ZFIN ID: ZDB-PUB-140416-6
Iron Regulatory Protein-1 Protects against Mitoferrin-1-deficient Porphyria
Chung, J., Anderson, S.A., Gwynn, B., Deck, K.M., Chen, M.J., Langer, N.B., Shaw, G.C., Huston, N.C., Boyer, L.F., Datta, S., Paradkar, P.N., Li, L., Wei, Z., Lambert, A.J., Sahr, K., Wittig, J.G., Chen, W., Lu, W., Galy, B., Schlaeger, T.M., Hentze, M.W., Ward, D.M., Kaplan, J., Eisenstein, R.S., Peters, L.L., and Paw, B.H.
Date: 2014
Source: The Journal of biological chemistry   289(11): 7835-7843 (Journal)
Registered Authors: Boyer, Leah, Datta, Sumon, Paw, Barry, Schlaeger, Thorsten, Shaw, George C., Wittig, Johannes
Keywords: Erythropoeisis, Fe-S Cluster Biogenesis, Heme, Iron, Iron-sulfur Protein, Mitochondrial Solute Carrier, Mitochondrial Transport, Protoporphyrin
MeSH Terms:
  • 5-Aminolevulinate Synthetase/metabolism*
  • Animals
  • Blastocyst/cytology
  • Cell Differentiation
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation*
  • Genotype
  • HEK293 Cells
  • Heme/chemistry
  • Humans
  • Iron/chemistry
  • Iron Regulatory Protein 1/metabolism*
  • Iron-Sulfur Proteins/metabolism
  • Male
  • Membrane Transport Proteins/metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Porphyrias/metabolism*
  • Protein Biosynthesis
  • Protoporphyrins/metabolism
  • Zebrafish
PubMed: 24509859 Full text @ J. Biol. Chem.

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 52-iron response element (IRE) of alas2 mRNA, inhibiting its translation. Ectopic expression of alas2 harboring a mutant IRE, preventing IRP1 binding, in Mfrn1gt/gt cells mimics Irp1 deficiency. Together, our data support a model whereby impaired mitochondrial [Fe-S] cluster biogenesis in Mfrn1gt/gt cells results in elevated IRP1 RNA-binding that attenuates ALAS2 mRNA translation and protoporphyrin accumulation.