Protein Succination: a Mechanistic Mediator of Adipocyte Dysfunction in Diabetes

蛋白质琥珀化：糖尿病脂肪细胞功能障碍的机制介质

基本信息

批准号：
9117530
负责人：
Norma Frizzell
金额：
$ 13.35万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117530
关键词：
Active Sites Adipocytes Adipose tissue Affect American Antioxidants Attention Biochemical CCAAT-Enhancer-Binding Proteins Chemicals Citric Acid Cycle Cysteine Data Deposition Development Diabetes Mellitus Early treatment Endocrine Endoplasmic Reticulum Enzymes Feedback Fumarate Hydratase Fumarates Functional disorder Glucose Health Homologous Protein In Vitro Inflammation Inner mitochondrial membrane Insulin Resistance Knock-out Knockout Mice Laboratories Lead Link Lipids Liver Mediating Mediator of activation protein Metabolic Metabolic stress Metabolism Mitochondria Mitochondrial Diseases Modeling Modification Muscle NADH NF-E2-related factor 2 Non-Insulin-Dependent Diabetes Mellitus Nutrient Oxidation-Reduction Oxidative Stress Pathway interactions Peripheral Post-Translational Protein Processing Prediabetes syndrome Protein Disulfide Isomerase Proteins Pyruvate Carboxylase Reaction Role Selenocysteine Stress Sulfhydryl Compounds Tissues Ubiquitination Work adiponectin base db/db mouse ebselen endoplasmic reticulum stress glucose tolerance glutathione peroxidase inflammatory marker innovation insulin tolerance knock-down mouse model novel novel therapeutic intervention novel therapeutics overexpression prevent protein folding protein misfolding protein structure function response selenoprotein small hairpin RNA targeted treatment thioredoxin reductase

项目摘要

DESCRIPTION (provided by applicant): Considering that ~26 million Americans have diabetes and an estimated 79 million have prediabetes, it is critical that we understand the role of expanding adipose tissue mass in the development of systemic metabolic dysfunction. However, many of the biochemical mechanisms underlying adipose tissue dysfunction remain unclear. Previously, we have detected S-(2-succinol)cysteine (2SC), also termed protein succination, a new chemical post-translational modification of proteins. 2SC is formed by reaction of the Krebs cycle intermediate fumarate with reactive cysteine residues in protein. Both fumarate and succination of proteins appear to be selectively increased in adipocytes in diabetes, impairing protein structure and function. The increase in fumarate develops as a result of excess fuel supply, accumulation of ATP and NADH, inner mitochondrial membrane (IMM) hyperpolarization and consequently feedback inhibition of the Krebs cycle. This proposal hypothesizes that the increase in protein succination is a novel mechanistic link between mitochondrial stress and the accumulation of misfolded proteins, contributing to endoplasmic reticulum (ER) stress in the adipocyte in diabetes. In addition, we propose that the succination of redox-active proteins modulates redox stress in diabetes. This project has 3 specific aims: (1) To examine the impact of fumarate accumulation and selective succination in the adipocyte; (2) To determine if succination mechanistically links mitochondrial and ER stress in the adipocyte; and (3) To examine the reactivity of fumarate with protein selenocysteines as a novel redox modulator. We plan to use a novel knockout mouse with selective fumarate accumulation in the adipose tissue. Upon completion of these studies, we will demonstrate the significant contribution of adipocyte protein succination to metabolic dysfunction in diabetes, with important implications for the development of novel therapeutic avenues for the treatment of mitochondrial diseases.

描述（由适用提供）：考虑到约有2600万美国人患有糖尿病，估计有7900万具有糖尿病前期，至关重要的是，我们了解扩大脂肪组织质量在系统性代谢功能障碍发展中的作用。但是，尚不清楚脂肪组织功能障碍的许多生化机制尚不清楚。以前，我们已经检测到S-（2-核醇）半胱氨酸（2SC），也称为蛋白质琥珀酸酯，这是一种新的化学化学后翻译后蛋白质修饰。 2SC是通过富马酸群中间体与反应性半胱氨酸在蛋白质中的反应形成的。在糖尿病的脂肪细胞中，蛋白质的富马酸酯和蛋白质的锻炼似乎有选择性地增加，损害了蛋白质的结构和功能。由于燃料供应过多，ATP和NADH的积累，内部线粒体膜（IMM）超极化以及KREBS循环的反馈抑制。该提议假设蛋白质琥珀酸的增加是线粒体应激与错误折叠蛋白的积累之间的新机械联系，导致糖尿病脂肪细胞中内质网应激（ER）胁迫。此外，我们建议氧化还原活性蛋白的琥珀色调节糖尿病中的氧化还原应激。该项目具有3个特定的目的：（1）检查脂肪细胞中富马酸盐积累和选择性琥珀的影响；（2）确定琥珀酸是否会在脂肪细胞中将线粒体和ER应力联系起来；（3）检验富马酸酯与蛋白质硒代蛋白作为一种新型氧化还原调节剂的反应性。我们计划在脂肪组织中使用具有选择性富马酸酯积累的新型基因敲除小鼠。这些研究完成后，我们将证明脂肪细胞蛋白辅助对糖尿病中代谢功能障碍的显着贡献，这对新型治疗途径的发展对治疗线粒体疾病的治疗具有重要意义。