title: Induction of ferritin expression by oxalomalate.
abstract: Ferritin is a ubiquitous protein required for intracellular iron storage; its biosynthesis is mainly regulated by iron-regulatory proteins (IRP1 and IRP2) at post-transcriptional level. This regulation prevents iron excess from promoting the formation of reactive oxygen species (ROS). IRP1 is regulated by such factors as intracellular iron levels, the oxidants H(2)O(2) and NO. We recently demonstrated that oxalomalate (OMA, alpha-hydroxy-beta-oxalosuccinic acid), a competitive inhibitor of aconitase, which is an enzyme of the citric acid cycle, remarkably decreases the binding activity of IRP1. The aim of the present study was to investigate whether this molecule could affect the expression of ferritin. The RNA-binding activity of IRP1, evaluated by gel retardation assay, decreased after treatment of several cell lines with 5 mM OMA, with a maximal decrease of about 3-fold after 6 h. This effect remained almost constant up to 48 h after which it returned to basal levels. Intracellular ferritin levels, determined by Western blot analysis, increased in correlation with the OMA-induced decrease of IRP1 binding activity. Furthermore, treatment of cells with OMA caused a rise in ferritin mRNA levels. Interestingly, in cells exposed to iron challenge, OMA-induced overexpression of ferritin prevented formation of ROS and cellular lipid peroxidation. These data show that an inhibitor of aconitase, OMA, besides being involved in energetic metabolism, is able to control ferritin expression, probably through molecular mechanisms of either post-transcriptional regulation or transcriptional modulation, with advantageous consequences for the cell.
authors.affiliation: Dipartimento di Farmacologia Sperimentale, Università di Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Santamaria
authors.forename: Carlo
authors.initials: C
authors.lastname: Irace
authors.forename: Michela
authors.initials: M
authors.lastname: Festa
authors.forename: Carmen
authors.initials: C
authors.lastname: Maffettone
authors.forename: Alfredo
authors.initials: A
authors.lastname: Colonna
mesh_terms: D000818:Animals; D002460:Cell Line; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007501:Iron / Q000633:toxicity; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D015227:Lipid Peroxidation; D051379:Mice; D010070:Oxalates / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D010070:Oxalates; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C015407:oxalomalic acid; D005293:Ferritins; D007501:Iron; D035941:Iron Regulatory Protein 1