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

项目摘要 硒(Se)是一种必需的微量营养素，具有抗氧化功能，因为它是合成25 不同的硒蛋白，其中许多是抗氧化剂，如谷胱甘肽过氧化物酶。观察到 硒的抗氧化作用太快太强，不能仅用硒蛋白的产生来解释，我们说 揭示了硒的一种新的生物学机制，在这种机制中，硒作为电子供体还原泛醌 在硫代苯醌氧化还原酶(SQOR)催化的反应中转化为泛喹酚。泛喹酚是一种关键的氧化还原 线粒体中的组成部分，以及细胞呼吸中间体，这一机制允许硒 快速抑制脂质过氧化，触发细胞呼吸。基于强劲的初步数据，我们将 验证这一假设，即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。这一机制预计将解释一些以前已知的 硒的细胞保护特性，解释为什么缺硒是有害的，以及介绍新的 基于硒的治疗方法。在目标1中，我们将研究Sqor催化的泛喹酚的作用 硒在抗氧化作用中的形成，以及它作为电子传递的先前未被认识的作用 燃料。这一机制对心肌缺血细胞疾病模型的有益影响 将检查运输功能障碍和损害ETC的环境毒素。在目标2中，我们将研究 假设这种泛喹酚，膜极化机制的过度激活是导致 高硒水平的毒性。在目标3中，我们将探索这样一个概念，即硒的形式以及 体内给药途径是决定Sqor/泛喹酚这一新机制能否发挥作用的关键。这项提议将 从机制上加强了对硒的生物学作用的理解，并介绍了策略 利用硒生物的治疗效果。

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.