University of Kaiserslautern, Erwin-Schrödinger-Strasse 13, 67663 Kaiserslautern, Germany.
Biochem Biophys Res Commun. 2010 Dec 3;403(1):114-9. doi: 10.1016/j.bbrc.2010.10.129. Epub 2010 Nov 3.
The antioxidative enzyme copper-zinc superoxide dismutase (Sod1) is an important cellular defence system against reactive oxygen species (ROS). While the majority of this enzyme is localized to the cytosol, about 1% of the cellular Sod1 is present in the intermembrane space (IMS) of mitochondria. These amounts of mitochondrial Sod1 are increased for certain Sod1 mutants that are linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). To date, only little is known about the physiological function of mitochondrial Sod1. Here, we use the model system Saccharomyces cerevisiae to generate cells in which Sod1 is exclusively localized to the IMS. We find that IMS-localized Sod1 can functionally substitute wild type Sod1 and that it even exceeds the protective capacity of wild type Sod1 under conditions of mitochondrial ROS stress. Moreover, we demonstrate that upon expression in yeast cells the common ALS-linked mutant Sod1(G93A) becomes enriched in the mitochondrial fraction and provides an increased protection of cells from mitochondrial oxidative stress. Such an effect cannot be observed for the catalytically inactive mutant Sod1(G85R). Our observations suggest that the targeting of Sod1 to the mitochondrial IMS provides an increased protection against respiration-derived ROS.
抗氧化酶铜锌超氧化物歧化酶（Sod1）是细胞对抗活性氧（ROS）的重要防御系统。虽然这种酶的大部分位于细胞质中，但约 1%的细胞 Sod1 存在于线粒体的膜间空间（IMS）中。这些数量的线粒体 Sod1 在与神经退行性疾病肌萎缩侧索硬化症（ALS）相关的某些 Sod1 突变体中增加。迄今为止，人们对线粒体 Sod1 的生理功能知之甚少。在这里，我们使用酿酒酵母模型系统来生成 Sod1 仅定位于 IMS 的细胞。我们发现 IMS 定位的 Sod1 可以替代野生型 Sod1 的功能，并且在线粒体 ROS 应激条件下，它甚至超过了野生型 Sod1 的保护能力。此外，我们证明在酵母细胞中表达时，常见的与 ALS 相关的突变体 Sod1(G93A)在富含线粒体的部分中富集，并为细胞提供了对线粒体氧化应激的增强保护。对于催化失活的突变体 Sod1(G85R)，则无法观察到这种效应。我们的观察结果表明，Sod1 靶向线粒体 IMS 可提供对呼吸衍生的 ROS 的增强保护。
