Mitochondrial H 2O 2 limits U937 cell survival to peroxynitrite by promoting ERK1/2 dephosphorylation

Abstract

Sequential activation of cytosolic phospholipase A 2 (cPLA 2) and 5-lipoxygenase (5-LO), critically regulated by extracellular signal-regulated kinase 1 and 2 (ERK1/2)-dependent phosphorylation, mediates U937 cell survival to peroxynitrite. In contrast, a limiting factor is represented by the parallel mitochondrial formation of H 2O 2 leading to suppression of the survival signaling. We now report that the inhibitory effects of H 2O 2 are at the level of ERK1/2 phosphorylation and involve activation of orthovanadate-sensitive phosphotyrosine protein phosphatase(s). Under these conditions, the otherwise stimulatory effects of peroxynitrite on ERK1/2 phosphorylation are concealed by phosphatase-dependent dephosphorylation and the activities of cPLA 2 and 5-LO are significantly reduced or suppressed, respectively. The ensuing inhibition of downstream events preventing mitochondrial permeability transition rapidly leads these cells to death. Thus, endogenous H 2O 2 limits U937 cell survival to peroxynitrite via activation of phosphotyrosine protein phosphatase(s) promoting upstream inhibition of the survival signaling critically regulated by the extent of ERK1/2 phosphorylation.