Role of CoQ in regulating thermogenesis

项目摘要 辅酶Q(辅酶Q)是线粒体的重要组成部分 电子传输链(ETC)以及膜结合抗氧化剂和 线粒体外氧化还原过程的辅助因素。可能会导致CoQ缺陷 通过生物合成途径中的遗传突变，但也与衰老有关， 2型糖尿病等慢性疾病及HMGCoA的药理作用 抑制剂(他汀类)。由于器官间沟通的复杂性，它一直是 难以剖析辅酶Q缺乏的组织特异性影响并确定原发症状 新陈代谢改变。由于非颤抖产热严重依赖于线粒体 功能和富含线粒体的棕色脂肪组织(BAT)，我们假设这是 组织将不成比例地受到辅酶Q缺陷的影响，并产生BAT 特异性辅酶Q缺乏症的体外模型(辅酶Q的药理抑制 合成)和体内(UCP1-cre驱动辅酶Q生物合成酶的缺失 PDSS2)。事实上，我们发现蝙蝠辅酶Q缺乏源于从头合成的减少 在BAT内会导致组织功能障碍和感冒敏感。有趣的是，我们发现 辅酶Q药理学和遗传学模型中的原发线粒体缺陷 缺乏似乎不是线粒体最大呼吸能力的下降，而是 UCP1表达和功能的快速下调。RNAseq数据显示 BAT中辅酶Q缺乏症的转录特征，涉及到 线粒体未折叠蛋白反应(UPRmt)与整合应激反应 (ISR)。我们认为，蝙蝠体内IRS的激活可触发代谢适应 包括UCP1表达降低和UCP1非依赖性增强 在蝙蝠和其他组织中，通过增加BAT辅助/自分泌的分泌来产热 FGF21等因素。

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.