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 catalyse 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 tumours (which afflict approximately 30% of A-T patients). To investigate iron regulation in A-T, iron indices, 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, ferritin, and significantly higher Hepcidin compared to wild-type mice. When challenged with the high iron diet Bmp6 and Hfe expression were significantly increased. Atm-/- mice had increased protein tyrosine nitration and significantly higher Hmox1 levels that were substantially increased by 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 which 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 up-regulation 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.
- heme oxygenase 1
- Copyright © 2010, American Journal of Physiology- Gastrointestinal and Liver Physiology