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


CONCLUSIONS
Our results provide evidence that the iron storage function of ferritin plays a major role in preventing iron-mediated cell and tissue damage.
Darshan
Deepak
D
Ecole Polytechnique Fédérale de Lausanne, ISREC - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
Vanoaica
Liviu
L
Richman
Larry
L
Beermann
Friedrich
F
Kühn
Lukas C
LC
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D001052:Apoferritins / Q000172:deficiency / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects; D064451:Hepcidins; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D008099:Liver; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D064451:Hepcidins; D012333:RNA, Messenger; D001052:Apoferritins; D007501:Iron