Jiménez-Jiménez Félix Javier, Alonso-Navarro Hortensia, García-Martín Elena, Cárcamo-Fonfría Alba, Martín-Gómez Miguel Angel, Agúndez José A G
Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, E 28500 Madrid, Spain.
University Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, E 10071 Caceres, Spain.
Cells. 2025 Sep 9;14(18):1406. doi: 10.3390/cells14181406.
The pathogenesis of Friedreich's ataxia (FRDA) remains poorly understood. The most important event is the deficiency of frataxin, a protein related to iron metabolism and, therefore, involved in oxidative stress. Studies on oxidative stress markers and gene expression in FRDA patients have yielded inconclusive results. This is largely due to the limited number of studies, small sample sizes, and methodological differences. A notable finding is the decreased activity of mitochondrial respiratory chain complexes I, II, and III, as well as aconitase, in endomyocardial tissue. In contrast, numerous studies in experimental models of FRDA (characterized by frataxin deficiency) have shown evidence of the involvement of oxidative stress in cellular degeneration. These findings include increased iron concentration, mitochondrial dysfunction (with reduced respiratory chain complex activity and membrane potential), and decreased aconitase activity. Additionally, there is the induction of antioxidant enzymes, reduced glutathione levels, elevated markers of lipoperoxidation, and DNA and carbonyl protein oxidation. The expression of NRF2 is decreased, along with the downregulation of PGC-1α. Therefore, it is plausible that antioxidant treatment may help improve symptoms and slow the progression of FRDA. Among the antioxidant treatments tested in FRDA patients, only omaveloxolone and, to a lesser extent, idebenone (particularly for cardiac hypertrophy) have shown some efficacy. However, many antioxidant drugs have shown the ability to reduce oxidative stress in experimental models of FRDA. Therefore, these drugs may be useful in treating FRDA and are likely candidates for future clinical trials. Future studies investigating oxidative stress and antioxidant therapies in FRDA should adopt a prospective, multicenter, long-term, double-blind design.
弗里德赖希共济失调（FRDA）的发病机制仍未完全明确。最重要的事件是铁调素缺乏，铁调素是一种与铁代谢相关的蛋白质，因此参与氧化应激过程。对FRDA患者氧化应激标志物和基因表达的研究结果尚无定论。这主要是由于研究数量有限、样本量小以及方法学差异。一个值得注意的发现是，心内膜心肌组织中线粒体呼吸链复合体I、II和III以及乌头酸酶的活性降低。相比之下，在FRDA实验模型（以铁调素缺乏为特征）中的大量研究表明，氧化应激参与细胞变性。这些发现包括铁浓度升高、线粒体功能障碍（呼吸链复合体活性和膜电位降低）以及乌头酸酶活性降低。此外，还存在抗氧化酶的诱导、谷胱甘肽水平降低、脂质过氧化标志物升高以及DNA和羰基蛋白氧化。NRF2的表达降低，同时PGC-1α下调。因此，抗氧化治疗可能有助于改善症状并减缓FRDA的进展，这似乎是合理的。在FRDA患者中测试的抗氧化治疗中，只有奥马伏索隆，以及在较小程度上艾地苯醌（特别是对心脏肥大）显示出一定疗效。然而，许多抗氧化药物已显示出在FRDA实验模型中降低氧化应激的能力。因此，这些药物可能对治疗FRDA有用，并且很可能是未来临床试验的候选药物。未来研究FRDA中氧化应激和抗氧化疗法应采用前瞻性、多中心、长期、双盲设计。
