Ferritin

Summary

Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload. Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body; hence, serum ferritin is used as a diagnostic test for iron-deficiency anemia. Aggregated ferritin transforms into a toxic form of iron called hemosiderin. Ferritin is a globular protein complex consisting of 24 protein subunits forming a hollow nanocage with multiple metal–protein interactions. Ferritin that is not combined with

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Disease tolerance is a defense strategy that limits the fitness costs of infection irrespectively of pathogen burden. While restricting iron (Fe) availability to pathogens is perceived as a host defense strategy, the resulting tissue Fe overload can be cytotoxic and promote tissue damage to exacerbate disease severity. Examining this interplay during malaria, the disease caused by Plasmodium infection, we find that expression of the Fe sequestering protein ferritin H chain (FtH) in mice, and ferritin in humans, is associated with reduced tissue damage irrespectively of pathogen burden. FtH protection relies on its ferroxidase activity, which prevents labile Fe from sustaining proapoptotic c-Jun N-terminal kinase (JNK) activation. FtH expression is inhibited by JNK activation, promoting tissue Fe overload, tissue damage, and malaria severity. Mimicking FtH's antioxidant effect or inhibiting JNK activation pharmacologically confers therapeutic tolerance to malaria in mice. Thus, FtH provides metabolic adaptation to tissue Fe overload, conferring tolerance to malaria.

Cell Press2012

Iron is a transitional metal required by virtually all organisms as a dietary micromineral, indispensable for cellular survival and proliferation. The management of iron absorption and distribution in the organism and inside the cell must be tightly regulated in order to avoid the deleterious consequences of free iron-induced oxidative stress. Ferritin is the major protein responsible for iron storage and release of intracellular iron. Ferritin shells are formed from two types of subunits, known as H and L. The present work investigates the effects of conditional ferritin H deletion in mice. A broad ferritin H deletion in liver, spleen, bone marrow and thymus results in an alteration of iron metabolism, characterized by increased transferrin saturation and hepcidin mRNA levels and decreased liver iron deposits. Iron loading prior to deletion leads to liver failure early after deletion, showing that ferritin H is indispensable for limiting iron toxicity through iron sequestration. A hepatocyte-specific deletion fails to reproduce the same phenotype, suggesting an important role for Kupffer macrophages in liver iron detoxification. Ferritin H is also required for B lymphocyte survival, as indicated by the loss of mature B cells in an CD19-specific ferritin H deletion mouse strain, where this population is substantially reduced because of massive reactive oxygen species generation. Conditional deletion in heart leads to fibrosis, increased oxidative stress and to a switch towards a gene expression profile characteristic for cardiac hypertrophy, while iron loading prior to deletion causes a dramatic alteration of the cardiac output function and ultimately to heart failure. An intestine-specific ferritin H deletion results in a typical hemochromatotic phenotype, characterized by increased transferrin saturation and liver iron stores, increased hepcidin expression and decreased IRP2 activity. Hepcidin-mediated ferroportin downregulation at protein level is also shown not to be sufficient to limit the intestinal iron export. An modified version of the current model of intestinal iron absorption is proposed, that includes the function of ferritin H as an iron sink in intestine. This work contributes to a better understanding of iron metabolism in general and intestinal iron absorption in particular, and it might have an impact on the development of treatments against human hemochomatosis and anemia.

EPFL2009

Fe-59-distribution in conditional ferritin-H-deleted mice

Liviu Vanoaica, Stefan Wagner

The objective was to explore how ferritin-H deletion influences Fe-59-distribution and excretion-kinetics in mice. Kinetics of Fe-59-release from organs, whole-body excretion, and distribution-kinetics of intravenously injected Fe-59 trace amounts were compared in iron-deficient and iron-replete mice with (Fth(Delta/Delta)) and without (Fth(lox/lox)) conditional Mx-Cre-induced ferritin-H deletion. Fe-59 was released from spleen and liver beginning on day 2 and day 5 after ferritin-H deletion, respectively, but was not excreted from the body. Plasma-Fe-59 was cleared significantly faster in iron-deficient Fth(Delta/Delta)-mice than in iron-adequate Fth(lox/lox)-controls. Fe-59-distribution showed a transient peak (e.g., in heart, kidney, muscle) in Fth(lox/lox) control mice, but not in ferritin-H deleted Fth(Delta/Delta) mice 24 hours after Fe-59 injection. Fe-59 uptake into the liver and spleen was significantly lower in iron-deficient Fth(Delta/Delta) than in Fth(lox/lox) mice 24 hours and 7 days after injection, respectively, and rapidly appeared in circulating erythrocytes instead. The rate of Fe-59 release after ferritin-H deletion supports earlier data on ferritin turnover in mammals; released Fe-59 is not excreted from the body. Instead, Fe-59 is channeled into erythropoiesis and circulating erythrocytes significantly more extensively and faster. Along with a lack of transient interim Fe-59 storage (e.g., in the heart and kidney), this finding is evidence for ferritin-related iron storage-capacity affecting rate and extent of iron utilization. (C) 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

Elsevier2014

EPFL2009