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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（由申请人提供）：考虑到约2600万美国人患有糖尿病，估计有7900万人患有前驱糖尿病，我们了解脂肪组织质量扩大在全身代谢功能障碍发展中的作用至关重要。然而，许多脂肪组织功能障碍的生化机制仍不清楚。以前，我们已经检测到S-（2-琥珀酰基）半胱氨酸（2SC），也称为蛋白琥珀酸，一种新的化学蛋白质翻译后修饰。2SC是由克雷布斯循环中间体富马酸盐与蛋白质中的反应性半胱氨酸残基反应形成的。蛋白质的延胡索酸和琥珀酸化似乎在糖尿病脂肪细胞中选择性增加，损害蛋白质结构和功能。富马酸盐的增加是由于过量的燃料供应、ATP和NADH的积累、线粒体内膜（IMM）超极化以及因此对克雷布斯循环的反馈抑制。该提议假设蛋白琥珀酸化的增加是线粒体应激和错误折叠蛋白质的积累之间的一种新的机制联系，有助于糖尿病脂肪细胞中的内质网（ER）应激。此外，我们提出，琥珀酸氧化还原活性蛋白调节氧化还原应激糖尿病。该项目有3个具体目标：（1）研究脂肪细胞中富马酸积累和选择性琥珀酸化的影响;（2）确定琥珀酸化是否在脂肪细胞中机械地连接线粒体和ER应激;和（3）研究富马酸与蛋白质硒代半胱氨酸作为新型氧化还原调节剂的反应性。我们计划使用一种新的基因敲除小鼠，在脂肪组织中具有选择性富马酸盐积累。完成这些研究后，我们将证明脂肪细胞蛋白琥珀酸化对糖尿病代谢功能障碍的重要贡献，这对开发治疗线粒体疾病的新治疗途径具有重要意义。