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（ROS）和线粒体功能障碍对于糖尿病、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至关重要。然而，减轻线粒体ROS产生和氧化损伤的努力受到进入该隔室的抗氧化剂不足的限制。最近，线粒体靶向抗氧化剂作为潜在的治疗剂引起了人们的注意。我们最近进行了几项研究的线粒体靶向辅酶Q类似物称为“mitoQ”（mitoquinol，mitoquinone，或这些氧化还原循环分子的组合）。我们证明了促氧化剂和抗氧化剂的作用。我们还报道了新的发现，mitoQ具有重要的代谢作用，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，但一些研究者已经报道，线粒体靶向辅酶Q类似物（MTQA）在病理学可追溯到氧化损伤的疾病状态的动物模型中提供有效的治疗。MTQA的双重抗氧化和促氧化作用进行了讨论，并作为本申请的一部分进一步解决。 拟议的研究解决了我们对MTQA的认识中的几个空白。这些涉及MTQA与呼吸链的相互作用、MTQA代谢效应的潜在机制以及MTQA在糖尿病、肥胖和胰岛素抵抗背景下的有效性。简而言之，我们的目标是：1。评估MTQA在培养细胞中的代谢效应，并确定相关机制。2.进一步描述MTQA的促氧化和抗氧化作用，并获得有关这些作用出现的线粒体位点的机制信息。确定促氧化剂和抗氧化剂作用之间的平衡。确定氧化还原效应是否对代谢效应有机械作用。3.确定MTQA是否对高脂喂养的胰岛素抵抗肥胖小鼠和胰岛素缺乏型糖尿病小鼠具有保护作用。4.确定MTQA对活体小鼠给药时对线粒体膜电位和呼吸偶联的影响，并描述该影响的潜在机制。 公共卫生相关性： 与退伍军人事务部的相关性：肥胖、胰岛素抵抗、胰岛素缺乏性糖尿病和相关并发症在退伍军人中非常普遍。线粒体活性氧对这些问题的病理生理学至关重要。这项工作可能会导致这些问题的新疗法，通过揭示有关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。

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.