title: Systemic and cerebral iron homeostasis in ferritin knock-out mice.
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.
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Wei
authors: W
authors: Li
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Holly J
authors: HJ
authors: Garringer
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Charles B
authors: CB
authors: Goodwin
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Briana
authors: B
authors: Richine
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Anthony
authors: A
authors: Acton
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Natalia
authors: N
authors: VanDuyn
authors: Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, 46202, United States of America.
authors: Barry B
authors: BB
authors: Muhoberac
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Jose
authors: J
authors: Irimia-Dominguez
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Rebecca J
authors: RJ
authors: Chan
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Munro
authors: M
authors: Peacock
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Richard
authors: R
authors: Nass
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Bernardino
authors: B
authors: Ghetti
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Ruben
authors: R
authors: Vidal
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D005293:Ferritins; D007501:Iron
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