The role of redox balance in cyanide toxicity and mitochondrial disease

项目总结 线粒体内膜上的电子传输链(ETC)对于有效地产生ATP是必不可少的 在牢房里。ETC功能可被线粒体疾病和线粒体疾病从遗传和药物上破坏 分别是代谢毒药。低效的ATP产生影响到所有组织，尤其是大脑 高能量需求，因此这是一个致命的神经问题。ETC功能障碍通常与 线粒体内初始电子供体NADH的积聚。NADH的这种增加对应于 氧化态NAD+的减少，导致总体NAD+/NADH比率失衡。由于NAD+和 NADH是细胞内许多氧化还原反应的辅助因子，导致氧化还原失衡和新陈代谢减少。 通量，加剧了能源生产问题。 氰化物，一种药物ETC抑制剂，以及Leigh综合征，一种致命的遗传线粒体的集合 这两种疾病都会导致ATP生产效率低下，NAD+/NADH比例失衡，以及严重的神经系统疾病 后果。目前存在的氰化物解毒剂很少，所有这些解毒剂的有效时间窗口都有限 行政管理。任何形式的利综合征都没有治愈方法。我们假设 NAD+/NADH比率将改善氰化物中毒和Leigh综合征的预后。在此的目标1内 建议，我们将调查1)恢复NAD+/NADH比率是否足以抢救氰化物中毒和2) 在氰化物中毒的情况下，恢复NAD+/NADH比率的下游发生了什么。在AIM 2中，我们 将确定氧化还原调节剂是否可以挽救Leigh斑马鱼模型的疾病表型 旨在涵盖与Leigh综合征相关的广泛突变的综合征。这些疾病 表型包括神经胶质细胞的反应性和运动、耗氧量和联想学习的缺陷。 总的来说，这些实验将评估恢复NAD+/NADH比率对不同疾病的治疗价值 线粒体功能障碍的形式，并将重点放在改善神经结果的氧化还原调节剂。

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.