Iron Regulatory Protein-1 Protects against Mitoferrin-1-deficient Porphyria.

Jacky Chung
Sheila A Anderson
Babette Gwynn, The Jackson Laboratory
Kathryn M Deck
Michael J Chen
Nathaniel B Langer
George C Shaw
Nicholas C Huston
Leah F Boyer
Sumon Datta
Prasad N Paradkar
Liangtao Li
Zong Wei
Amy J Lambert
Kenneth Sahr
Johannes G Wittig
Wen Chen
Wange Lu
Bruno Galy
Thorsten M Schlaeger
Matthias W Hentze
Diane M Ward
Jerry Kaplan
Richard S Eisenstein
Luanne L. Peters, The Jackson Laboratory
Barry H Paw


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. J Biol Chem 2014 Mar 14; 289(11):7835-43.