Arachidonic acid induces calcium-dependent mitochondrial formation of species promoting strand scission of genomic DNA

Both the phospholipase A, activator melittin and reagent arachidonic acid ( AA) are poor inducers of DNA single strand breaks in U937 cells. These resp onses, however, were dramatically increased by the calcium-mobilizing agent caffeine (Cf) or by the respiratory substrate pyruvate via a mechanism tha t involved enforced mitochondrial Ca2+ accumulation and that was sensitive to lipoxygenase inhibitors. In permeabilized cells, the DNA damage generate d by AA in combination with either Cf, L-malate or CaCl2 was blunted by cat alase. AA generated DNA strand scission also in HeLa cells supplemented wit h pyruvate via a mechanism identical to that observed in U937 cells. This r esponse was associated with an enforced formation of free radical species. These results demonstrate that mitochondria play a pivotal role in the DNA- damaging response evoked by AA and provide the bases for a calcium-dependen t mechanism whereby the AA produced during inflammatory processes may affec t various pathologic conditions, including carcinogenesis.