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

Abstract

Both the phospholipase A 2 activator melittin and reagent arachidonic acid (AA) are poor inducers of DNA single strand breaks in U937 cells. These responses, however, were dramatically increased by the calcium-mobilizing agent caffeine (Cf) or by the respiratory substrate pyruvate via a mechanism that involved enforced mitochondrial Ca 2+ accumulation and that was sensitive to lipoxygenase inhibitors. In permeabilized cells, the DNA damage generated by AA in combination with either Cf, L-malate or CaCl 2 was blunted by catalase. AA generated DNA strand scission also in HeLa cells supplemented with pyruvate via a mechanism identical to that observed in U937 cells. This response 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-dependent mechanism whereby the AA produced during inflammatory processes may affect various pathologic conditions, including carcinogenesis.