N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.
N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.
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DOI：
10.1016/j.ymgme.2018.02.013
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发表时间：
2018-04
影响因子：
3.8
通讯作者：
Falk MJ
中科院分区：
文献类型：
--
作者：
Polyak E;Ostrovsky J;Peng M;Dingley SD;Tsukikawa M;Kwon YJ;McCormack SE;Bennett M;Xiao R;Seiler C;Zhang Z;Falk MJ
氧化应激是线粒体呼吸链（RC）疾病发病机制中的已知促成因素。然而，不存在有效的手段来客观地评估经验性地用于人类RC疾病的不同抗氧化剂化合物的比较治疗功效或毒性。我们假设，临床前比较分析的各种抗氧化剂药物已建议效用在原发性RC疾病，使用动物和细胞模型的RC功能障碍可能会提高他们的综合作用和生理机制的理解，并使优先的铅抗氧化剂分子追求在人体临床试验。在这里，N-乙酰半胱氨酸（NAC）、维生素E、维生素C、辅酶Q10（CoQ 10）、靶向辅酶Q10（MS 010）、硫辛酸和乳清酸盐的寿命效应被评估为一个成熟的、寿命短的C。elegans gas-1（fc21）模型。询问Healthspan效应以评估其整体破坏的体内线粒体生理学、转录组谱和中间代谢通量的潜在逆转。NAC、维生素E和部分辅酶Q将气体-1（fc21）的寿命挽救到野生型N2布里斯托蠕虫的寿命。MS 010和CoQ 10在很大程度上逆转了Gas-1（fc21）蠕虫的生化途径表达变化。尽管几乎所有的药物都能使“细胞抗氧化途径”的上调表达正常化，但它们未能挽救突变蠕虫体内线粒体氧化剂负荷的增加。在人成纤维细胞和/或斑马鱼复合体I疾病模型中验证NAC和维生素E的治疗功效。值得注意的是，鱼藤酮诱导的斑马鱼脑死亡可以部分用NAC预防，完全用维生素E预防。总体而言，这些临床前模型动物数据表明，几种经典的抗氧化剂药物确实对原发性线粒体疾病的生存力和存活率产生了显着的益处，其中它们的主要治疗益处似乎来自靶向全局细胞而不是脑内特异性氧化应激。需要临床试验来评估在转化模型动物中显示出最大功效的两种抗氧化剂NAC和维生素E是否显著改善患有原发性线粒体RC疾病的人类受试者的生存、功能和感觉。
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that the pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC, vitamin E, and partially coenzyme Q rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the ‘cellular antioxidant pathway’, they failed to rescue the mutant worms’ increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these preclinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.
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影响因子：
3.9
作者：
Douiev L;Soiferman D;Alban C;Saada A
通讯作者：
Saada A
影响因子：
9.8
作者：
Gai, Xiaowu;Ghezzi, Daniele;Zeviani, Massimo
通讯作者：
Zeviani, Massimo
影响因子：
3.7
作者：
Abadi A;Crane JD;Ogborn D;Hettinga B;Akhtar M;Stokl A;Macneil L;Safdar A;Tarnopolsky M
通讯作者：
Tarnopolsky M
DOI：
10.1007/978-1-61779-504-6_16
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dingley, Stephen;Chapman, Kimberly A;Falk, Marni J
通讯作者：
Falk, Marni J
影响因子：
4.3
作者：
Dale, K.;Rasinger, J. D.;Ellingsen, S.
通讯作者：
Ellingsen, S.