Goldsteins Gundars, Keksa-Goldsteine Velta, Ahtoniemi Toni, Jaronen Merja, Arens Egils, Akerman Karl, Chan Pak H, Koistinaho Jari
Department of Neurobiology, A I Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.
J Biol Chem. 2008 Mar 28;283(13):8446-52. doi: 10.1074/jbc.M706111200. Epub 2008 Jan 2.
This work demonstrates how increased activity of copper-zinc superoxide dismutase (SOD1) paradoxically boosts production of toxic reactive oxygen species (ROS) in the intermembrane space (IMS) of mitochondria. Even though SOD1 is a cytosolic enzyme, a fraction of it is found in the IMS, where it is thought to provide protection against oxidative damage. We found that SOD1 controls cytochrome c-catalyzed peroxidation in vitro when superoxide is available. The presence of SOD1 significantly increased the rate of ROS production in mitoplasts, which are devoid of outer membrane and IMS. In response to inhibition of respiration with antimycin A, isolated mouse wild-type mitochondria increased ROS production, but the mitochondria from mice lacking SOD1 (SOD1(-/-)) did not. Also, lymphocytes isolated from SOD1(-/-) mice produced significantly less ROS than did wild-type cells and were more resistant to apoptosis induced by inhibition of respiration. Moreover, an increased amount of the toxic mutant G93A SOD1 in the IMS increased ROS production. The mitochondrial dysfunction and cell damage paradoxically induced by SOD1-mediated ROS production may be implicated in chronic degenerative diseases.
这项研究表明，铜锌超氧化物歧化酶（SOD1）活性增加反而会促进线粒体膜间隙（IMS）中有毒活性氧（ROS）的产生。尽管SOD1是一种胞质酶，但在IMS中也能发现一小部分，人们认为它能提供抗氧化损伤的保护作用。我们发现，当有超氧化物存在时，SOD1在体外可控制细胞色素c催化的过氧化反应。SOD1的存在显著提高了线粒体质（缺乏外膜和IMS）中ROS的产生速率。用抗霉素A抑制呼吸作用时，分离出的小鼠野生型线粒体中ROS产生增加，但缺乏SOD1的小鼠（SOD1(-/-)）的线粒体中ROS没有增加。此外，从SOD1(-/-)小鼠分离出的淋巴细胞产生的ROS明显少于野生型细胞，并且对呼吸抑制诱导的凋亡更具抗性。此外，IMS中有毒突变体G93A SOD1数量的增加也会增加ROS的产生。SOD1介导的ROS产生反常地诱导的线粒体功能障碍和细胞损伤可能与慢性退行性疾病有关。
