title: Iron loading and oxidative stress in the Atm-/- mouse liver.
abstract: Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder resulting in a myriad of abnormalities, including progressive neurodegeneration and cancer predisposition. At the cellular level, A-T is a disease of chronic oxidative stress (OS) causing damage to proteins, lipids, and DNA. OS is contributed to by pro-oxidative transition metals such as iron that catalyze the conversion of weakly reactive oxygen species to highly reactive hydroxyl radicals. Iron-associated OS has been linked to neurodegeneration in Alzheimer's and Parkinson's diseases and development of lymphoid tumors (which afflict ∼30% of A-T patients). To investigate iron regulation in A-T, iron indexes, regulatory genes, and OS markers were studied in livers of wild-type and Ataxia telangiectasia mutated (Atm) null mice on control or high-iron diets. Atm(-/-) mice had increased serum iron, hepatic iron, and ferritin and significantly higher Hepcidin compared with wild-type mice. When challenged with the high-iron diet, Bmp6 and Hfe expression was significantly increased. Atm(-/-) mice had increased protein tyrosine nitration and significantly higher Heme Oxygenase (decycling) 1 levels that were substantially increased by a high-iron diet. Ferroportin gene expression was significantly increased; however, protein levels were unchanged. We demonstrate that Atm(-/-) mice have a propensity to accumulate iron that is associated with a significant increase in hepatic OS. The iron-induced increase in hepcidin peptide in turn suppresses ferroportin protein levels, thus nullifying the upregulation of mRNA expression in response to increased OS. Our results suggest that increased iron status may contribute to the chronic OS seen in A-T patients and development of disease pathology.
authors.affiliation: Membrane Transport Laboratory, Division of Cancer and Cell Biology, Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: McDonald
authors.forename: Lesa
authors.initials: L
authors.lastname: Ostini
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wallace
authors.forename: Abraham N
authors.initials: AN
authors.lastname: John
authors.forename: Dianne J
authors.initials: DJ
authors.lastname: Watters
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D019266:Iron, Dietary / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019266:Iron, Dietary; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D025521:Tumor Suppressor Proteins; D000098742:Ferroportin; D005293:Ferritins; D007501:Iron; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases