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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：
9268095
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/9268095
关键词：
5 year old 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 Foundations Fumarate Hydratase Fumarates Genes Genetic Glucose Impairment In Vitro Knock-out Knockout Mice Lateral Lead Leigh Disease 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 Pathologic Pathology Pathway interactions Pharmacology Phenotype Post-Translational Protein Processing Property Proteins Reaction Reporting Respiratory Chain Rest Selenium Site Stress Succinates Sulfhydryl Compounds Testing Therapeutic Translating Tubulin Work antioxidant therapy 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）：以脑病为表现的线粒体疾病的发生率为1/5000活产，并且通常在~5岁时是致命的。线粒体疾病是呼吸链疾病，其中线粒体不再有效地运作以产生ATP，通常是由于电子传递链（ETC）的一个或多个组分的问题。幸运的是，基因测序已经确定了导致这些脑肌病的线粒体或核DNA中的大量突变。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，并且很少有有效的治疗方法。该提案中描述的创新研究有望揭示ETC活性降低与神经病理学之间的新代谢联系。以前，我们已经发现了一种新的蛋白质翻译后修饰，S-（2-琥珀酰基）半胱氨酸（2SC），它是由克雷布斯循环中间体富马酸与蛋白质中的反应性半胱氨酸残基反应形成的。在糖尿病中脂肪细胞中蛋白质的富马酸和琥珀酸化均增加，干扰蛋白质功能和周转。富马酸盐的增加是由于过量的燃料供应、NADH的积累和克雷布斯循环的反馈抑制。在这些观察结果的新的横向扩展中，我们提出ETC的类似抑制，例如在Leigh综合征期间的复合物I缺乏中，将导致线粒体疾病中的NADH、富马酸盐和琥珀酸化增加。在初步研究中，我们证明了在与神经变性相关的Leigh综合征小鼠模型（Ndufs 4敲除（KO）小鼠）的脑干中的几种蛋白质上可检测到蛋白质的琥珀酸化增加。我们假设线粒体应激导致富马酸盐的积累，琥珀酸化改变蛋白质结构或功能，从而导致疾病病理学。我们将在具体目标1中确认这一点。我们已经确定了几个琥珀酸化的目标，我们计划机械地解决这些琥珀酸化如何导致特定目标2中线粒体功能的进一步降低。在具体目标3中，我们将使用分子策略来区分生物能量缺陷与蛋白琥珀酸化，并研究旨在减少富马酸和琥珀酸化的治疗策略，从而改善线粒体功能和疾病表型。总的来说，这些基础研究将证明琥珀酸化是线粒体应激和神经病理学之间的机制联系，对阐明治疗线粒体疾病的新治疗途径具有重要意义。