title: Role of extracellular Hydrogen peroxide in regulation of iron homeostasis genes in neuronal cells: Implication in iron accumulation.
abstract: 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.
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110 067, India.
authors.forename: Som
authors.initials: S
authors.lastname: Dev
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110 067, India.
authors.forename: Sanju
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland,OH 44106, USA.
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110 067, India.
authors.forename: Saswat
authors.initials: S
authors.lastname: Kumar Bal
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110 067, India. Electronic address: ckm2300@mail.jnu.ac.in.
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mukhopadhyay
mesh_terms: D061745:Antioxidant Response Elements; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C507433:FTL protein, human; D000098742:Ferroportin; D001052:Apoferritins; D006861:Hydrogen Peroxide; D007501:Iron
keywords: Ferritin; Ferroportin degradation; Free radicals; Gene regulation; Hydrogen peroxide; Iron accumulation; Neurodegenerative diseases; Oxidative stress