线粒体未折叠蛋白反应(mtUPR)激活改善乙基丙二酸脑病细胞模型的病理改变。

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
José Manuel Romero-Domínguez, Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Diana Reche-López, Ana Romero-González, Mónica Álvarez-Córdoba, Alejandra López-Cabrera, Marta Castro De Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo, Angeles Aroca, José A Sánchez-Alcázar
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引用次数: 0

摘要

乙基丙二酸脑病(EE)是一种严重的代谢性疾病,通常出现在儿童发育早期,其影响主要见于大脑、胃肠道和周围血管。EE是由编码ETHE1蛋白的基因的致病性变异引起的,其主要特征是体液中酸性化合物含量高,线粒体复合体IV活性降低,这限制了需要大量能量供应的组织中的能量产生。ETHE1是一种线粒体硫双加氧酶,起硫化氢(H2S)解毒的作用,当它被改变时,由于其缺乏消除,导致这种气体分子的积累。在这篇文章中,我们在细胞模型、成纤维细胞和诱导神经元中描述了ETHE1缺乏症的病理生理学,这些模型来源于一个ETHE1纯合子致病变异的患者。此外,我们评估了线粒体未折叠蛋白反应(mtUPR)的激活对突变表型的影响。我们的研究结果表明,突变型成纤维细胞有ETHE1蛋白表达水平的改变,这与H2S和蛋白质过硫化水平升高、线粒体功能障碍、铁/脂褐素积累和氧化应激有关。我们还鉴定了一种由紫檀芪、烟酰胺、核黄素、硫胺素、生物素、硫辛酸和左旋肉碱组成的混合物,这些化合物改善了细胞和代谢的改变。鸡尾酒的积极作用依赖于sirtuin 3激活(SIRT3),并且在通过直接重编程获得的诱导神经元中也得到证实。总之,在情感表达中使用患者来源的细胞模型进行个性化精准医疗可能是一种筛选和评估潜在治疗方法的有趣方法。此外,激活mtUPR的SIRT3斧头是挽救ETHE1致病变异的一种有希望的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy.

Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H2S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H2S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants.

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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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