Mitochondrial-targeted CoQ analogs: Bioenergetic Effects in Obesity

描述(由申请人提供)： 肥胖是一个主要的世界性健康问题，在我们的退伍军人中非常普遍。治疗选择是有限的。改变生活方式是有效的，但很难实施，现有的药物最低限度有效和/或不安全。手术治疗可能是有效的，但需要进行大手术，并与几个长期并发症相关。尽管到目前为止药物治疗存在问题，但我们认为有一种有趣的方法需要进一步评估。这种方法是用诱导轻度呼吸解偶联的药物来靶向线粒体。正如在本申请的正文中所讨论的，线粒体解偶联有可能将热量的摄入转移到热量产生上，而不是作为脂肪块来储存能量。虽然剧烈脱钩可能是危险的，但轻微脱钩(随着时间的推移)可能会以一种被比作锻炼的方式安全地减肥。辅酶Q(CoQ)一直被认为是一种抗氧化剂和代谢活性化合物，对健康有好处。然而，辅酶Q不能或很差地穿透线粒体膜，并未被证明有效。因此，人们试图将辅酶Q靶向线粒体。一种常见的方法是缩短辅酶Q侧链，并添加由带正电的阳离子三苯基膦(TPP)组成的共价连接。这导致了我们称为线粒体靶向辅酶Q类似物(MTQA)的化合物。其原型是一种名为Mitoquone(MitoQ)的化合物，它已被开发为一种针对线粒体的抗氧化剂，目前正在研究中，用于治疗神经退行性疾病、衰老、肝脏脂肪变性和其他疾病。在退伍军人事务部最近支持的工作中，我的实验室发现了MTQAs的显著新陈代谢效应。考虑到线粒体的靶向性，这似乎并不令人惊讶。然而，到目前为止，人们对研究这些代谢反应的兴趣相对较少。 适用于治疗目的的效果。在初步的和已发表的工作中，我们发现MTQAs在诱导培养细胞线粒体呼吸解偶联方面表现出剂量依赖的效应。此外，我们有初步证据表明，它们在预防小鼠肥胖方面有效。有些令人惊讶的是，我们有数据表明，这不仅是通过增加能量消耗，而且还通过在中枢神经系统水平上抑制能量摄入来实现的。这使我们得出了一个总体假设，即作用于线粒体水平的MTQA化合物可以以最小的毒性预防肥胖，并最终证明 足够临床使用。简而言之，这项应用的三个具体目标是：1.基于培养细胞的代谢研究，检查选定的MTQA化合物的治疗潜力的效果。我们建议检查MitoQ，SKQ1，以及代表MitoQ和SKQ1的化合物，但每个母体化合物都有两个侧链修饰(总共六个化合物)。2.评估2-3种选定化合物在肥胖啮齿动物模型中的作用，并注意对能量消耗和能量摄入的影响。3.选择1-2种化合物进行更详细的机制研究，旨在了解AIM中观察到的体内效应2.意义和创新：退伍军人肥胖的临床重要性是显而易见的。我们解决这一问题的方法是创新的。很明显，我们将应用新的和创新的方法来寻找以前未确定的影响MTQA效果的机制。我们指出，我们对MTQAs的商业开发没有兴趣，因此对任何一种特定的化合物都没有偏见。我们感兴趣的是轻度脱偶联体作为一种可能的肥胖治疗方法的科学方面。

DESCRIPTION (provided by applicant): Obesity is a major worldwide health problem and highly prevalent among our veteran population. Therapeutic options are limited. Lifestyle change is effective but difficult to implement and available drugs are minimally effective and/or unsafe. Surgical therapy can be effective, but requires a major operation and is associated with several long-term complications. In spite of the problems with drug therapy to date, we believe there is an intriguing approach that needs further evaluation. That approach is to target mitochondria with agents that induce mild respiratory uncoupling. As discussed in the body of this application, mitochondrial uncoupling has the potential to divert caloric intake to heat production rather to energy storage as fat mass. Although vigorous uncoupling is likely dangerous, mild uncoupling (over time) could lead to safe weight loss in a manner that has been likened to exercise. Coenzyme Q (CoQ) has been advocated as an antioxidant and metabolically active compound offering health benefits. However, CoQ does not, or very poorly, penetrates mitochondrial membranes and has not proven effective. Therefore, attempts have been made to target CoQ to mitochondria. A common approach is to shorten the CoQ side chain and add a covalent attachment consisting of the positively charged cation, triphenylphosphonium (TPP). This has led to compounds we refer to as mitochondrial-targeted CoQ analogs (MTQAs). The prototype is the compound, mitoquinone (MitoQ), which has been developed as a mitochondrial-targeted antioxidant and is now under investigation for the treatment of neurodegenerative diseases, aging, hepatic steatosis, and other disorders. In recent VA supported work, my laboratory has found prominent metabolic effects of MTQAs. This does not seem surprising, given the mitochondrial targeting. However, to date, there has been relatively little interest in examining these metabolic effects as applicable for therapeutic purposes. In preliminary and published work to date, we found that MTQAs manifest dose-dependent effects to induce mitochondrial respiratory uncoupling in cultured cells. Moreover, we have preliminary evidence that they are effective in preventing obesity in mice. Somewhat surprisingly, we have data suggesting that this occurs, not only through enhanced energy expenditure, but also by inhibiting energy intake at the level of the central nervous system. This has led us to an overall hypothesis that a MTQA compound acting at the mitochondrial level can prevent obesity with minimal toxicity, and, ultimately, prove sufficient for clinical use. Briefly stated, the three specific aims of this application are: 1. Examine the effects of selected MTQA compounds for therapeutic potential based on metabolic studies in cultured cells. We propose to examine MitoQ, SKQ1, and compounds representing MitoQ and SKQ1 but with two side chain modifications for each parent compound (six compounds total). 2. Evaluate 2-3 selected compounds for their actions in a rodent model of obesity with attention to effects on energy expenditure and energy intake. 3. Select 1-2 compounds for more detailed mechanistic study directed at understanding the in vivo effects observed in aim 2. Significance and Innovation: The clinical importance of obesity among veterans is obvious. Our approach to addressing this issue is innovative. As will become clear, we will apply new and innovative methodology to look for previously unidentified mechanisms underlying the effects of MTQAs. We point out that we have no interest in the commercial development of MTQAs and, therefore, no bias towards any one particular compound. Our interest is in the scientific aspects of mild uncoupling as a possible treatment for obesity.