title: Intracellular labile iron determines H2O2-induced apoptotic signaling via sustained activation of ASK1/JNK-p38 axis.
abstract: Hydrogen peroxide (H2O2) acts as a second messenger in signal transduction participating in several redox regulated pathways, including cytokine and growth factor stimulated signals. However, the exact molecular mechanisms underlying these processes remain poorly understood and require further investigation. In this work, using Jurkat T lymphoma cells and primary human umbilical vein endothelial cells, it was observed that changes in intracellular "labile iron" were able to modulate signal transduction in H2O2-induced apoptosis. Chelation of intracellular labile iron by desferrioxamine rendered cells resistant to H2O2-induced apoptosis. In order to identify the exact points of iron action, we investigated selected steps in H2O2-mediated apoptotic pathway, focusing on mitogen activated protein kinases (MAPKs) JNK, p38 and ERK. It was observed that spatiotemporal changes in intracellular labile iron, induced by H2O2, influenced the oxidation pattern of the upstream MAP3K ASK1 and promoted the sustained activation of JNK-p38 axis in a defined time-dependent context. Moreover, we indicate that H2O2 induced spatiotemporal changes in intracellular labile iron, at least in part, by triggering the destabilization of lysosomal compartments, promoting a concomitant early response in proteins of iron homeostasis. These results raise the possibility that iron-mediated oxidation of distinct proteins may be implicated in redox signaling processes. Since labile iron can be pharmacologically modified in vivo, it may represent a promising target for therapeutic interventions in related pathological conditions.
authors.affiliation: Laboratory of Biological Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece.
authors.forename: M D
authors.initials: MD
authors.lastname: Mantzaris
authors.affiliation: Foundation for Research & Technology-Hellas, Institute of Molecular Biology & Biotechnology, Department of Biomedical Research, Ioannina, Greece.
authors.forename: S
authors.initials: S
authors.lastname: Bellou
authors.affiliation: Laboratory of Biological Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece.
authors.forename: V
authors.initials: V
authors.lastname: Skiada
authors.affiliation: Laboratory of Biological Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Kitsati
authors.affiliation: Laboratory of Biological Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece; Foundation for Research & Technology-Hellas, Institute of Molecular Biology & Biotechnology, Department of Biomedical Research, Ioannina, Greece.
authors.forename: T
authors.initials: T
authors.lastname: Fotsis
authors.affiliation: Laboratory of Biological Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Greece. Electronic address: dgalaris@uoi.gr.
authors.forename: D
authors.initials: D
authors.lastname: Galaris
mesh_terms: D017209:Apoptosis; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D008247:Lysosomes / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D010084:Oxidation-Reduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D006861:Hydrogen Peroxide; D007501:Iron; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: Apoptosis; Apoptosis signal-regulating kinase (ASK-1); Hydrogen peroxide; Labile iron; Mitogen activated protein kinases (MAPKs); Redox signaling