Mitochondrial-targeted CoQ: Metabolic and Redox Effects and role in Diabetes

描述(由申请人提供)： 线粒体活性氧簇(ROS)和线粒体功能障碍对糖尿病、肥胖和胰岛素抵抗的病理生理学以及这些疾病的血管并发症是至关重要的。然而，减少线粒体ROS的产生和氧化损伤的努力因抗氧化剂进入这一隔室而受到限制。近年来，线粒体靶向抗氧化剂作为潜在的治疗药物引起了人们的关注。我们最近对线粒体靶向辅酶Q类似物进行了几项研究，称为“MitoQ”(MitoQuol、MitoQuone或这些氧化还原循环分子的组合)。我们证明了促氧化和抗氧化两种作用。我们还报道了新的发现，MitoQ具有重要的代谢效应，包括增加呼吸和诱导营养选择性，有利于葡萄糖氧化而不是脂肪酸氧化。尽管有促氧化作用，一些研究人员已经报道，线粒体靶向辅酶Q类似物(MTQA)在疾病状态的动物模型中提供了有效的治疗，这些疾病的病理可以追溯到氧化损伤。讨论了MTQA的双重抗氧化剂和促氧化作用，并作为这一应用的一部分进行了进一步讨论。这项拟议的研究解决了我们对MTQA知识的几个空白。这些包括MTQA与呼吸链的相互作用，MTQA代谢影响的潜在机制(S)，以及MTQA在糖尿病、肥胖症和胰岛素抵抗中的有效性。简而言之，我们的目标是：1.评估MTQAs对培养细胞的代谢影响，并确定相关的机制。2.进一步描述MTQAs的促氧化和抗氧化作用，并获得有关这些作用发生的线粒体部位的机制信息。确定促氧化剂和抗氧化剂效果之间的平衡。确定氧化还原效应是否对代谢效应有机械作用。3.确定MTQAs对高脂饮食胰岛素抵抗肥胖小鼠和胰岛素缺乏性糖尿病小鼠是否具有保护作用。4.研究MTQAs对小鼠线粒体膜电位和呼吸偶联的影响，并探讨其作用机制(S)。 公共卫生相关性： 与退伍军人相关：肥胖、胰岛素抵抗、胰岛素缺乏性糖尿病及其相关并发症在退伍军人中非常普遍。线粒体的活性氧对于这些问题背后的病理生理学是至关重要的。这项工作可能会通过揭示线粒体靶向抗氧化剂化合物的作用机制和有效性的新信息(S)，为这些问题带来新的治疗方法。

DESCRIPTION (provided by applicant): Mitochondrial reactive oxygen species (ROS) and mitochondrial dysfunction are critical to the pathophysiology of diabetes, obesity and insulin resistance as well to the vascular complications of these disorders. However, efforts to mitigate mitochondrial ROS production and oxidative damage have been limited by poor antioxidant entry into this compartment. Recently, mitochondrial targeted antioxidants have attracted attention as potential therapeutic agents. We recently carried out several studies of a mitochondrial targeted coenzyme Q analog termed "mitoQ" (mitoquinol, mitoquinone, or a combination of these redox cycling molecules). We demonstrated both prooxidant and antioxidant effects. We also reported the novel finding that mitoQ has important metabolic effects including increased respiration and induction of nutrient selectivity favoring glucose oxidation over fatty acid oxidation. In spite of prooxidant effects, several investigators have reported that mitochondrial targeted coenzyme Q analogs (MTQAs) offer effective therapy in animal models of disease states where pathology can be traced to oxidative damage. The dual antioxidant and prooxidant effects of MTQAs are discussed and further addressed as part of this application. The proposed research addresses several gaps in our knowledge of MTQAs. These involve interactions of MTQAs with the respiratory chain, the mechanism(s) underlying the metabolic effects of MTQAs, and the effectiveness of MTQAs in the setting of diabetes, obesity, and insulin resistance. Briefly stated, our objectives are: 1. Assess the metabolic effects of MTQAs in cultured cells and determine the mechanisms responsible. 2. Further delineate the prooxidant and antioxidant effects of MTQAs and obtain mechanistic information concerning mitochondrial sites where these effects arise. Determine the balance between prooxidant and antioxidant effects. Determine whether the redox effects contribute mechanistically to metabolic effects. 3. Determine whether MTQAs have protective effects in high-fat fed insulin resistant obese mice and in insulin deficient diabetic mice. 4. Determine the effects of MTQAs on mitochondrial membrane potential and respiratory coupling when administered to live mice and delineate the mechanism(s) underlying this effect. PUBLIC HEALTH RELEVANCE: Relevance to the VA: Obesity, insulin resistance, insulin deficient diabetes, and associated complications are highly prevalent among veterans. Mitochondrial reactive oxygen species are critical to the pathophysiology underlying these problems. This work may lead to new therapy for these problems by uncovering novel information about the mechanism(s) of action and effectiveness of mitochondrial targeted antioxidant compounds.