NADPH oxidase-derived ROS: key modulators of heme-induced mitochondrial stability in human neutrophils.

Heme is a proinflammatory molecule able to cause a profound delay of constitutive apoptosis of human neutrophils, an effect that likely contributes to chronic inflammation associated with hemolytic diseases. Herein we show that heme-induced delay of neutrophil apoptosis correlates with the prevention of mitochondrial potential (Deltapsi(m)) dissipation by a mechanism dependent on NADPH oxidase (NADPHox)-generated reactive oxygen species (ROS) and NF-kappaB. Deltapsi(m) maintenance is accompanied by inhibition of Bax insertion into mitochondria and by a decrease in the Bad/Bcl-X(L) ratio. Heme induces Bad degradation in a completely ROS-dependent manner, as well as Bcl-X(L) synthesis, a phenomenon that also requires NF-kappaB activation. These data indicate that heme-induced preservation of mitochondrial integrity is a critical checkpoint controlled by NADPH oxidase generated-ROS and redox-sensitive NF-kappaB activation.