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"KAPLAN, Jerry"
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Regulation of iron acquisition and storage: consequences for iron-linked disorders
Key Points
Iron is essential but toxic. Mammals regulate systemic iron through acquisition and storage. Iron is absorbed in the gut and transported into plasma by an apical divalent metal transporter, DMT1, and a basolateral transporter, ferroportin. Only 1–2 mg of iron is absorbed per day in the gut.
Most of the iron in the body is found as haem in red blood cells. Old red blood cells are ingested by macrophages and degraded; iron is then recycled back into plasma by ferroportin. Iron in plasma is carried by the protein transferrin, which provides a chelating environment in plasma and a delivery system to cells that express transferrin receptors.
Iron in cells can be used for cellular processes or stored in the cytosolic protein ferritin. Levels of iron transporters, carriers and storage proteins are regulated transcriptionally and post-transcriptionally according to iron status.
Hepcidin, a peptide hormone secreted by the liver, is the key molecule that regulates systemic iron metabolism by regulating iron entry into plasma. The transcription of hepcidin is tightly regulated by signalling molecules, which sense iron levels, oxygen levels and inflammation. Hepcidin binds to ferroportin, leading to ferroportin degradation and a consequent decrease in cellular iron export.
Iron-overload diseases result from inappropriate iron acquisition in response to iron need. Excess iron can damage tissue, cause fibrosis and give rise to organ failure. Iron-deficiency disorders result in anaemia, which in turn give rise to poor oxygenation of tissue. Insight into the regulation of iron metabolism and iron-related diseases has occurred through genetics and the use of model organisms.
Mammalian iron homeostasis is achieved through iron acquisition and storage. Intestinal iron absorption and macrophage-mediated recycling of iron from red blood cells are highly regulated. The discovery of iron transporters and insight into their regulation has provided important information about iron-related disorders.
Mammalian iron homeostasis must be meticulously regulated so that this essential element is available for use, but at the same time prevented from promoting the formation of toxic radicals. Controlling the entry of iron into blood plasma is the main mechanism by which iron stores in the body are physiologically manipulated and regulated. Defects in iron acquisition at the cellular and systemic levels lead to human disorders, which involve either iron overload or iron deficiency. Discoveries of iron transporters and insights into their regulation have provided important information about iron metabolism and genetic iron disorders.
Journal Article
الذكاء الاصطناعي : ما يحتاج الجميع إلى معرفته
في هذا الكتاب الذي يحمل عنوان \"الذكاء الاصطناعي ما يحتاج الجميع إلى معرفته\" يتناول كابلان الموضوعات المعقدة المتعلقة بالذكاء الاصطناعي بأسلوب واضح يخلو من المصطلحات التقنية هل تستطيع الآلات حقا التفوق على الذكاء البشري ؟ كيف سيؤثر الذكاء الاصطناعي على الوظائف والدخل ؟ هل من الممكن أن يرتكب الروبوت جريمة عمدا ؟ كيف يمكن للآلة التحلي بالوعي أو ممارسة الإرادة الحرة ؟ في الوقت الراهن تتعلم كثير من أنظمة الذكاء الاصطناعي من التجربة وتقوم بأفعال تتجاوز نطاق برمجتها المبدئية ولذلك فهي تثير أسئلة مقلقة في عقول المجتمع هل من الممكن السماح للروبوت الخاص بك بالوقوف بدلا منك في الطابور ؟ أو هل من الممكن إجباره على الشهادة ضدك في المحكمة ؟ هل أنت المسئول الوحيد عن كل أفعال الروبوت ؟ هل يجب منح الروبوت الحق في التملك وإبرام العقود ؟ إذا أصبح ممكنا تحميل عقلك إلى آلة فهل ستظل هذة الآلة أنت ؟ الأجوبة قد تدهشك.
Book
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.
Journal Article
Generative artificial intelligence : what everyone needs to know
\"Advances in Generative Artificial Intelligence (GAI) have created a new class of computer systems that exhibit astonishing proficiency on a wide variety of tasks with superhuman performance, producing novel text, images, music, and software by analyzing enormous collections of digitized information. Soon, these systems will provide expert medical care; offer legal advice; draft documents; write computer programs; tutor our children; and generate music and art. These advances will accelerate progress in science, art, and human knowledge, but they will also bring new dangers. Have we finally discovered the holy grail of AI - machines that match or exceed human intelligence? Which industries and professions will thrive, and which will wither? What risks and dangers will it pose? How can we ensure that these systems respect our ethical principles? Will the benefits be broadly distributed or accrue to a lucky few? How will GAI alter our political systems and international conflicts? Are we merely a stepping stone to a new form of non-biological life, or are we just getting better at building useful gadgets?\"--Publisher.
Book
Ferroportin Metal Efflux Proteins Function in Iron and Cobalt Homeostasis in Arabidopsis
Relatively little is known about how metals such as iron are effluxed from cells, a necessary step for transport from the root to the shoot. Ferroportin (FPN) is the sole iron efflux transporter identified to date in animals, and there are two closely related orthologs in Arabidopsis thaliana, IRON REGULATED1 (IREG1/FPN1) and IREG2/FPN2. FPN1 localizes to the plasma membrane and is expressed in the stele, suggesting a role in vascular loading; FPN2 localizes to the vacuole and is expressed in the two outermost layers of the root in response to iron deficiency, suggesting a role in buffering metal influx. Consistent with these roles, fpn2 has a diminished iron deficiency response, whereas fpn1 fpn2 has an elevated iron deficiency response. Ferroportins also play a role in cobalt homeostasis; a survey of Arabidopsis accessions for ionomic phenotypes showed that truncation of FPN2 results in elevated shoot cobalt levels and leads to increased sensitivity to the metal. Conversely, loss of FPN1 abolishes shoot cobalt accumulation, even in the cobalt accumulating mutant frd3. Consequently, in the fpn1 fpn2 double mutant, cobalt cannot move to the shoot via FPN1 and is not sequestered in the root vacuoles via FPN2; instead, cobalt likely accumulates in the root cytoplasm causing fpn1 fpn2 to be even more sensitive to cobalt than fpn2 mutants.
Journal Article
Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin
Ferroportin (Fpn), a ferrous iron Fe(II) transporter responsible for the entry of iron into plasma, is regulated post‐translationally through internalization and degradation following binding of the hormone hepcidin. Cellular iron export is impaired in mice and humans with aceruloplasminemia, an iron overload disease due to mutations in the ferroxidase ceruloplasmin (Cp). In the absence of Cp Fpn is rapidly internalized and degraded. Depletion of extracellular Fe(II) by the yeast ferroxidase Fet3p or iron chelators can maintain cell surface Fpn in the absence of Cp. Iron remains bound to Fpn in the absence of multicopper oxidases. Fpn with bound iron is recognized by a ubiquitin ligase, which ubiquitinates Fpn on lysine 253. Mutation of lysine 253 to alanine prevents ubiquitination and maintains Fpn‐iron on cell surface in the absence of ferroxidase activity. The requirement for a ferroxidase to maintain iron transport activity represents a new mechanism of regulating cellular iron export, a new function for Cp and an explanation for brain iron overload in patients with aceruloplasminemia.
Journal Article
Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2
Hepcidin is a hormone secreted in response to iron loading and inflammation. Hepcidin binds to the iron exporter ferroportin, inducing its degradation and thus preventing iron entry into plasma. We determined that hepcidin binding to ferroportin leads to the binding and activation of the protein Janus Kinase2 (Jak2), which is required for phosphorylation of ferroportin. Ferroportin is a dimer and both monomers must be capable of binding hepcidin for Jak2 to bind to ferroportin. Once Jak2 is bound to the ferroportin dimer, both ferroportin monomers must be functionally competent to activate Jak2 and for ferroportin to be phosphorylated. These results show that cooperativity between the ferroportin monomers is required for hepcidin-mediated Jak2 activation and ferroportin down-regulation. These results provide a molecular explanation for the dominant inheritance of hepcidin resistant iron overload disease.
Journal Article
Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron Homeostasis
Hemoproteins are critical for the function and integrity of aerobic cells. However, free heme is toxic. Therefore, cells must balance heme synthesis with its use. We previously demonstrated that the feline leukemia virus, subgroup C, receptor (FLVCR) exports cytoplasmic heme. Here, we show that FLVCR-null mice lack definitive erythropoiesis, have craniofacial and limb deformities resembling those of patients with Diamond-Blackfan anemia, and die in midgestation. Mice with FLVCR that is deleted neonatally develop a severe macrocytic anemia with proerythroblast maturation arrest, which suggests that erythroid precursors export excess heme to ensure survival. We further demonstrate that FLVCR mediates heme export from macrophages that ingest senescent red cells and regulates hepatic iron. Thus, the trafficking of heme, and not just elemental iron, facilitates erythropoiesis and systemic iron balance.
Journal Article
Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome
Ferritin is a cytosolic molecule comprised of subunits that self‐assemble into a nanocage capable of containing up to 4500 iron atoms. Iron stored within ferritin can be mobilized for use within cells or exported from cells. Expression of ferroportin (Fpn) results in export of cytosolic iron and ferritin degradation. Fpn‐mediated iron loss from ferritin occurs in the cytosol and precedes ferritin degradation by the proteasome. Depletion of ferritin iron induces the monoubiquitination of ferritin subunits. Ubiquitination is not required for iron release but is required for disassembly of ferritin nanocages, which is followed by degradation of ferritin by the proteasome. Specific mammalian machinery is not required to extract iron from ferritin. Iron can be removed from ferritin when ferritin is expressed in
Saccharomyces cerevisiae
, which does not have endogenous ferritin. Expressed ferritin is monoubiquitinated and degraded by the proteasome. Exposure of ubiquitination defective mammalian cells to the iron chelator desferrioxamine leads to degradation of ferritin in the lysosome, which can be prevented by inhibitors of autophagy. Thus, ferritin degradation can occur through two different mechanisms.
Journal Article