Systemic and cerebral iron homeostasis in ferritin knock-out Mice

Wei Li, Holly J. Garringer, Charles B. Goodwin, Briana Richine, Anthony Acton, Natalia VanDuyn, Barry B. Muhoberac, Jose Irimia-Dominguez, Rebecca J. Chan, Munro Peacock, Richard Nass, Bernardino Ghetti, Ruben Vidal

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Abstract

Ferritin, a 24-mer heteropolymer of heavy (H) and light (L) subunits, is the main cellular iron storage protein and plays a pivotal role in iron homeostasis by modulating free iron levels thus reducing radical-mediated damage. The H subunit has ferroxidase activity (converting Fe(II) to Fe(III)), while the L subunit promotes iron nucleation and increases ferritin stability. Previous studies on the H gene (Fth ) in mice have shown that complete inactivation of Fth is lethal during embryonic development, without ability to compensate by the L subunit. In humans, homozygous loss of the L gene (FTL ) is associated with generalized seizure and atypical restless leg syndrome, while mutations in FTL cause a form of neurodegeneration with brain iron accumulation. Here we generated mice with genetic ablation of the Fth and Ftl genes. As previously reported, homozygous loss of the Fth allele on a wild-type Ftl background was embryonic lethal, whereas knock-out of the Ftl allele (Ftl-/-) led to a significant decrease in the percentage of Ftl-/- newborn mice. Analysis of Ftl-/- mice revealed systemic and brain iron dyshomeostasis, without any noticeable signs of neurodegeneration. Our findings indicate that expression of the H subunit can rescue the loss of the L subunit and that H ferritin homopolymers have the capacity to sequester iron in vivo. We also observed that a single allele expressing the H subunit is not sufficient for survival when both alleles encoding the L subunit are absent, suggesting the need of some degree of complementation between the subunits as well as a dosage effect.

Original languageEnglish (US)
Article numbere0117435
JournalPLoS ONE
Volume10
Issue number1
DOIs
StatePublished - Jan 28 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Li, W., Garringer, H. J., Goodwin, C. B., Richine, B., Acton, A., VanDuyn, N., Muhoberac, B. B., Irimia-Dominguez, J., Chan, R. J., Peacock, M., Nass, R., Ghetti, B., & Vidal, R. (2015). Systemic and cerebral iron homeostasis in ferritin knock-out Mice. PLoS ONE, 10(1), [e0117435]. https://doi.org/10.1371/journal.pone.0117435