The role of redox balance in cyanide toxicity and mitochondrial disease

氧化还原平衡在氰化物毒性和线粒体疾病中的作用

基本信息

批准号：
10536383
负责人：
Emily Tippetts
金额：
$ 3.63万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536383
关键词：
Affect Aftercare Age Antidotes Behavioral Binding Biological Assay Brain Cells Characteristics Collection Complex Consumption Cyanides Cytosol Deacetylase Deacetylation Disease Electron Transport Electrons Equilibrium Family suidae Functional disorder Genes Genetic Genus Hippocampus Homeostasis Human Immunohistochemistry Industrial Accidents Inner mitochondrial membrane Intraperitoneal Injections Investigation Knock-out Lead Leigh Disease Link Locomotion Longevity Metabolic Metabolism Mitochondria Mitochondrial Diseases Modeling Monitor Motion Mus Mutate Mutation NADH NADH oxidase Neurologic Neurological outcome Nicotinamide Mononucleotide Oryctolagus cuniculus Oxidation-Reduction Oxides Oxygen Consumption Patients Pharmacology Phenotype Poisoning Production Protons Reaction Risk Role Sirtuins Smoke Syndrome Technology Therapeutic Time Tissues Toxic effect Zebrafish alternative treatment classical conditioning cofactor complex IV conditioning design disease phenotype disease-causing mutation drug development effective therapy electron donor experimental study glyoxylate improved improved outcome inhibitor metabolic poison mitochondrial dysfunction mouse model oxidation prevent protein complex restoration sensor

Affect Aftercare Age Antidotes Behavioral Binding Biological Assay Brain Cells Characteristics Collection Complex Consumption Cyanides Cytosol Deacetylase Deacetylation Disease Electron Transport Electrons Equilibrium Family suidae Functional disorder Genes Genetic Genus Hippocampus Homeostasis Human Immunohistochemistry Industrial Accidents Inner mitochondrial membrane Intraperitoneal Injections Investigation Knock-out Lead Leigh Disease Link Locomotion Longevity Metabolic Metabolism Mitochondria Mitochondrial Diseases Modeling Monitor Motion Mus Mutate Mutation NADH NADH oxidase Neurologic Neurological outcome Nicotinamide Mononucleotide Oryctolagus cuniculus Oxidation-Reduction Oxides Oxygen Consumption Patients Pharmacology Phenotype Poisoning Production Protons Reaction Risk Role Sirtuins Smoke Syndrome Technology Therapeutic Time Tissues Toxic effect Zebrafish alternative treatment classical conditioning cofactor complex IV conditioning design disease phenotype disease-causing mutation drug development effective therapy electron donor experimental study glyoxylate improved improved outcome inhibitor metabolic poison mitochondrial dysfunction mouse model oxidation prevent protein complex restoration sensor

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项目摘要

PROJECT SUMMARY The electron transport chain (ETC) in the inner mitochondrial membrane is essential for efficient ATP production in the cell. ETC function can be disrupted both genetically and pharmacologically by mitochondrial diseases and metabolic poisons, respectively. Inefficient ATP production affects all tissues, but particularly the brain with its high energy demands, thus making this a deadly neurological problem. ETC dysfunction is often associated with buildup of the initial electron donor, NADH, within the mitochondria. This increase in NADH corresponds with a decrease in its oxidized form, NAD+, contributing to an overall NAD+/NADH ratio imbalance. Since NAD+ and NADH are cofactors for many redox reactions in the cell, this results in redox imbalance and reduced metabolic flux, intensifying the energy production problem. Cyanide, a pharmacological ETC inhibitor, and Leigh syndrome, a collection of fatal genetic mitochondrial diseases, both result in inefficient ATP production, NAD+/NADH ratio imbalances, and severe neurological consequences. Few cyanide antidotes exist, all of which have a limited efficacious time window for administration. No cure is available for any form of Leigh syndrome. We hypothesize that normalization of the NAD+/NADH ratio will improve outcomes for both cyanide poisoning and Leigh syndrome. Within Aim 1 of this proposal, we will investigate 1) if restoring NAD+/NADH ratio is sufficient for rescuing cyanide poisoning and 2) what occurs downstream of restoring NAD+/NADH ratio in the context of cyanide poisoning. Within Aim 2, we will determine if redox modulators can rescue disease phenotypes in an array of zebrafish models of Leigh syndrome designed to cover a wide breadth of mutations associated with Leigh syndrome. These disease phenotypes include glial reactivity and deficits in locomotion, oxygen consumption, and associative learning. Collectively, these experiments will evaluate the therapeutic value of restoring the NAD+/NADH ratio for different forms of mitochondrial dysfunction, and will focus on redox modulators that improve neurological outcomes.

项目摘要线粒体膜中的电子传输链（ETC）对于有效的ATP产生至关重要在细胞中。 ETC功能可以通过线粒体疾病和药理学上的遗传和药理破坏代谢毒物分别。效率低下的ATP产生会影响所有组织，尤其是大脑高能量需要，因此使这是致命的神经系统问题。 ETC功能障碍通常与线粒体内的最初电子供体NADH的堆积。纳德的增加与减少其氧化形式NAD+，导致总体NAD+/NADH比率不平衡。自NAD+和 NADH是细胞中许多氧化还原反应的辅助因子，这导致氧化还原不平衡和代谢降低通量，加剧了能源生产问题。氰化物，药理学等抑制剂和利综合症，这是致命的遗传线粒体的集合疾病，两者都导致ATP产生效率低下，NAD+/NADH比率不平衡和严重的神经系统结果。很少有氰化物解毒剂，所有这些都有有限的有效时间窗口行政。任何形式的利综合症都无法治愈。我们假设 NAD+/NADH比率将改善氰化物中毒和利综合症的预后。在目标1中提案，我们将调查1）如果恢复NAD+/NADH比率足以挽救氰化物中毒； 2）在氰化物中毒的背景下，恢复NAD+/NADH比的下游发生的事情。在目标2中，我们将确定氧化还原调节器是否可以在一系列斑马鱼模型中挽救疾病表型综合征旨在涵盖与利综合症有关的广泛突变。这些疾病表型包括神经胶质反应性和运动的缺陷，消耗氧和关联学习。总的来说，这些实验将评估恢复NAD+/NADH比的治疗价值线粒体功能障碍的形式，并将集中于改善神经系统结果的氧化还原调节剂。