Action Filename Description Size Access License Resource Version
Show more files...


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.