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

硒在硒缺乏和过量时的独立于硒蛋白的生物学作用

基本信息

批准号：
10737250
负责人：
Dohoon Kim
金额：
$ 34.34万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737250
关键词：
Anabolism Antioxidants Biological Biology Bypass CRISPR screen Cardiac Myocytes Cardiovascular Physiology Cell Death Cell Respiration Cell Survival Cell model Cells Chronic Clinical Cytoprotection Data Disease Disease model Dose Electron Transport Electrons Functional disorder Genes Genetic Health Impairment Intoxication Intravenous Ischemia Knockout Mice Lipid Peroxidation Mediating Membrane Metabolic Micronutrients Mitochondria Mitochondrial Diseases Modeling Mus Myocardial Infarction Nerve Degeneration Oxidation-Reduction Oxidative Stress Oxidoreductase Pathologic Pathway interactions Peptides Physiological Production Property Quinones Reaction Role Route Selenite Selenium Selenocysteine Selenomethionine Skin Source Sulfides Supplementation Testing Textbooks Therapeutic Therapeutic Effect Toxic Environmental Substances Toxic effect Trace Elements Ubiquinone arm dietary supplements electron donor glutathione peroxidase in vitro activity in vivo intravenous administration mitochondrial membrane novel pharmacologic selenium deficiency selenium poisoning selenocysteine lyase selenoprotein success thioredoxin reductase ubiquinol

项目摘要

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.

项目概要硒 (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 种物质所必需的。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。硒的抗氧化作用太快、太强，无法仅用硒蛋白的产生来解释，我们发现了硒的一种新的生物机制，其中它充当电子供体来还原泛醌在硫化醌氧化还原酶 (SQOR) 催化的反应中，泛醇是一种关键的氧化还原反应。线粒体中的成分，以及细胞呼吸中间体，这种机制允许硒化物基于强有力的初步数据，我们将快速抑制脂质过氧化并引发细胞呼吸。检查这一假设，即这种机制允许硒充当强大的抗氧化剂以及替代电子传输燃料预计可以解释一些先前已知的问题。硒的细胞保护特性，解释为什么缺硒有害，并介绍新的在目标 1 中，我们将研究 SQOR 催化的泛醇的作用。硒在抗氧化作用中的形成，以及其以前未被认识到的电子传输作用这种机制对心肌细胞缺血、电子细胞疾病模型的有益影响。在目标 2 中，我们将检查运输功能障碍和损害 ETC 的环境毒素。假设这种泛醇膜极化机制的过度激活是造成在目标 3 中，我们将探讨硒的形态以及硒的毒性。体内传递途径是该提案是否参与这种新颖的 SQOR/泛醇机制的关键。机械地增强对硒的生物学作用的理解并引入策略利用硒生物学来达到治疗效果。