Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency.
Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency.
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DOI：
10.1172/jci.insight.156222
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发表时间：
2022-10-24
期刊：
影响因子：
8
通讯作者：
Falk, Marni J.
中科院分区：
文献类型：
--
作者：
Broxton, Chynna N.;Kaur, Prabhjot;Lavorato, Manuela;Ganesh, Smruthi;Xiao, Rui;Mathew, Neal D.;Nakamaru-Ogiso, Eiko;Anderson, Vernon E.;Falk, Marni J.
二氢硫辛酰胺脱氢酶 (DLD) 缺乏症是一种隐性线粒体疾病，由 α-酮酸脱氢酶复合物消耗 DLD 引起。通过 dld-1(RNAi) 分级喂养产生的 DLD 缺乏的秀丽隐杆线虫动物模型显示，DLD-1 表达的全部或部分减少再现了丙酮酸脱氢酶复合物缺乏症典型的丙酮酸水平增加，并显着改变了动物的生存和健康，伴随着幼崽大小、成体长度和神经肌肉功能的减少。 DLD-1 缺乏显着增加线粒体未折叠蛋白应激反应诱导和适应性线粒体增殖。虽然 ATP 水平降低，但呼吸链酶活性和体内线粒体膜电位没有显着改变。 DLD-1 耗竭与线粒体应激的诱导以及线虫生长和神经肌肉功能的损害直接相关。通过寿命和线粒体应激反应研究，客观评估了二氯乙酸盐、硫胺素、核黄素、5-氨基咪唑-4-甲酰胺-1-β-d-呋喃核苷 (AICAR)、左旋肉碱和硫辛酸补充疗法对人类 DLD 疾病的经验使用的安全性和有效性。只有二氯乙酸盐和硫胺素显示出单独和协同的治疗效果。总的来说，这些线虫 dld-1(RNAi) 动物模型研究证明了疾病机制和候选治疗方案的临床前建模的转化相关性。结果表明，有必要进行临床试验来评估二氯乙酸盐和硫胺素在人类 DLD 疾病中的安全性和有效性。
Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.
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影响因子：
9.3
作者：
Debray, Francois-Guillaume;Mitchell, Grant A.;Lambert, Marie
通讯作者：
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影响因子：
3.6
作者：
Barcelos I;Shadiack E;Ganetzky RD;Falk MJ
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影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.94.26.14512
发表时间：
1997-12-23
影响因子：
11.1
作者：
Johnson, MT;Yang, HS;Patel, MS
通讯作者：
Patel, MS