Role of CoQ in regulating thermogenesis

CoQ 在调节生热作用中的作用

基本信息

批准号：
10360456
负责人：
Andreas Stahl
金额：
$ 45.36万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-26 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360456
关键词：
Affect Aging Anabolism Animal Testing Animals Antioxidants Brown Fat Cells Chronic Disease Communication Creatine Data Defect Diagnosis Down-Regulation Electron Transport Energy Metabolism Enzymes Event FGF21 gene Functional disorder Gene Expression Profile Genetic Models Germ-Line Mutation Human In Vitro Knockout Mice Lead Link Liver Location Mediator of activation protein Membrane Membrane Potentials Metabolic Mitochondria Mitochondrial Proteins Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Oxidation-Reduction Oxygen Pathway interactions Pharmacology Play Process Production Proteins Regulation Respiration Respiration Disorders Role Stress System Temperature Testing Thermogenesis Tissues Ubiquinone autocrine biological adaptation to stress combat in vivo in vivo Model inhibitor innovation knock-down mitochondrial membrane novel programs response transcriptome sequencing

项目摘要

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.

项目概要辅酶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。 CoQ 缺乏可能会导致由生物合成途径中的遗传突变引起，但也与衰老有关， 2 型糖尿病等慢性疾病以及 HMGCoA 的药理用途抑制剂（他汀类药物）。由于器官间通讯的复杂性，难以剖析 CoQ 缺乏的组织特异性影响并确定主要的代谢改变。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），我们假设这组织将受到 CoQ 缺乏的不成比例的影响并产生 BAT 体外特定辅酶Q缺乏症模型（辅酶Q的药理抑制合成）和体内（UCP1-cre 驱动的 CoQ 生物合成酶缺失 PDSS2）。事实上，我们发现 BAT CoQ 缺乏是由于从头合成减少所致 BAT 内会导致组织功能障碍和冷敏感性。有趣的是，我们发现 CoQ 药理学和遗传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，而是 UCP1 表达和功能的快速下调。 RNAseq 数据揭示了 BAT 中 CoQ 缺乏的转录特征涉及关键调节因子线粒体未折叠蛋白反应（UPRmt）和综合应激反应（情监侦）。我们认为 BAT 中 IRS 的激活会引发代谢适应包括降低 UCP1 表达和增强 UCP1 依赖性在 BAT 和其他组织中，通过增加 BAT 副/自分泌的分泌来产热 FGF21 等因子。