Ferroptosis as a Novel Therapeutic Target for Friedreich's Ataxia
Ferroptosis as a Novel Therapeutic Target for Friedreich's Ataxia
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DOI：
10.1124/jpet.118.252759
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发表时间：
2019-04-01
影响因子：
3.5
通讯作者：
Wilson, Robert B.
中科院分区：
文献类型：
--
作者：
Cotticelli, M. Grazia;Xia, Shujuan;Wilson, Robert B.
弗里德赖希共济失调（FRDA）是一种以共济失调、感觉丧失和肥厚型心肌病为特征的进行性神经和心脏退行性疾病。在大多数情况下，这种疾病是由FXN基因的两个等位基因的第一内含子中的GAA重复扩增引起的，导致编码蛋白Frataxin的表达减少。Frataxin定位于线粒体基质，并且是铁硫簇生物合成所需的。共济失调蛋白表达减少与线粒体功能障碍、线粒体铁积累和氧化应激增加相关。铁缺乏症是最近发现的一种受调控的铁依赖性细胞死亡途径，其在生化上不同于细胞凋亡。我们评估了FRDA细胞模型中是否有铁蛋白途径激活的证据。我们发现，原代患者来源的成纤维细胞，FRDA相关突变的鼠成纤维细胞，和鼠成纤维细胞，其中已引入重复扩增（敲入/敲除）比正常对照细胞erastin，一个已知的铁凋亡诱导剂更敏感。我们还发现，铁凋亡抑制剂乙基3-（苄氨基）4-（环己基氨基）苯甲酸酯（SRS 11 -92）和3-氨基-4-乙基在500 nM下使用的（环己基氨基）苯甲酸盐有效保护用柠檬酸铁铵（FAC）和谷胱甘肽合成抑制剂[L-丁硫氨酸（S，R）-亚砜亚胺（BSO）]处理的FRDA的人和小鼠细胞模型，而胱天蛋白酶-3抑制剂未能显示出显著的生物活性。用FAC和BSO处理的细胞一致地显示谷胱甘肽依赖性过氧化物酶活性降低和脂质过氧化增加，这两个都是铁凋亡的标志。最后，铁凋亡抑制剂SRS 11 -92减少了健康人成纤维细胞中与共济失调蛋白敲低相关的细胞死亡。总之，这些数据表明，铁凋亡抑制剂可能具有治疗FRDA的潜力。
Friedreich ataxia (FRDA) is a progressive neuro- and cardio-degenerative disorder characterized by ataxia, sensory loss, and hypertrophic cardiomyopathy. In most cases, the disorder is caused by GAA repeat expansions in the first introns of both alleles of the FXN gene, resulting in decreased expression of the encoded protein, frataxin. Frataxin localizes to the mitochondrial matrix and is required for iron-sulfur-cluster biosynthesis. Decreased expression of frataxin is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (knockin/knockout) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors ethyl 3-(benzylamino)4-(cyclohexylamino)benzoate (SRS11-92) and ethyl 3-amino-4-(cyclohexylann ino)benzoate, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis [L-buthionine (S,R)-sulfoximine (BSO)], whereas caspase-3 inhibitors failed to show significant biologic activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.