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

Liviu Vanoaica, Stefan Wagner
Elsevier, 2014
Journal paper

Abstract

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.

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Liviu Vanoaica, Stefan Wagner
Elsevier, 2014
Journal paper

Abstract

Official source

https://infoscience.epfl.ch/record/196095?ln=en

About this result

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Conditional Deletion of Ferritin H in Mice Reduces B and T Lymphocyte Populations

Maike Jaworski, Liviu Vanoaica

The immune system and iron availability are intimately linked as appropriate iron supply is needed for cell proliferation, while excess iron, as observed in hemochromatosis, may reduce subsets of lymphocytes. We have tested the effects of a ferritin H gene deletion on lymphocytes. Mx-Cre mediated conditional deletion of ferritin H in bone marrow reduced the number of mature B cells and peripheral T cells in all lymphoid organs. FACS analysis showed an increase in the labile iron pool, enhanced reactive oxygen species formation and mitochondrial depolarization. The findings were confirmed by a B-cell specific deletion using Fth(lox/lox); CD19-Cre mice. Mature B cells were strongly under-represented in bone marrow and spleen of the deleted mice, whereas pre-B and immature B cells were not affected. Bone marrow B cells showed increased proliferation as judged by the number of cells in S and G2/M phase as well as BrdU incorporation. Upon in vitro culture with B-cell activating factor of the tumor necrosis factor family (BAFF), ferritin H-deleted spleen B cells showed lower survival rates than wild type cells. This was partially reversed with iron-chelator deferiprone. The loss of T cells was also confirmed by a T cell-specific deletion in Fth(lox/lox); CD4-Cre mice. Our data show that ferritin H is required for B and T cell survival by actively reducing the labile iron pool. They further suggest that natural B and T cell maturation is influenced by intracellular iron levels and possibly deregulated in iron excess or deprivation.

Public Library of Science2014

, ,

Ferritin plays a central role in iron metabolism by acting both as iron storage and detoxifying protein. We have generated a ferritin H allele with loxP sites and studied the conditional ferritin H deletion in adult mice. Ten days after Mx-Cre induced deletion, ferritin H mRNA was below 5% in the liver, spleen and bone marrow of deleted mice compared to control littermates. Mice lost their cellular iron stores indicating the requirement of ferritin H in iron deposition. Serum iron and transferrin saturation were slightly increased and correlated with a 2-fold increased iver hepcidin 1 mRNA and a reduced duodenal DcytB mRNA level. Under normal iron regimen, deleted mice survived for 2 years without visible disadvantage. Mice fed on a high iron diet prior to ferritin H deletion suffered from severe liver damage. Similarly, ferritin H deleted mouse embryonic fibroblasts showed rapid cell death after exposure to iron salt in the medium. This was reversed by wildtype ferritin H but not by a ferritin H mutant lacking ferroxidase activity. Cell death was preceded by an increase in cytoplasmic free iron, reactive oxygen species, and mitochondrial depolarization. Conclusion: Our results provide evidence that the iron storage function of ferritin plays a major role in preventing iron-mediated cell and tissue damage.

2009