Systemic and cerebral iron homeostasis in ferritin knock-out Mice

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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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ferritin
Ferritins
Knockout Mice
homeostasis
Homeostasis
Iron
iron
mice
Alleles
alleles
Genes
lethal genes
Brain
Apoferritins
Restless Legs Syndrome
Ceruloplasmin
Aptitude
brain
ferroxidase
genes

ASJC Scopus subject areas

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

Cite this

Systemic and cerebral iron homeostasis in ferritin knock-out Mice. / Li, Wei; Garringer, Holly; Goodwin, Charles B.; Richine, Briana; Acton, Anthony; VanDuyn, Natalia; Muhoberac, Barry B.; Irimia-Dominguez, Jose; Chan, Rebecca; Peacock, Munro; Nass, Richard; Ghetti, Bernardino; Vidal, Ruben.

In: PLoS One, Vol. 10, No. 1, e0117435, 28.01.2015.

Research output: Contribution to journalArticle

Li, W, Garringer, H, Goodwin, CB, Richine, B, Acton, A, VanDuyn, N, Muhoberac, BB, Irimia-Dominguez, J, Chan, R, Peacock, M, Nass, R, Ghetti, B & Vidal, R 2015, 'Systemic and cerebral iron homeostasis in ferritin knock-out Mice', PLoS One, vol. 10, no. 1, e0117435. https://doi.org/10.1371/journal.pone.0117435
Li W, Garringer H, Goodwin CB, Richine B, Acton A, VanDuyn N et al. Systemic and cerebral iron homeostasis in ferritin knock-out Mice. PLoS One. 2015 Jan 28;10(1). e0117435. https://doi.org/10.1371/journal.pone.0117435
Li, Wei ; Garringer, Holly ; Goodwin, Charles B. ; Richine, Briana ; Acton, Anthony ; VanDuyn, Natalia ; Muhoberac, Barry B. ; Irimia-Dominguez, Jose ; Chan, Rebecca ; Peacock, Munro ; Nass, Richard ; Ghetti, Bernardino ; Vidal, Ruben. / Systemic and cerebral iron homeostasis in ferritin knock-out Mice. In: PLoS One. 2015 ; Vol. 10, No. 1.
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