Peroxynitrite damages U937 cell DNA via the intermediate formation of mitochondrial oxidants.
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.
Cantoni
Orazio
O
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo, Via S. Chiara, 27- 61029 Urbino (PU), Italy. orazio.cantoni@uniurb.it
Guidarelli
Andrea
A
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
D004272:DNA, Mitochondrial; D004277:DNA, Single-Stranded; D016877:Oxidants; D013481:Superoxides; D030421:Peroxynitrous Acid; D012433:Ryanodine; D006861:Hydrogen Peroxide; D002118:Calcium