Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria.
Various proapoptotic stimuli increase the production of superoxide and H(2)O(2) by mitochondria. Whereas superoxide impairs mitochondrial function and is removed by Mn(2+)-dependent superoxide dismutase, the role and metabolism of mitochondrial H(2)O(2) during apoptosis have remained unclear. The effects on apoptotic signaling of depletion of peroxiredoxin (Prx) III, a mitochondrion-specific H(2)O(2)-scavenging enzyme, have now been investigated by RNA interference in HeLa cells. Depletion of Prx III resulted in increased intracellular levels of H(2)O(2) 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 H(2)O(2), which itself promotes apoptosis in cooperation with other mediators of apoptotic signaling.
Chang
Tong-Shin
TS
Laboratory of Cell Signaling, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cho
Chun-Seok
CS
Park
Sunjoo
S
Yu
Shiqin
S
Kang
Sang Won
SW
Rhee
Sue Goo
SG
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D007425:Intracellular Membranes; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D010544:Peroxidases / Q000502:physiology*; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction
D024101:Mitochondrial Proteins; C516116:Prdx3 protein, mouse; D034741:RNA, Small Interfering; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D010544:Peroxidases; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D020169:Caspases