Protein Succination as a Mediator of Neuropathology in Mitochondrial Disease

蛋白琥珀化作为线粒体疾病神经病理学的中介

基本信息

批准号：
8942973
负责人：
Norma Frizzell
金额：
$ 23.96万
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：
2015-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8942973
关键词：
5 year old Accounting Address Adipocytes Affect Biochemical Bioenergetics Brain Brain Stem Brain region Cells Citric Acid Cycle Clinical Treatment Complex Cysteine Cytochrome c Reductase DNA DNA Sequence Alteration Defect Development Diabetes Mellitus Disease Disease Progression Electron Transport Encephalopathies Energy Metabolism Enzymes Event Feedback Fumarate Hydratase Fumarates Genes Genetic Glucose In Vitro Knock-out Knockout Mice Lateral Lead Leigh Disease Life Link Live Birth Mediating Mediator of activation protein Metabolic Mitochondria Mitochondrial Diseases Mitochondrial Electron Transport Chain Deficiencies Modeling Molecular Motor Mus Mutation NADH Nerve Degeneration Neuroglia Neurons Nuclear Nutrient Organelles Pathology Pathway interactions Phenotype Post-Translational Protein Processing Property Protein S Proteins Reaction Reporting Respiratory Chain Rest Selenium Site Stress Sulfhydryl Compounds Testing Therapeutic Translating Tubulin Work antioxidant therapy base design disease phenotype ebselen effective therapy in vivo innovation mitochondrial dysfunction mouse model neuropathology new therapeutic target novel novel therapeutics overexpression prevent protein degradation protein function protein structure public health relevance pyruvate dehydrogenase relating to nervous system targeted treatment therapeutic target trafficking voltage-dependent anion channel 2

项目摘要

DESCRIPTION (provided by applicant): ABSTRACT Mitochondrial diseases manifesting as encephalopathies occur at a rate of 1 in 5000 live births and are often fatal by ~5 years old. Mitochondrial diseases are respiratory chain disorders in which the mitochondria are no longer operating efficiently to produce ATP, usually due to a problem with one or more components of the electron transport chain (ETC). Fortunately, genetic sequencing has identified a large number of the mutations in mitochondrial or nuclear DNA which cause these encephalomyopathies. However, in most cases there is still no clear metabolic link between the genetic defect and the neuropathology, and very few effective treatments. The innovative studies described in this proposal are expected to reveal a novel metabolic link between reduced ETC activity and neural pathology. Previously, we have detected a new post-translational modification of proteins, S-(2-succino)cysteine (2SC), which is formed by reaction of the Krebs cycle intermediate fumarate with reactive cysteine residues in protein. Both fumarate and succination of proteins are increased in adipocytes in diabetes, disturbing protein function and turnover. The increase in fumarate develops as a result of excess fuel supply, accumulation of NADH, and feedback inhibition of the Krebs cycle. In a novel, lateral extension of these observations we propose that a similar inhibition of the ETC, e.g. in Complex I deficiency during Leigh Syndrome, would result in increased NADH, fumarate and succination in mitochondrial disease. In Preliminary Studies, we demonstrate that increased succination of proteins is detectable on several proteins in the brainstem of a mouse model of Leigh syndrome (Ndufs4 knockout (KO) mouse) in association with neurodegeneration. We hypothesize that mitochondrial stress results in the accumulation of fumarate and that succination alters protein structure or function contributing to disease pathology. We will confirm this in Specific Aim 1. We have identified several succinated targets already and we plan to mechanistically address how succination of these leads to further reductions in mitochondrial function in Specific Aim 2. In Specific Aim 3 we will use a molecular strategy to distinguish the bioenergetic defect from protein succination and investigate therapeutic strategies designed to reduce fumarate and succination leading to improvements in mitochondrial function and the disease phenotype. Overall, these foundational studies will demonstrate that succination is a mechanistic link between mitochondrial stress and neuropathology, with important implications for the elucidation of novel therapeutic avenues for the treatment of mitochondrial diseases.

描述（由申请人提供）：摘要表现为脑病的线粒体疾病的发生率为五千分之一，通常在 5 岁左右时致命。线粒体疾病是一种呼吸链疾病，通常由于出现问题，线粒体不再有效地产生 ATP。幸运的是，基因测序已经识别出线粒体或核 DNA 中的大量突变，这些突变会导致这些突变。然而，在大多数情况下，遗传缺陷和神经病理学之间仍然没有明确的代谢联系，并且该提案中描述的创新研究有望揭示 ETC 活性降低和神经病理学之间的新代谢联系。此前，我们检测到了一种新的蛋白质翻译后修饰，S-(2-琥珀酰)半胱氨酸(2SC)，它是由克雷布斯循环中间体富马酸与反应性半胱氨酸残基反应形成的糖尿病患者的脂肪细胞中蛋白质的富马酸和琥珀酸都会增加，从而扰乱蛋白质功能和周转。富马酸的增加是由于燃料供应过多、NADH 积累和克雷布斯循环的抑制反馈而产生的。这些观察结果的横向延伸，我们提出类似的 ETC 抑制，例如 Leigh 综合征期间的复合物 I 缺乏，将导致线粒体疾病中 NADH、延胡索酸和琥珀酸的增加。初步研究表明，Leigh 综合征小鼠模型（Ndufs4 敲除 (KO) 小鼠）脑干中的几种蛋白质可检测到蛋白质琥珀化增加，这与神经变性有关。琥珀化改变了导致疾病病理学的蛋白质结构或功能，我们将在具体目标 1 中证实这一点。我们已经确定了几个琥珀化靶点，并计划从机制上解决如何解决这一问题。在特定目标 2 中，这些物质的琥珀化会导致线粒体功能进一步降低。在特定目标 3 中，我们将使用分子策略来区分生物能缺陷和蛋白质琥珀化，以及旨在减少延胡索酸和琥珀化的治疗策略，从而研究线粒体功能和蛋白质琥珀化的改善。总的来说，这些基础研究将证明琥珀化是线粒体应激和神经病理学之间的机制联系，对于阐明新的治疗方法具有重要意义。线粒体疾病的治疗途径。