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 Ill 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.

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

CANTONI, ORAZIO;GUIDARELLI, ANDREA
2008-01-01

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 Ill 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/1880534
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