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Hepatology. 2009 Sep;50(3):852-60. doi: 10.1002/hep.23058.

Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage.

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1
Ecole Polytechnique Fédérale de Lausanne, ISREC - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.

Abstract

Ferritin plays a central role in iron metabolism by acting both as iron storage and a detoxifying protein. We 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 messenger RNA (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 two-fold increased liver hepcidin 1 mRNA and a reduced duodenal DcytB mRNA level. Under a 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 wild-type 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.

PMID:
19492434
DOI:
10.1002/hep.23058
[Indexed for MEDLINE]
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