title: Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria.
abstract: Mitochondrial iron is essential for the biosynthesis of heme and iron-sulfur ([Fe-S]) clusters in mammalian cells. In developing erythrocytes, iron is imported into the mitochondria by MFRN1 (mitoferrin-1, SLC25A37). Although loss of MFRN1 in zebrafish and mice leads to profound anemia, mutant animals showed no overt signs of porphyria, suggesting that mitochondrial iron deficiency does not result in an accumulation of protoporphyrins. Here, we developed a gene trap model to provide in vitro and in vivo evidence that iron regulatory protein-1 (IRP1) inhibits protoporphyrin accumulation. Mfrn1(+/gt);Irp1(-/-) erythroid cells exhibit a significant increase in protoporphyrin levels. IRP1 attenuates protoporphyrin biosynthesis by binding to the 5'-iron response element (IRE) of alas2 mRNA, inhibiting its translation. Ectopic expression of alas2 harboring a mutant IRE, preventing IRP1 binding, in Mfrn1(gt/gt) cells mimics Irp1 deficiency. Together, our data support a model whereby impaired mitochondrial [Fe-S] cluster biogenesis in Mfrn1(gt/gt) cells results in elevated IRP1 RNA-binding that attenuates ALAS2 mRNA translation and protoporphyrin accumulation.
authors: From the Division of Hematology, Brigham and Women's Hospital; Division of Hematology-Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors: Jacky
authors: J
authors: Chung
authors: Sheila A
authors: SA
authors: Anderson
authors: Babette
authors: B
authors: Gwynn
authors: Kathryn M
authors: KM
authors: Deck
authors: Michael J
authors: MJ
authors: Chen
authors: Nathaniel B
authors: NB
authors: Langer
authors: George C
authors: GC
authors: Shaw
authors: Nicholas C
authors: NC
authors: Huston
authors: Leah F
authors: LF
authors: Boyer
authors: Sumon
authors: S
authors: Datta
authors: Prasad N
authors: PN
authors: Paradkar
authors: Liangtao
authors: L
authors: Li
authors: Zong
authors: Z
authors: Wei
authors: Amy J
authors: AJ
authors: Lambert
authors: Kenneth
authors: K
authors: Sahr
authors: Johannes G
authors: JG
authors: Wittig
authors: Wen
authors: W
authors: Chen
authors: Wange
authors: W
authors: Lu
authors: Bruno
authors: B
authors: Galy
authors: Thorsten M
authors: TM
authors: Schlaeger
authors: Matthias W
authors: MW
authors: Hentze
authors: Diane M
authors: DM
authors: Ward
authors: Jerry
authors: J
authors: Kaplan
authors: Richard S
authors: RS
authors: Eisenstein
authors: Luanne L
authors: LL
authors: Peters
authors: Barry H
authors: BH
authors: Paw
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000378:metabolism*; D000818:Animals; D001755:Blastocyst / Q000166:cytology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D057809:HEK293 Cells; D006418:Heme / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000737:chemistry; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011164:Porphyrias / Q000378:metabolism*; D014176:Protein Biosynthesis; D011524:Protoporphyrins / Q000378:metabolism; D015027:Zebrafish
chemical_list: D007506:Iron-Sulfur Proteins; D026901:Membrane Transport Proteins; D011524:Protoporphyrins; C509051:mitoferrin protein, mouse; D006418:Heme; D007501:Iron; D000624:5-Aminolevulinate Synthetase; C588337:ALAS2 protein, mouse; D035941:Iron Regulatory Protein 1
keywords: Erythropoeisis; Fe-S Cluster Biogenesis; Heme; Iron; Iron-sulfur Protein; Mitochondrial Solute Carrier; Mitochondrial Transport; Protoporphyrin