Role of CoQ in regulating thermogenesis

CoQ 在调节生热作用中的作用

• 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
• 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

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.

项目摘要 辅酶Q（COQ，aka泛酮）是线粒体的重要组成部分 电子传输链（ETC）以及结合膜的抗氧化剂和A 线粒体以外的氧化还原过程的联合因素。 COQ缺陷可能是引起的 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，例如2型糖尿病和HMGCOA的药理用途 抑制剂（他汀类药物）。由于沟通间的复杂性， 难以剖析COQ缺陷的组织特异性效应并确定原发性 代谢改变。由于不动的热发生在很大程度上依赖于线粒体 功能和富含线粒体的棕色脂肪组织（BAT），我们假设这是 组织将受到COQ缺陷的影响不成比例的，并且已经产生了BAT 特定的COQ缺乏模型均在体外（COQ的药理学抑制 合成）和体内（coq生物合成酶的UCP1-CRE驱动的缺失 PDSS2）。确实，我们发现从头综合降低的BAT COQ缺乏症 在蝙蝠中会导致组织功能障碍和冷灵敏度。有趣的是，我们发现 COQ的药理学和遗传模型中的原发性线粒体缺陷 缺乏症似乎不是线粒体呼吸能力的下降，而是 快速降低UCP1表达和功能的调节。 RNASEQ数据揭示了 蝙蝠中COQ缺乏的转录签名涉及关键调节剂 线粒体展开的蛋白质反应（UPRMT）和综合应力反应 （ISR）。我们建议在BAT中激活IRS的激活触发代谢适应 包括降低UCP1表达和增强的UCP1无关 在BAT和其他组织中的热生成，通过增加BAT Para/Autocrine的分泌 诸如FGF21之类的因素。