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.