Systemic and cerebral iron homeostasis in ferritin knock-out mice

• Published in: PloS one Vol. 10; no. 1; p. e0117435
• Main Authors: Li, Wei, Garringer, Holly J, Goodwin, Charles B, Richine, Briana, Acton, Anthony, VanDuyn, Natalia, Muhoberac, Barry B, Irimia-Dominguez, Jose, Chan, Rebecca J, Peacock, Munro, Nass, Richard, Ghetti, Bernardino, Vidal, Ruben
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.01.2015; Public Library of Science (PLoS)
• Subjects: Ablation; Alleles; Analysis; Animals; Brain; Cerebral Cortex - metabolism; Complementation; Copolymers; Deactivation; Embryogenesis; Embryonic development; Embryonic growth stage; Ferritin; Ferritins - genetics; Ferritins - metabolism; Ferroxidase; Genes; H gene; Homeostasis; Homeostasis - physiology; House mouse; Inactivation; Iron; Iron - metabolism; Irritable bowel syndrome; L gene; Laboratories; Light; Medicine; Metabolism; Mice; Mice, Knockout; Mutation; Neurodegeneration; Oxidative stress; Pathology; Pediatrics; Polypeptides; Proteins; Rodents; Toxicology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0117435

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.