Peroxynitrite damages U937 cell DNA via the intermediate formation of mitochondrial oxidants

✍ Scribed by Orazio Cantoni; Andrea Guidarelli

• Book ID: 102286994
• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 111 KB
• Volume: 60
• Category: Article
• ISSN: 1521-6543
• DOI: 10.1002/iub.116

✦ Synopsis

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.