Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria

Authors

Marie-Berengere Troadec, University of Utah
David Warner, University of Utah
Jared Wallace, University of Utah
Kirk Thomas, University of Utah
Gerald J. Spangrude, University of Utah
John Phillips, University of Utah
Oleh Khalimonchuk, University of Nebraska-LincolnFollow
Barry H. Paw, Brigham and Women's Hospital
Diane McVey Ward, Brigham and Women's Hospital
Jerry Kaplan, University of Utah

Document Type

Article

Date of this Version

2011

Citation

Blood. 117(20): 5494-5502

Comments

© 2011 by The American Society of Hematology. Used by permission.

Abstract

Mitoferrin1 is 1 of 2 homologous mitochondrial iron transporters and is required for mitochondrial iron delivery in developing erythroid cells. We show that total deletion of Mfrn1 in embryos leads to embryonic lethality. Selective deletion of Mfrn1 in adult hematopoietic tissues leads to severe anemia because of a deficit in erythroblast formation. Deletion of Mfrn1 in hepatocytes has no phenotype or biochemical effect under normal conditions. In the presence of increased porphyrin synthesis, however, deletion of Mfrn1 in hepatocytes results in a decreased ability to convert protoporphyrin IX into heme, leading to protoporphyria, cholestasis, and bridging cirrhosis. Our results show that the activity of mitoferrin1 is required to manage an increase in heme synthesis. The data also show that alterations in heme synthesis within hepatocytes can lead to protoporphyria and hepatotoxicity.