title: Peroxynitrite damages U937 cell DNA via the intermediate formation of mitochondrial oxidants.
abstract: Eight years ago, we published in this journal the first evidence that peroxynitrite does not directly produce DNA single-strand breakage in intact U937 cells (Guidarelli et al., IUBMB Life, 50, 195-201). This event was rather attributed to the secondary reactive species produced at the mitochondrial level via a Ca2+-dependent reaction, in which ubisemiquinone serves as an electron donor. Under these conditions, electrons are directly transferred to molecular oxygen and superoxide/H2O2, and the ensuing DNA damage can therefore be produced in a time- dependent manner for at least 30 min. Formation of H2O2 and DNA single-strand breaks was therefore dependent on interference with electron transport at the complex III level as well as on mitochondrial Ca2+ accumulation. Further studies led to the demonstrations that peroxynitrite mobilizes Ca2+ from the ryanodine receptor. Finally, in U937 cells, a pro-monocytic cell line sharing with monocytes/macrophages the same signaling events to survive to peroxynitrite, mitochondrial H2O2 promotes inhibition of survival via tyrosine phosphatase activation, leading to ERK1/2 dephosphorylation and thus to upstream inhibition of the survival signaling.
authors.affiliation: Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo, Via S. Chiara, 27- 61029 Urbino (PU), Italy. orazio.cantoni@uniurb.it
authors.forename: Orazio
authors.initials: O
authors.lastname: Cantoni
authors.forename: Andrea
authors.initials: A
authors.lastname: Guidarelli
mesh_terms: D002118:Calcium / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D012433:Ryanodine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D020298:U937 Cells
chemical_list: D004272:DNA, Mitochondrial; D004277:DNA, Single-Stranded; D016877:Oxidants; D013481:Superoxides; D030421:Peroxynitrous Acid; D012433:Ryanodine; D006861:Hydrogen Peroxide; D002118:Calcium