Essential role of the mitochondrial respiratory chain in peroxynitrite-induced strand scission of genomic DNA.
A large body of experimental evidence suggests that DNA damage and cytotoxicity mediated by peroxynitrite are linked by a causal relationship and important events in various pathological conditions. In the present study, we investigated the mechanism whereby peroxynitrite causes DNA single strand breakage in intact cells and found that the respiratory chain plays a pivotal role in this response. In particular, peroxynitrite mediates inhibition of complex III and, under these conditions, electrons are directly transferred from ubisemiquinone to molecular oxygen. Hydrogen peroxide produced by the dismutation of superoxides is the species mediating the peroxynitrite-dependent DNA cleavage.
Guidarelli
A
A
Istituto di Farmacologia e Farmacognosia and Centro di Farmacologia Oncologica Sperimentale, Università degli Studi di Urbino, Italy.
Tommasini
I
I
Fiorani
M
M
Cantoni
O
O
D004249:DNA Damage; D004579:Electron Transport / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008689:Methacrylates; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009566:Nitrates / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D011190:Potassium Cyanide / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D020298:U937 Cells
D008689:Methacrylates; D009566:Nitrates; D013844:Thiazoles; D012402:Rotenone; C039642:peroxynitric acid; C030517:myxothiazol; D006861:Hydrogen Peroxide; D011190:Potassium Cyanide