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Human transferrin receptor 1 (CD71) guarantees iron supply by endocytosis upon binding of iron-loaded transferrin and ferritin. Arenaviruses and the malaria parasite exploit CD71 for cell invasion and epitopes on CD71 for interaction with transferrin and pathogenic hosts were identified. Here, we provide the molecular basis of the CD71 ectodomain-human ferritin interaction by determining the 3.9 Å resolution single-particle cryo-electron microscopy structure of their complex and by validating our structural findings in a cellular context. The contact surfaces between the heavy-chain ferritin and CD71 largely overlap with arenaviruses and Plasmodium vivax binding regions in the apical part of the receptor ectodomain. Our data account for transferrin-independent binding of ferritin to CD71 and suggest that select pathogens may have adapted to enter cells by mimicking the ferritin access gate. The human transferrin receptor 1 (CD71) is a transmembrane protein responsible for iron uptake. Here the authors present the 3.9 Å resolution cryo-EM structure of the CD71 ectodomain-human ferritin (H-Ft) complex and find that H-Ft binds a CD71 region different from the transferrin one that overlaps with the surface recognized by select pathogens.

Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer’s disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.

Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, siramesine and a tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24 h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with siramesine and lapatinib. Furthermore, we determined that FeCl3 levels were elevated in cells treated with siramesine and lapatinib indicating an iron-dependent cell death, ferroptosis. To confirm this, we treated cells with a potent inhibitor of ferroptosis, ferrastatin-1 that effectively inhibited cell death following siramesine and lapatinib treatment. The increase levels of iron could be due to changes in iron transport. We found that the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. Knocking down of transferrin resulted in decreased cell death and ROS after treatment. In addition, ferroportin-1 (FPN) is an iron transport protein, responsible for removal of iron from cells. We found its expression is decreased after treatment with siramesine alone or in combination with lapatinib. Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor.

Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.

Background Serum iron biomarkers are disordered on the progression of obesity and its associated metabolic syndrome (MetS). However, limited evidence is explored the interactions between serum iron biomarkers and the incidence of MetS. Thus, the purpose of this study is to discuss whether epigenetic modifications of nuclear and mitochondrial DNA (mtDNA) are associated with the disturbance of serum iron biomarkers among the metabolically unhealthy obesity (MUO) school-age children. Methods A representative cross-sectional study was performed using the data from 104 obesity school-age children, while the subjects without obesity were as controls ( n  = 65). Then, the 104 obesity subjects were defined as metabolically healthy obesity (MHO, n  = 60) and MUO ( n  = 44) subgroups according to whether they were accompanied with MetS. Their serum metabolic indicators, transferrin receptor 1 (TFR1), transferrin (TF) and genome-wide methylation were determined by the Elisa method. Moreover, the methylation levels of TFR1 and TF were measured by the Bisulfite sequencing PCR (BSP-PCR). Furthermore, the copy number (mtDNA-CN) and methylation of mtDNA were detected by the RT-PCR, while the semi-long RT-PCR was then used to estimate the lesions of mtDNA. Results Compared with the control and MHO groups, the levels of MetS related indicators, anthropological characteristics and 8-OHdG were higher, and the concentrations of CAT, GSH-Px, TF, TFR1 and genome-wide methylation were lower in the MUO group in a BMI-independent manner ( P  < 0.05). Then, the contents of serum iron were lower in both the MHO and MUO groups than those in the control group ( P  < 0.017). Moreover, they were positively related with the contents of serum CAT and GSH-Px, and negatively with 8-OHdG, TF and TFR1 ( P  < 0.05). Furthermore, the methylation patterns on the TF, TFR1 and mtDNA were higher in the MUO group than those in the MHO and control groups ( P  < 0.017), which were negatively correlated with their serum contents ( P  < 0.05). Meanwhile, the ratio of methylated/unmethylated mtDNA was significantly associated with their mtDNA-CN and lesions ( P  < 0.05). Conclusions Our findings suggested that the impairments on the epigenetic modifications of nuclear (genome-wide DNA, TF and TFR1) and mtDNA were associated with the disturbance of serum iron biomarkers to involve in the pathophysiology of MetS among the school-age MUO children. Trial registration This study was approved by the Ethics Committee of Beijing Children’s Hospital affiliated to Capital Medical University (No. IEC-C−006-A04-V.06), which was also registered at the website of http://www.chictr.org.cn/showproj.aspx?proj=4673 (No: ChiCTR-OCH−14004900).

Iron is one of the most important nonorganic substances that make life possible. Iron plays major roles in oxygen transport (eg, hemoglobin; -67% of total body iron [TBI]), short-term oxygen storage (eg, myoglobin; -3.5% of TBI), and energy generation (eg, cytochromes; -3% of TBI). Iron also serves vital roles in various nonheme-containing enzymes (-2% of TBI). Figure 1 lists heme-containing and nonheme iron-containing proteins. TBI is controlled by the rate of iron absorption; there are no physiologic mechanisms to excrete excess iron. Iron deficiency has many adverse consequences, including anemia, and in children, behavioral and learning disorders. Iron excess is toxic to the body, harming the heart, liver, skin, pancreatic islet beta cells, bones, joints, and pituitary gland. Maintaining proper iron balance is essential for maintaining homeostasis and health. TBI in adults normally ranges between 3.5 and 5.0 g. A total of 75% of TBI is functional, and 25% is stored within cells as ferritin or hemosiderin. Ferritin contains 24 subunits of light chains (L chains; 19.7 kDa) and heavy chains (H chains; 21.1 kDa). The L chains are encoded on chromosome 19q13.33 and are 175 amino acids long. The H chains are encoded on chromosome 11q1 and are 183 amino acids long. Each ferritin molecule can contain as many as approximately 4500 ferric ions. Because the major role of iron is in hemoglobin synthesis, this review will focus on iron, iron transport, and hematopoiesis.

Iron sequestration provides an innate defense, termed nutritional immunity, leading pathogens to scavenge iron from hosts. Although the molecular basis of this battle for iron is established, its potential as a force for evolution at host-pathogen interfaces is unknown. We show that the iron transport protein transferrin is engaged in ancient and ongoing evolutionary conflicts with TbpA, a transferrin surface receptor from bacteria. Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes. Furthermore, the C2 transferrin polymorphism in humans evades TbpA variants from Haemophilus influenzae, revealing a functional basis for standing genetic variation. These findings identify a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens.

Anemia in women of reproductive age is highly prevalent globally and remains a public health problem. In Ethiopia, despite efforts to minimize the burden of anemia, it is still a moderate public health problem. Anemia has various etiologies including nutritional deficiency, parasitic infection, and inflammation. The aim of this study was to examine contributing factors to anemia in lactating women. Following ethical approval, and six months after delivery, all lactating women (n = 150) were recruited to participate in this study from eight randomly selected rural villages. Anthropometric and socio-economic factors were assessed. From each, a blood sample was collected for measuring hemoglobin, iron biomarkers, zinc, selenium, and inflammation markers. The median (IQR) hemoglobin (Hb) was 132 (123, 139) g/L. Of the women, 19% were anemic and 7% had iron deficiency anemia; 31% were iron deficient and 2% had iron overload. Also, 8% had functional iron deficit, 6% had acute inflammation, 13% had chronic inflammation, and 16% had tissue iron deficiency. The majority (78%) of the women had low plasma zinc out of which more than 16% were anemic. Hb was positively associated with plasma iron and plasma zinc and negatively associated with transferrin receptor (TfR) and α-1-acid glycoprotein (AGP). Plasma iron, AGP, TfR, hepcidin and plasma zinc were significant predictors of maternal anemia. Additionally MUAC and level of education were associated positively with maternal hemoglobin. This study showed that maternal anemia was associated with multiple factors including nutritional deficiencies, inflammation and limited education.

Abnormal hepatic iron metabolism is detrimental to health. The objective of this study was to detect repeated restraint stress on liver iron metabolism in rats. Twenty-four male rats aged 7 weeks were randomly divided into 2 groups: control group (Con) and repeated restraint stress group (RS). Rats were subjected to 6 h of daily restraint stress for 14 consecutive days in the repeated restraint stress group. The results showed that repeated restraint stress exposure decreased growth performance including impaired final weight (P = 0.07), reducing average daily gain (P = 0.01), and average daily feed intake (P = 0.00) during the 14-day experimental period. Repeated restraint stress exposure did not affect hemoglobin content and plasma iron parameters except downregulated unsaturated iron-binding capacity (P = 0.04). Repeated restraint stress exposure inhibited liver development (P = 0.03) and induced liver iron accumulation (P = 0.05). In addition, repeated restraint stress downregulated the expression of transferrin (TF) and transferrin receptor 2 (TFR2) at the mRNA level (P < 0.01), but upregulated at the protein level (P = 0.03 for TF; P = 0.00 for TFR2). These results indicated that repeated restraint stress induces hepatic iron accumulation, which is closely related to higher expression of hepatic TFR2 protein in rats.

Chuvash polycythemia is an autosomal recessive disorder that is endemic to the mid-Volga River region. We previously mapped the locus associated with Chuvash polycythemia to chromosome 3p25. The gene associated with von Hippel–Lindau syndrome, VHL , maps to this region, and homozygosity with respect to a C→T missense mutation in VHL , causing an arginine-to-tryptophan change at amino-acid residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash polycythemia. The protein VHL modulates the ubiquitination and subsequent destruction of hypoxia-inducible factor 1, subunit α (HIF1α). Our data indicate that the Arg200Trp substitution impairs the interaction of VHL with HIF1α, reducing the rate of degradation of HIF1α and resulting in increased expression of downstream target genes including EPO (encoding erythropoietin), SLC2A1 (also known as GLUT1 , encoding solute carrier family 2 (facilitated glucose transporter), member 1), TF (encoding transferrin), TFRC (encoding transferrin receptor (p90, CD71)) and VEGF (encoding vascular endothelial growth factor).