Conditional deletion of ferritin H in mice induces loss of iron storage and liver damageReportar como inadecuado

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Published in: Hepatology, vol. 50, num. 3, p. 852-860 Publication date: 2009

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.

Keywords: targeted gene deletion ; Mx-Cre ; hepcidin 1 ; macrophage ; mouse embryonic fibroblast Reference GR-KUHN-ARTICLE-2009-001doi:10.1002/hep.23058View record in Web of Science

Autor: Darshan, Deepak; Vanoaica, Liviu; Richman, Larry; Beermann, Friedrich; Kühn, Lukas C.


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