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International Journal of Molecular... Apr 2021Iron is a critical metal for several vital biological processes. Most of the body's iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is... (Review)
Review
Iron is a critical metal for several vital biological processes. Most of the body's iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.
Topics: Animals; Cation Transport Proteins; Enterocytes; Ferritins; Hemoglobins; Hepatocytes; Humans; Iron; Iron, Dietary; Liver; Receptors, Transferrin; Spleen; Transferrin
PubMed: 33925597
DOI: 10.3390/ijms22094591 -
Cell Reports Mar 2020Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no...
Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ∼4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts.
Topics: Animals; Antibodies, Monoclonal; Antigens; Biomarkers; Cell Line; Cell Line, Tumor; Cell Membrane; Ferroptosis; Golgi Apparatus; Humans; Injections; Mice; Piperazine; Piperazines; Receptors, Transferrin; Xenograft Model Antitumor Assays
PubMed: 32160546
DOI: 10.1016/j.celrep.2020.02.049 -
Cell Death & Disease Oct 2019Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. Recently, the...
Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. Recently, the induction of autophagy has been suggested during ferroptosis. However, this relationship between autophagy and ferroptosis is still controversial and the autophagy-inducing mediator remains unknown. In this study, we confirmed that autophagy is indeed induced by the ferroptosis inducer erastin. Furthermore, we show that autophagy leads to iron-dependent ferroptosis by degradation of ferritin and induction of transferrin receptor 1 (TfR1) expression, using wild-type and autophagy-deficient cells, BECN1 and LC3B. Consistently, autophagy deficiency caused depletion of intracellular iron and reduced lipid peroxidation, resulting in cell survival during erastin-induced ferroptosis. We further identified that autophagy was triggered by erastin-induced reactive oxygen species (ROS) in ferroptosis. These data provide evidence that ROS-induced autophagy is a key regulator of ferritin degradation and TfR1 expression during ferroptosis. Our study thus contributes toward our understanding of the ferroptotic processes and also helps resolve some of the controversies associated with this phenomenon.
Topics: Antigens, CD; Apoptosis; Autophagy; Beclin-1; Cytoplasm; Ferroptosis; Humans; Iron; Lipid Peroxidation; Microtubule-Associated Proteins; Piperazines; Reactive Oxygen Species; Receptors, Transferrin
PubMed: 31659150
DOI: 10.1038/s41419-019-2064-5 -
The American Journal of Clinical... Dec 2017Iron is an essential trace element, but it is also toxic in excess, and thus mammals have developed elegant mechanisms for keeping both cellular and whole-body iron... (Review)
Review
Iron is an essential trace element, but it is also toxic in excess, and thus mammals have developed elegant mechanisms for keeping both cellular and whole-body iron concentrations within the optimal physiologic range. In the diet, iron is either sequestered within heme or in various nonheme forms. Although the absorption of heme iron is poorly understood, nonheme iron is transported across the apical membrane of the intestinal enterocyte by divalent metal-ion transporter 1 (DMT1) and is exported into the circulation via ferroportin 1 (FPN1). Newly absorbed iron binds to plasma transferrin and is distributed around the body to sites of utilization with the erythroid marrow having particularly high iron requirements. Iron-loaded transferrin binds to transferrin receptor 1 on the surface of most body cells, and after endocytosis of the complex, iron enters the cytoplasm via DMT1 in the endosomal membrane. This iron can be used for metabolic functions, stored within cytosolic ferritin, or exported from the cell via FPN1. Cellular iron concentrations are modulated by the iron regulatory proteins (IRPs) IRP1 and IRP2. At the whole-body level, dietary iron absorption and iron export from the tissues into the plasma are regulated by the liver-derived peptide hepcidin. When tissue iron demands are high, hepcidin concentrations are low and vice versa. Too little or too much iron can have important clinical consequences. Most iron deficiency reflects an inadequate supply of iron in the diet, whereas iron excess is usually associated with hereditary disorders. These disorders include various forms of hemochromatosis, which are characterized by inadequate hepcidin production and, thus, increased dietary iron intake, and iron-loading anemias whereby both increased iron absorption and transfusion therapy contribute to the iron overload. Despite major recent advances, much remains to be learned about iron physiology and pathophysiology.
Topics: Anemia, Iron-Deficiency; Cation Transport Proteins; Enterocytes; Ferritins; Hemochromatosis; Hepcidins; Homeostasis; Humans; Intestinal Absorption; Iron; Iron Deficiencies; Iron Overload; Iron Regulatory Protein 1; Iron Regulatory Protein 2; Receptors, Transferrin; Transferrin
PubMed: 29070551
DOI: 10.3945/ajcn.117.155804 -
Frontiers in Immunology 2021The transferrin receptor 1 (TfR1), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds transferrin (Tf) and performs a... (Review)
Review
The transferrin receptor 1 (TfR1), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds transferrin (Tf) and performs a critical role in cellular iron uptake through the interaction with iron-bound Tf. Iron is required for multiple cellular processes and is essential for DNA synthesis and, thus, cellular proliferation. Due to its central role in cancer cell pathology, malignant cells often overexpress TfR1 and this increased expression can be associated with poor prognosis in different types of cancer. The elevated levels of TfR1 expression on malignant cells, together with its extracellular accessibility, ability to internalize, and central role in cancer cell pathology make this receptor an attractive target for antibody-mediated therapy. The TfR1 can be targeted by antibodies for cancer therapy in two distinct ways: (1) indirectly through the use of antibodies conjugated to anti-cancer agents that are internalized by receptor-mediated endocytosis or (2) directly through the use of antibodies that disrupt the function of the receptor and/or induce Fc effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Although TfR1 has been used extensively as a target for antibody-mediated cancer therapy over the years, interest continues to increase for both targeting the receptor for delivery purposes and for its use as direct anti-cancer agents. This review focuses on the developments in the use of antibodies targeting TfR1 as direct anti-tumor agents.
Topics: Animals; Antibody-Dependent Cell Cytotoxicity; Antigens, CD; Antineoplastic Agents, Immunological; Biological Transport; Biomarkers, Tumor; Cell Line, Tumor; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Humans; Iron; Molecular Targeted Therapy; Receptors, Transferrin; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 33815364
DOI: 10.3389/fimmu.2021.607692 -
Science Immunology Jan 2023T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights...
T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights into this potential role of iron in SLE, we performed a CRISPR screen of iron handling genes on T cells. Transferrin receptor (CD71) was identified as differentially critical for T1 and inhibitory for induced regulatory T cells (iT). Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Cell surface CD71 was enhanced in SLE-prone T cells by increased endosomal recycling. Blocking CD71 reduced intracellular iron and mTORC1 signaling, which inhibited T1 and T17 cells yet enhanced iT. In vivo treatment reduced kidney pathology and increased CD4 T cell production of IL-10 in SLE-prone mice. Disease severity correlated with CD71 expression on T17 cells from patients with SLE, and blocking CD71 in vitro enhanced IL-10 secretion. T cell iron uptake via CD71 thus contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.
Topics: Animals; Mice; Interleukin-10; Lupus Erythematosus, Systemic; Receptors, Transferrin; T-Lymphocytes, Regulatory; Humans
PubMed: 36638190
DOI: 10.1126/sciimmunol.abq0178 -
ELife Jun 2022Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing...
Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing activities. Transferrin receptor 1 (Tfr1) mediates cellular iron uptake through endocytosis of iron-loaded transferrin, and its expression increases during osteoclast differentiation. Nonetheless, the precise functions of Tfr1 and Tfr1-mediated iron uptake in osteoclast biology and skeletal homeostasis remain incompletely understood. To investigate the role of Tfr1 in osteoclast lineage cells in vivo and in vitro, we crossed (encoding Tfr1)-floxed mice with Cre and ()-Cre mice to generate conditional knockout mice in myeloid osteoclast precursors (Tfr1) or differentiated osteoclasts (Tfr1), respectively. Skeletal phenotyping by µCT and histology unveiled a significant increase in trabecular bone mass with normal osteoclast number in long bones of 10-week-old young and 6-month-old adult female but not male Tfr1 mice. Although high trabecular bone volume in long bones was observed in both male and female Tfr1 mice, this phenotype was more pronounced in female knockout mice. Consistent with this gender-dependent phenomena, estrogen deficiency induced by ovariectomy decreased trabecular bone mass in Tfr1 mice. Mechanistically, disruption of Tfr1 expression attenuated mitochondrial metabolism and cytoskeletal organization in mature osteoclasts in vitro by attenuating mitochondrial respiration and activation of the Src-Rac1-WAVE regulatory complex axis, respectively, leading to decreased bone resorption with little impact on osteoclast differentiation. These results indicate that Tfr1-mediated iron uptake is specifically required for osteoclast function and is indispensable for bone remodeling in a gender-dependent manner.
Topics: Animals; Bone Resorption; Cytoskeleton; Female; Iron; Mice; Mice, Knockout; Mitochondria; Osteoclasts; Receptors, Transferrin
PubMed: 35758636
DOI: 10.7554/eLife.73539 -
Cell Death and Differentiation Sep 2022Hepatic ischemia followed by reperfusion (I/R), a major clinical problem during liver surgical procedures, can induce liver injury with severe cell death including...
Hepatic ischemia followed by reperfusion (I/R), a major clinical problem during liver surgical procedures, can induce liver injury with severe cell death including ferroptosis which is characterized by iron-dependent accumulation of lipid peroxidation. The HECT domain-containing ubiquitin E3 ligase HUWE1 (also known as MULE) was initially shown to promote apoptosis. However, our preliminary study demonstrates that high expression of HUWE1 in the liver donors corelates with less injury and better hepatic function after liver transplantation in patients. Thus, we investigate the role of HUWE1 in acute liver injury, and identify HUWE1 as a negative ferroptosis modulator through transferrin receptor 1(TfR1). Deficiency of Huwe1 in mice hepatocytes (HKO) exacerbated I/R and CCl-induced liver injury with more ferroptosis occurrence. Moreover, Suppression of Huwe1 remarkably enhances cellular sensitivity to ferroptosis in primary hepatocytes and mouse embryonic fibroblasts. Mechanistically, HUWE1 specifically targets TfR1 for ubiquitination and proteasomal degradation, thereby regulates iron metabolism. Importantly, chemical and genetic inhibition of TfR1 dramatically diminishes the ferroptotic cell death in Huwe1 KO cells and Huwe1 HKO mice. Therefore, HUWE1 is a potential protective factor to antagonize both aberrant iron accumulation and ferroptosis thereby mitigating acute liver injury. These findings may provide clinical implications for patients with the high-expression Huwe1 alleles.
Topics: Animals; Equidae; Ferroptosis; Fibroblasts; Iron; Liver; Mice; Proteasome Endopeptidase Complex; Receptors, Transferrin; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases
PubMed: 35260822
DOI: 10.1038/s41418-022-00957-6 -
Advanced Science (Weinheim,... Apr 2023Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower iron uptake and...
Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower iron uptake and toxicity. However, the mechanism whereby TFRC expression is maintained at high levels in iron-enriched cancer cells and the contribution of TFRC to cancer development are enigmatic. Here the work shows TFRC is induced by adenomatous polyposis coli (APC) gene loss-driven β-catenin activation in colorectal cancer, whereas TFRC-mediated intratumoral iron accumulation potentiates β-catenin signaling by directly enhancing the activity of tankyrase. Disruption of TFRC leads to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of axis inhibition protein 2 (AXIN2) and subsequent repression of the β-catenin/c-Myc/E2F Transcription Factor 1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation, and TFRC disruption increase DNA replication stress, DNA damage response, apoptosis, and reduce colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents increases DNA damage response and reduces colon tumor cell growth. TFRC-mediated iron import is at the center of a novel feed-forward loop that facilitates colonic epithelial cell survival. This discovery may provide novel strategies for colorectal cancer therapy.
Topics: Humans; beta Catenin; Iron; Tankyrases; Colonic Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Receptors, Transferrin
PubMed: 36703617
DOI: 10.1002/advs.202207693 -
Redox Biology Feb 2023The global rate of human male infertility is rising at an alarming rate owing to environmental and lifestyle changes. Phthalates are the most hazardous chemical...
The global rate of human male infertility is rising at an alarming rate owing to environmental and lifestyle changes. Phthalates are the most hazardous chemical additives in plastics and have an apparently negative impact on the function of male reproductive system. Ferroptosis is a recently described form of iron-dependent cell death and has been linked to several diseases. Transferrin receptor (TfRC), a specific ferroptosis marker, is a universal iron importer for all cells using extracellular transferrin. We aim to investigate the potential involvement of ferroptosis during male reproductive toxicity, and provide means for drawing conclusions on the effect of ferroptosis in phthalates-induced male reproductive disease. In this study, we found that di (2-ethylhexyl) phthalate (DEHP) triggered blood-testis barrier (BTB) dysfunction in the mouse testicular tissues. DEHP also induced mitochondrial morphological changes and lipid peroxidation, which are manifestations of ferroptosis. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) induced ferroptosis by inhibiting glutathione defense network and increasing lipid peroxidation. TfRC knockdown blocked MEHP-induced ferroptosis by decreasing mitochondrial and intracellular levels of Fe. Our findings indicate that TfRC can regulate Sertoli cell ferroptosis and therefore is a novel therapeutic molecule for reproductive disorders in male patients with infertility.
Topics: Humans; Male; Mice; Animals; Diethylhexyl Phthalate; Blood-Testis Barrier; Ferroptosis; Receptors, Transferrin
PubMed: 36580806
DOI: 10.1016/j.redox.2022.102584