Sulfiredoxin protein is critical for redox balance and survival of cells exposed to low steady-state levels of H 2O 2

Abstract

Sulfiredoxin (Srx) is an enzyme that catalyzes the reduction of cysteine sulfinic acid of hyperoxidized peroxiredoxins (Prxs). Having high affinity toward H 2O 2, 2-Cys Prxs can efficiently reduce H 2O 2 at low concentration. We previously showed that Prx I is hyperoxidized at a rate of 0.072% per turnover even in the presence of low steady-state levels ofH 2O 2. Here we examine the novel role of Srx in cells exposed to low steady-state levels of H 2O 2, which can be achieved by using glucose oxidase. Exposure of low steady-state levels of H 2O 2 (10-20 μM) to A549 or wild-type mouse embryonic fibroblast (MEF) cells does not lead to any significant change in oxidative injury because of the maintenance of balance between H 2O 2 production and elimination. In contrast, loss-of-function studies using Srx-depleted A549 and Srx -/- MEF cells demonstrate a dramatic increase in extra- and intracellular H 2O 2, sulfinic 2-Cys Prxs, and apoptosis. Concomitant with hyperoxidation of mitochondrial Prx III, Srx-depleted cells show an activation of mitochondria-mediated apoptotic pathways including mitochondria membrane potential collapse, cytochrome c release, and caspaseactivation.Furthermore, adenoviralre-expressionofSrxin Srx-depleted A549 or Srx -/- MEF cells promotes the reactivation of sulfinic 2-Cys Prxs and results in cellular resistance to apoptosis, with enhanced removal of H 2O 2. These results indicate that Srx functions as a novel component to maintain the balance between H 2O 2 production and elimination and then protects cells from apoptosis even in the presence of low steady-state levels of H 2O 2. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.