Role of CoQ in regulating thermogenesis

项目摘要 辅酶Q（CoQ，又名泛醌）是线粒体的重要组成部分， 电子传递链（ETC）以及膜结合的抗氧化剂和 线粒体外氧化还原过程的辅助因子。辅酶Q缺乏可能导致 通过生物合成途径中的遗传突变，但也与衰老有关， 慢性疾病，如2型糖尿病，以及HMGCoA的药理学用途 抑制剂（他汀类）。由于器官间交流的复杂性， 难以剖析辅酶Q缺乏的组织特异性影响， 代谢改变由于非颤抖性产热严重依赖于线粒体 功能和富含脂肪酸的棕色脂肪组织（BAT），我们假设， 组织将不成比例地受到辅酶Q缺乏的影响，并产生BAT 体外特异性CoQ缺乏模型（CoQ的药理学抑制 合成）和体内（UCP 1-cre驱动的CoQ生物合成酶的缺失 PDSS2）。事实上，我们发现BAT CoQ缺乏是由于从头合成减少， 在BAT内导致组织功能障碍和冷敏感性。有趣的是，我们发现 辅酶Q药理学和遗传学模型中的原发性线粒体缺陷 缺乏似乎不是最大线粒体呼吸能力的下降， UCP 1表达和功能的快速下调。RNAseq数据显示， BAT中CoQ缺乏的转录特征，涉及 线粒体未折叠蛋白反应（UPRmt）和整合应激反应 （ISR）。我们认为BAT中IRS的激活触发了代谢适应 包括降低UCP 1表达和增强UCP 1非依赖性 产热，在BAT和其他组织中，通过增加BAT的分泌， 如FGF 21。

Project Summary Coenzyme Q (CoQ, aka ubiquinone) is an important component of the mitochondrial electron transport chain (ETC) as well as a membrane-incorporated antioxidant and a co-factor for redox processes outside the mitochondria. CoQ deficiencies can be caused by hereditary mutations in the biosynthesis pathway but are also associated with aging, chronic diseases such as Type-2 Diabetes, and the pharmacological use of HMGCoA inhibitors (statins). Due to the complexities of inter-organ communication, it has been difficult to dissect the tissue specific effects of CoQ deficiencies and to identify primary metabolic alterations. Since non-shivering thermogenesis heavily relies on mitochondrial function and mitochondria-rich brown adipose tissue (BAT), we hypothesize that this tissue will be disproportionately affected by CoQ deficiencies and have generated BAT specific CoQ deficiency models both in vitro (pharmacological inhibition of CoQ synthesis) and in vivo (UCP1-cre driven deletion of the CoQ biosynthetic enzyme PDSS2). Indeed, we find that BAT CoQ deficiency from diminished de novo synthesis within BAT results in tissue dysfunction and cold sensitivity. Interestingly, we find that the primary mitochondrial defect in both pharmacological and genetic models of CoQ deficiency appears not to be a decline in maximal mitochondrial respiration capacity but a rapid down regulation of UCP1 expression and function. RNAseq data reveal a transcriptional signature of CoQ deficiency in BAT that involves key regulators of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). We propose that activation of the IRS in BAT triggers metabolic adaptations including decreased UCP1 expression and enhanced UCP1-independent thermogenesis, in BAT and other tissues, via increased secretion of BAT para/autocrine factors such as FGF21.