Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria

Various proapoptotic stimuli increase the production of superoxide and H2O2 by mitochondria. Whereas superoxide impairs mitochondrial function and is removed by Mn2+-dependent superoxide dismutase, the role and metabolism of mitochondrial H2O2 during apoptosis have remained unclear. The effects on apoptotic signaling of depletion of peroxiredoxin (Prx) III, a mitochondrion-specific H2O2-scavenging enzyme, have now been investigated by RNA interference in HeLa cells. Depletion of Prx III resulted in increased intracellular levels of H2O2 and sensitized cells to induction of apoptosis by staurosporine or TNF-alpha. The rates of mitochondrial membrane potential collapse, cytochrome c release, and caspase activation were increased in Prx III-depleted cells, and these effects were reversed by ectopic expression of Prx III or mitochondrion-targeted catalase. Depletion of Prx III also exacerbated damage to mitochondrial macromolecules induced by the proapoptotic stimuli. Our results suggest that Prx III is a critical regulator of the abundance of mitochondrial H2O2, which itself promotes apoptosis in cooperation with other mediators of apoptotic signaling.