Role of extracellular Hydrogen peroxide in regulation of iron homeostasis genes in neuronal cells: Implication in iron accumulation

• Published in: Free radical biology & medicine Vol. 86; pp. 78 - 89
• Main Authors: Dev, Som, Kumari, Sanju, Singh, Neena, Kumar Bal, Saswat, Seth, Pankaj, Mukhopadhyay, Chinmay K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015
• Subjects: Antioxidant Response Elements; Apoferritins - genetics; Apoferritins - metabolism; Cation Transport Proteins - metabolism; Cell Line, Tumor; Down-Regulation; Enhancer Elements, Genetic; Ferritin; Ferroportin degradation; Free radicals; Gene Expression Regulation; Gene regulation; Homeostasis; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Hydrogen Peroxide - pharmacology; Iron - metabolism; Iron accumulation; Neurodegenerative diseases; Neurons - metabolism; Oxidative Stress; APP; Oxidative stress; Hydrogen peroxide; Free radicals; Neurodegenerative diseases; Fpn; DMT1; IRP; Gene regulation; Ferritin; Ft-H; Iron accumulation; FAC; GFP; LIP; UTR; ARE; Nrf2; TfR1; GSH; IRE; Ferroportin degradation; BSO
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.05.025

Iron accumulation and oxidative stress are associated with neurodegenerative disease. Labile iron is known to catalyze free radical generation and subsequent neuronal damage, whereas the role of oxidative stress in neuronal iron accumulation is less well understood. Here, we examined the effect of hydrogen peroxide (H2O2) treatment on cellular iron-uptake, -storage, and -release proteins in the neuroblastoma cell line SH-SY5Y. We found no detectable change in the iron-uptake proteins transferrin receptor-1 and divalent metal ion transporter. In contrast, H2O2 treatment resulted in significant degradation of the iron-exporter ferroportin (Fpn). A decrease in Fpn is expected to increase the labile iron pool (LIP), reducing the iron-regulatory protein (IRP)–iron-responsive element interaction and increasing the expression of ferritin-H (Ft-H) for iron storage. Instead, we detected IRP1 activation, presumably due to oxidative stress, and a decrease in Ft-H translation. A reduction in Ft-H mRNA was also observed, probably dependent on an antioxidant-response element present in the Ft-H enhancer. The decrease in Fpn and Ft-H upon H2O2 treatment led to a time-dependent increase in the cellular LIP. Our study reveals a complex regulation of neuronal iron-release and iron-storage components in response to H2O2 that may explain iron accumulation detected in neurodegenerative diseases associated with oxidative stress. •H2O2 treatment promotes ferroportin degradation in the neuronal cell line SH-SY5Y.•It does not affect the iron-uptake components of the cell.•Ferritin-H expression is reduced at both transcriptional and translational levels.•Glutathione biosynthesis inhibitor shows a similar effect.•H2O2 treatment increases the labile iron pool in a time-dependent manner.