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：
9122509
负责人：
Norma Frizzell
金额：
$ 21.57万
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/9122509
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 knock-down 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 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）：抽象的线粒体疾病表现为脑病，以5000例活产的速度1，通常是致命的5岁。线粒体疾病是呼吸链疾病，其中线粒体不再有效地产生ATP，这通常是由于电子传输链的一个或多个成分的问题（ETC）。幸运的是，遗传测序已经确定了导致这些脑病的线粒体或核DNA中的大量突变。但是，在大多数情况下，遗传缺陷与神经病理学之间仍然没有明确的代谢联系，并且很少有有效的治疗方法。预计该提案中描述的创新研究将揭示降低的活动和神经病理学之间的新代谢联系。以前，我们已经检测到了蛋白质S-（2-核）半胱氨酸（2SC）的新的翻译后修饰，该蛋白质是由Krebs循环中间富马酸中间富马酸酯与蛋白质中反应性半胱氨酸保留的反应形成的。糖尿病的脂肪细胞中的富马酸盐和蛋白质的锻炼都增加了，干扰了蛋白质功能和周转。由于燃料供应过多，NADH的积累以及对克雷布斯周期的反馈抑制，富马酸盐的增加是由于过量的燃料供应而出现的。在这些观察结果的小说，横向延伸中，我们提出了对etc的类似抑制作用，例如在Leigh综合征期间的复杂I缺乏症中，线粒体疾病中的NADH，富马酸盐和辅助会导致NADH升高。在初步研究中，我们证明，在Leigh综合征小鼠模型（NDUFS4基因敲除（KO）小鼠）与神经变性的小鼠模型的脑干中，可以发现蛋白质的增加。我们假设线粒体应激会导致富马酸盐的积累，并且琥珀酸会改变蛋白质的结构或功能，从而导致疾病病理学。我们将在特定的目标1中确认这一点。我们已经确定了几个持续的靶标，我们计划机械地解决这些导致在特定目标中的线粒体功能的进一步降低。在特定目的2中。在特定目标3中，我们将使用分子策略来区分生物能缺陷，从而区分蛋白质的生物能力脱离蛋白质与蛋白质的治疗策略，并降低了fumaration and Remitty and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and rect and rect and MIT in M.MIT in MIT，并在MIT中降低了MIT的良好现象。总体而言，这些基础研究将表明，琥珀色是线粒体应激与神经病理学之间的机械联系，对阐明新型治疗途径的治疗治疗线粒体疾病具有重要意义。