Selenoprotein-independent biological roles for selenium in selenium deficiency and excess

项目摘要 硒（Se）是一种具有抗氧化功能的必需微量营养素，因为它是合成25 不同的硒蛋白，其中许多是抗氧化剂，例如谷胱甘肽过氧化物酶。注意到 硒的抗氧化作用过于迅速和强大，不能仅用硒蛋白的产生来解释，我们 揭示了硒的一种新的生物学机制，其中硒作为电子供体还原泛醌 在硫化物醌氧化还原酶（SQOR）催化的反应中转化为泛醇。泛醇是一种关键的氧化还原 硒是线粒体中的一种成分，也是细胞呼吸的中间体，这种机制允许硒化物 迅速抑制脂质过氧化并触发细胞呼吸。根据初步数据，我们将 研究假设，这种机制允许硒作为一种强大的抗氧化剂，以及 替代电子传输燃料。这一机制有望解释一些先前已知的 硒的细胞保护特性，解释为什么硒缺乏是有害的，以及介绍新的 硒基治疗方法。在目标1中，我们将研究SQOR催化的泛醇的作用， 硒的抗氧化作用的形成，以及它以前未被重视的电子传递作用， 燃料该机制对心肌缺血、电子转移和心肌细胞凋亡等基于细胞的疾病模型的有益作用， 运输功能障碍和ETC损害环境毒素将被检查。在目标2中，我们将检查 假设这种泛醇的过度激活，膜极化机制是负责 高硒水平的毒性。在目标3中，我们将探讨硒的形式以及 体内的递送途径是这种新的SQOR/泛醇机制是否参与的关键。该提案将 导致对硒的生物学作用的机械性增强的理解，并引入策略 利用硒生物学来达到治疗效果。

Project Summary Selenium (Se) is an essential micronutrient with antioxidant function as it is required in the synthesis of 25 different selenoproteins, many of which are antioxidants such as glutathione peroxidases. Observing that selenium’s antioxidant effects are too rapid and robust to be explained by selenoprotein production alone, we uncovered a novel biological mechanism for selenium, in which it acts as an electron donor to reduce ubiquinone to ubiquinol in a reaction that is catalyzed by sulfide quinone oxidoreductase (SQOR). Ubiquinol is a key redox component in mitochondria, as well as a cellular respiration intermediate, and this mechanism allows selenide to rapidly suppress lipid peroxidation and trigger cellular respiration. Based on strong preliminary data, we will examine the hypothesis that this mechanism allows selenium to act as a powerful antioxidant as well as an alternative electron transport fuel. This mechanism is expected to account for some of the previously known cytoprotective properties of selenium, explain why selenium deficiency is harmful, as well as introduce novel selenium-based therapeutic approaches. In Aim 1, we will examine the role of SQOR-catalyzed ubiquinol formation in the antioxidant role of selenium, as well as its previously unappreciated role as an electron transport fuel. The beneficial effects of this mechanism on cell-based disease models for cardiomyocyte ischemia, electron transport dysfunction, and ETC-impairing environmental toxins will be examined. In Aim 2, we will examine the hypothesis that excess activation of this ubiquinol, membrane-polarizing mechanism is responsible for the toxicity of high selenium levels. In Aim 3, we will explore the notion that the form of selenium as well as the delivery route in vivo is key in whether this novel SQOR / ubiquinol mechanism is engaged. The proposal will result in a mechanistically enhanced understanding of the biological roles of selenium and introduce strategies to harness selenium biology for therapeutic effects.