title: Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria.
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.
authors.affiliation: Department of Pathology, School of Medicine, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA.
authors.forename: Marie-Berengere
authors.initials: MB
authors.lastname: Troadec
authors.forename: David
authors.initials: D
authors.lastname: Warner
authors.forename: Jared
authors.initials: J
authors.lastname: Wallace
authors.forename: Kirk
authors.initials: K
authors.lastname: Thomas
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Spangrude
authors.forename: John
authors.initials: J
authors.lastname: Phillips
authors.forename: Oleh
authors.initials: O
authors.lastname: Khalimonchuk
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
authors.forename: Diane McVey
authors.initials: DM
authors.lastname: Ward
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D000740:Anemia / Q000209:etiology* / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D020964:Embryo Loss / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D006418:Heme / Q000096:biosynthesis; D022781:Hepatocytes / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D011247:Pregnancy; D046351:Protoporphyria, Erythropoietic / Q000209:etiology* / Q000235:genetics; D011524:Protoporphyrins / Q000378:metabolism
chemical_list: D017931:DNA Primers; D026901:Membrane Transport Proteins; D011524:Protoporphyrins; C509051:mitoferrin protein, mouse; D006418:Heme; C028025:protoporphyrin IX; D007501:Iron