Chang Tong-Shin, Cho Chun-Seok, Park Sunjoo, Yu Shiqin, Kang Sang Won, Rhee Sue Goo
Laboratory of Cell Signaling, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2004 Oct 1;279(40):41975-84. doi: 10.1074/jbc.M407707200. Epub 2004 Jul 27.
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.
多种促凋亡刺激可增加线粒体超氧化物和H₂O₂的生成。超氧化物会损害线粒体功能，并被锰离子依赖性超氧化物歧化酶清除，而线粒体H₂O₂在细胞凋亡过程中的作用和代谢仍不清楚。现在通过RNA干扰技术在HeLa细胞中研究了线粒体特异性H₂O₂清除酶——过氧化物还原酶（Prx）III缺失对凋亡信号传导的影响。Prx III缺失导致细胞内H₂O₂水平升高，并使细胞对星形孢菌素或肿瘤坏死因子-α诱导的凋亡更加敏感。Prx III缺失的细胞中线粒体膜电位崩溃、细胞色素c释放和半胱天冬酶激活的速率增加，这些效应可通过Prx III或线粒体靶向过氧化氢酶的异位表达而逆转。Prx III的缺失还加剧了促凋亡刺激对线粒体大分子的损伤。我们的结果表明，Prx III是线粒体H₂O₂丰度的关键调节因子，其本身与凋亡信号传导的其他介质协同促进细胞凋亡。
