Sulfiredoxin Translocation into Mitochondria Plays a Crucial Role in Reducing Hyperoxidized Peroxiredoxin III
Sulfiredoxin Translocation into Mitochondria Plays a Crucial Role in Reducing Hyperoxidized Peroxiredoxin III
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DOI：
10.1074/jbc.m808981200
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发表时间：
2009-03-27
影响因子：
4.8
通讯作者：
Chang, Tong-Shin
中科院分区：
文献类型：
--
作者：
Noh, You Hyun;Baek, Jin Young;Chang, Tong-Shin
线粒体是细胞呼吸过程中产生的活性氧（ROS）的主要细胞内来源。过氧化物氧还蛋白（Peroxiredoxin，Prx）III是2-Cys Prx家族的成员，在线粒体H2 O2清除中的作用最近被强调。在清除H2 O2的同时，Prx可以通过将活性半胱氨酸修饰为半胱氨酸亚磺酸（Cys-SO2 H）而变得过氧化和失活。当2-Cys Prx在体外失活时，硫氧还蛋白（Srx）将半胱氨酸亚磺酸还原为半胱氨酸。然而，Srx定位于细胞质中，Prx III仅存在于线粒体中。虽然Srx在体外减少亚磺酸Prx III，但仍不清楚Prx III在细胞中的减少是否实际上由Srx介导。我们的增益和功能丧失的实验表明，Srx是负责减少不仅亚磺酸胞浆Prx（I和II），但也亚磺酸线粒体Prx III。我们进一步证明，Srx易位从细胞质线粒体在氧化应激反应。过表达的靶向Srx促进亚磺酸Prx III的再生，并导致细胞对凋亡的抵抗，增强线粒体H2 O2的消除和线粒体膜电位崩溃的速率降低。这些结果表明，Srx在亚磺酸线粒体Prx III的重新激活中起着至关重要的作用，并且其线粒体易位在维持线粒体H2 O2产生和消除之间的平衡中至关重要。
The mitochondria are the major intracellular source of reactive oxygen species (ROS), which are generated during cellular respiration. The role of peroxiredoxin (Prx) III, a 2-Cys Prx family member, in the scavenging of mitochondrial H2O2 has recently been emphasized. While eliminating H2O2, Prx can become overoxidized and inactivated by modifying the active cysteine into cysteine sulfinic acid (Cys-SO2H). When 2-Cys Prxs are inactivated in vitro, sulfiredoxin (Srx) reduces the cysteine sulfinic acid to cysteines. However, whereas Srx is localized in the cytoplasm, Prx III is present exclusively in the mitochondria. Although Srx reduces sulfinic Prx III in vitro, it remains unclear whether the reduction of Prx III in cells is actually mediated by Srx. Our gain- and loss-of-function experiments show that Srx is responsible for reducing not only sulfinic cytosolic Prxs (I and II) but also sulfinic mitochondrial Prx III. We further demonstrate that Srx translocates from the cytosol to mitochondria in response to oxidative stress. Overexpression of mitochondrion-targeted Srx promotes the regeneration of sulfinic Prx III and results in cellular resistance to apoptosis, with enhanced elimination of mitochondrial H2O2 and decreased rates of mitochondrial membrane potential collapse. These results indicate that Srx plays a crucial role in the reactivation of sulfinic mitochondrial Prx III and that its mitochondrial translocation is critical in maintaining the balance between mitochondrial H2O2 production and elimination.