in conditions of iron overload. When the iron storage and antioxidant capacity of the liver is overwhelmed, iron overload can lead to marked oxidantmediated liver and bone injury and iron overload was a risk factor for osteoporosis via affecting osteoblast survival. Aim of the work to examine the possible protective effect of Deferoxamine (DFO) on liver cirrhosis rat model induced osteoporosis. Material and Method rats was divided into 4 groups Animal Groups: Naïve control, DFO-treated group, TAA-treated group received Thioacetamide (TAA) ip (200 mg/kg/rat) twice weekly for 12 weeks, TAA+DFO treated group received TAA intra-peritoneal in addition to DFO intraperitoneal injections (300 mg/kg/3 times/week, for the last 4 weeks of TAA injections. Results and Conclusion Deferoxamine produced significant improvement in bone mineralization alongside its significant effect on liver function test in a rat model of liver cirrhosis induced osteoporosis.

Bacterioferritin: a key iron storage modulator that affects strain growth and butenyl-spinosyn biosynthesis in Saccharopolyspora pogona

BackgroundButenyl-spinosyn, produced by Saccharopolyspora pogona, is a promising biopesticide due to excellent insecticidal activity and broad pesticidal spectrum. Bacterioferritin (Bfr, encoded by bfr) regulates the storage and utilization of iron, which is essential for the growth and metabolism of microorganisms. However, the effect of Bfr on the growth and butenyl-spinosyn biosynthesis in S. pogona has not been explored.ResultsHere, we found that the storage of intracellular iron influenced butenyl-spinosyn biosynthesis and the stress resistance of S. pogona, which was regulated by Bfr. The overexpression of bfr increased the production of butenyl-spinosyn by 3.14-fold and enhanced the tolerance of S. pogona to iron toxicity and oxidative damage, while the knockout of bfr had the opposite effects. Based on the quantitative proteomics analysis and experimental verification, the inner mechanism of these phenomena was explored. Overexpression of bfr enhanced the iron storage capacity of the strain, which activated polyketide synthase genes and enhanced the supply of acyl-CoA precursors to improve butenyl-spinosyn biosynthesis. In addition, it induced the oxidative stress response to improve the stress resistance of S. pogona.ConclusionOur work reveals the role of Bfr in increasing the yield of butenyl-spinosyn and enhancing the stress resistance of S. pogona, and provides insights into its enhancement on secondary metabolism, which provides a reference for optimizing the production of secondary metabolites in actinomycetes.

Intrinsically magnetic susceptibility in human blood and its potential impact on cell separation: Non-classical and intermediate monocytes have the strongest magnetic behavior in fresh human blood

The presence of iron in circulating monocytes is well known as they play an essential role in iron recycling. It has been demonstrated that the iron content of blood cells can be measured through their magnetic behavior; however, the magnetic properties of different monocyte subtypes remain unknown. In this study we report, for the first time, the magnetic behavior of classical, intermediate and non-classical monocytes, which may be related to their iron storage capacity. The magnetic properties of monocytes were compared with those of other blood cells, such as lymphocytes and red blood cells in the oxyhemoglobin and methemoglobin states, and a cancer cell type. For this analysis, we used an instrument referred to as a Cell Tracking Velocimetry (CTV), which quantitatively characterizes the magnetic behavior of biological entities. Our results revealed that significant fractions of the intermediate and non-classical monocytes (up to 59% and 65% depending on the sample, respectively) have paramagnetic properties, suggesting their higher iron storage capacities. Moreover, our findings have implications for the immunomagnetic separation industry; we propose that negative magnetic isolation techniques for recovering monocytes from blood should be used with caution, as it is possible to lose magnetic monocytes when using this technique.

Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants

The role of abnormal brain iron metabolism in neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain iron homeostasis is the primary cause of neurodegeneration. We mutagenized ferritin’s three-fold pores (3FPs), i.e. the main entry route for iron, to investigate ferritin’s iron management when iron must traverse the protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the ferritin light chain (FtL) gene in HF. We assessed the structure and properties of ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter ferritin structure but led to a decrease in protein solubility and iron storage. Abnormal 4FPs acted as alternate routes for iron entry and exit in the absence of functional 3FPs, further reducing ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises ferritin solubility and function, providing a rationale for the presence of ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF.

Tetrachlorobenzoquinone exposure triggers ferroptosis contributing to its neurotoxicity

Halogenated quinones are representative metabolites of persistent organic pollutants. Tetrachlorobenzoquinone (TCBQ) is a reactive metabolite of the widely used fungicide hexachlorobenzene (HCB) and wood preservative pentachlorophenol (PCP). Our previous studies have demonstrated that TCBQ induced neuron-like cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Here, we found that TCBQ caused lipid peroxidation and cellular morphological changes including shrinked mitochondrial size, suggesting the involvement of a recently uncovered form of programmed cell death (PCD), ferroptosis. Indeed, we then identified that ferroptosis is a novel PCD driven by TCBQ, which was correlated with a decrease in glutathione peroxidase 4 (GPX4) level and iron accumulation by altering iron metabolism. Notably, nuclear factor erythroid-derived 2-like 2 (Nrf2) is a negative regulator in modulating the outcomes of ferroptosis as an adaptive cellular defense response. Nrf2 activation enhanced iron storage capacity and GPX4 activity by elevating ferritin heavy chain 1 (FTH1) expression and glutathione (GSH) level, respectively. On the contrary, Nfe2l2 (Nrf2) deficiency enhanced PC12 cells susceptibility to ferroptosis.

Fostered Nrf2 expression antagonizes iron overload and glutathione depletion to promote resistance of neuron-like cells to ferroptosis

Neurological diseases were often characterized by progressive neuronal death, and emerging evidences suggested that ferroptosis may be an active driver of multiple neurodegenerative diseases. However, the mechanisms underlying ferroptosis in neuron cells are unclear. Here, we demonstrated that ferroptotic stimuli caused injury in neuron-like PC12 cells by modulating the expression of proteins involved in iron metabolism and lipid peroxidation at multiple levels, such as altering iron import/export, activating ferritinophagy, and decreasing glutathione (GSH) level. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple genes involved in ferroptosis, however, its exact role remain elusive. Our mechanistic inquiry revealed that Nrf2 expression enhanced iron storage capacity by increasing ferritin heavy chain 1 (FTH1) expression in PC12 cells. Moreover, Nrf2 alleviated the decrease in GSH level by promoting the expression of genes related to GSH synthesis, including solute carrier family 7 member 11 (SLC7A11) and cysteine ligase (GCL). The contribution of Nrf2 on ferroptosis resistance was further verified by increasing cell tolerance to oxidative stress. Furthermore, Nfe2l2 (Nrf2) knockdown sensitized cells to ferroptotic cell death. Taken together, our findings suggested that iron accumulation caused by altering iron metabolism and the decrease of GSH content are key factors in determining ferroptosis in PC12 cells, and Nrf2 inhibits ferroptosis by combating iron-induced oxidative stress. Our present study provided new clues for the intervention and prevention against ferroptosis-associated neurological diseases.

Consequences of parenteral iron-dextran loading investigated in minipigs. A new model of transfusional iron overload

Patients with blood transfusion-dependent anemias develop transfusional iron overload (TIO), which may cause cardiosiderosis. In patients with an ineffective erythropoiesis, such as thalassemia major, common transfusion regimes aim at suppression of erythropoiesis and of enteral iron loading. Recent data suggest that maintaining residual, ineffective erythropoiesis may protect from cardiosiderosis. We investigated the common consequences of TIO, including cardiosiderosis, in a minipig model of iron overload with normal erythropoiesis. TIO was mimicked by long-term, weekly iron-dextran injections.Iron-dextran loading for around one year induced very high liver iron concentrations, but extrahepatic iron loading, and iron-induced toxicities were mild and did not include fibrosis. Iron deposits were primarily in reticuloendothelial cells, and parenchymal cardiac iron loading was mild. Compared to non-thalassemic patients with TIO, comparable cardiosiderosis in minipigs required about 4-fold greater body iron loads.It is suggested that this resistance against extrahepatic iron loading and toxicity in minipigs may at least in part be explained by a protective effect of the normal erythropoiesis, and additionally by a larger total iron storage capacity of RES than in patients with TIO.Parenteral iron-dextran loading of minipigs is a promising and feasible large-animal model of iron overload, that may mimic TIO in non-thalassemic patients.

Large protein organelles form a new iron sequestration system with high storage capacity.

Iron storage proteins are essential for cellular iron homeostasis and redox balance. Ferritin proteins are the major storage units for bioavailable forms of iron. Some organisms lack ferritins, and it is not known how they store iron. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment from Quasibacillus thermotolerans. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo and show interactions underlying cargo-shell co-assembly. This compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. Our results reveal a new approach for survival in diverse habitats with limited or fluctuating iron availability via an iron storage system able to store 10 to 20 times more iron than ferritin.

Multitissue analysis of exercise and metformin on doxorubicin-induced iron dysregulation.

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart and skeletal muscle. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, major cellular changes to iron regulation in response to DOX are poorly understood in liver, heart, and skeletal muscle. Additionally, two cotreatments, exercise (EX) and metformin (MET), were studied for their effectiveness in reducing DOX toxicity by ameliorating iron dysregulation and preventing oxidative stress. The purposes of this study were to 1) characterize the DOX-induced changes of the major iron regulation pathway in liver, heart, and skeletal muscle and 2) to determine whether EX and MET exert their benefits by minimizing DOX-induced iron dysregulation. Mice were assigned to receive saline or DOX (15 mg/kg) treatments, paired with either EX (5 days) or MET (500 mg/kg), and were euthanized 3 days after DOX treatment. Results suggest that the cellular response to DOX is protective against oxidative stress by reducing iron availability. DOX increased iron storage capacity through elevated ferritin levels in liver, heart, and skeletal muscle. DOX reduced iron transport capacity through reduced transferrin receptor levels in heart and skeletal muscle. EX and MET cotreatments had protective effects in the liver through reduced transferrin receptor levels. At 3 days after DOX, oxidative stress was mild, as shown by normal glutathione and lipid peroxidation levels. Together these results suggest that the cellular response to reduce iron availability in response to DOX treatment is sufficient to match oxidative stress.

Iron storage capacities and associated ferritin gene expression among marine diatoms

AbstractIn large regions of the ocean, low iron availability regulates diatom growth and species composition. Diatom species often vary in their physiological response to iron enrichment, with natural and artificial iron additions in iron‐limited regions of the ocean resulting in large blooms of primarily pennate diatoms. The ability of pennate diatoms to proliferate following pulse iron additions has been partly attributed to their ability to acquire and store excess intracellular iron in the iron storage protein ferritin. Recent transcriptome sequencing of diatoms indicate that some centric diatoms also possess ferritin. Using a combination of physiological and molecular techniques, we examined the iron storage capacities and associated ferritin gene expression in phylogenetically diverse centric and pennate diatoms grown under high and low iron concentrations. There were no systematic differences among ferritin‐containing and non‐containing diatom lineages in their ability to store iron in excess of that needed to support maximum growth rates. An exception, however, was the ferritin‐containing pennate diatom Pseudo‐nitzschia granii, native to iron‐limited waters of the Northeast Pacific Ocean. This species exhibited an exceptionally large luxury iron storage capacity and increased ferritin gene expression at high iron concentrations, supporting a role in long‐term iron storage. By contrast, two other diatoms species that exhibited minimal iron storage capacities contained two distinct ferritin genes where one ferritin gene increased in expression under iron limitation while the second showed no variation with cellular iron status. We conclude that ferritin may serve multiple functional roles that are independent of diatom phylogeny.

Vitreous Humor Changes Expression of Iron-Handling Proteins in Lens Epithelial Cells.

PurposeIn humans, vitrectomy is associated with development of nuclear cataracts. Iron catalyzes free radical formation causing oxidative damage, which is implicated in cataract formation. This study was designed to determine if vitreous humor, which can initiate differentiation of lens epithelial cells, would have an effect on iron-handling proteins.MethodsCultured canine lens epithelial cells were treated with collected canine vitreous humor. Lysates of treated and control cells were separated by SDS-PAGE. Ferritin H- and L-chains, transferrin receptor 1, and aquaporin 0 were immunodetected and quantitated with specific antibodies. Morphologic changes in treated cells were assessed.ResultsTreatment of lens epithelial cells with a 33% (vol/vol) solution of vitreous humor changed the morphology of lens cells and induced expression of aquaporin 0, a marker of fiber cell differentiation that was undetectable in control cells. Treatment did not modify the size of iron-handling proteins but significantly increased content of ferritin from 2.9- to 8.8-fold over control and decreased levels of transferrin receptor by 37% to 59%.ConclusionsVitreous humor may significantly limit iron uptake by transferrin/transferrin receptor pathway, and by increasing ferritin levels could profoundly increase the iron-storage capacity of ferritin in lens cells. Vitreous humor may play a significant protective role against iron-catalyzed oxidative damage of lens epithelial cells and therefore in the formation of cataracts.