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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.

项目总结