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首页> 外文期刊>The FEBS journal >Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy
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Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy

机译：具有Leber遗传性视神经病变的mtDNA突变的杂种的抗氧化防御作用

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摘要

Oxidative stress and imbalance between free radical generation and detoxification may play a pivotal role in the pathogenesis of Leber's hereditary optic neuropathy (LHON). Mitochondria, carrying the homoplasmic 11778/ND4, 3460/ND1 and 14484/ND6 mtDNA point mutations associated with LHON, were used to generate osteosarcoma-derived cybrids. Enhanced mitochondrial production of reactive oxygen species has recently been demonstrated in these cybrids [Beretta S, Mattavelli L, Sala G, Tremolizzo L, Schapira AHV, Martinuzzi A, Carelli V O Ferrarese C (2004) Brain 127, 2183-2192]. The aim of this study was to characterize the antioxidant defences of these LHON-affected cells. The activities of glutathione peroxidase (GPx), glutathione reductase (GR) superoxide dismutases, (SOD) and catalase, and the amounts of glutathione (GSH) and oxidized glutathione (GSSG) were measured in cybrids cultured both in glucose-rich medium and galactose-rich medium. The latter is known to cause oxidative stress and to trigger apoptotic death in these cells. In spite of reduced SOD activities in all LHON cybrids, and of low GPx and GR activities in cells with the most severe 3460/ND1 and 11778/ND4 mutations, GSH and GSSG content were not significantly modified in LHON cybrids cultured in glucose medium. In contrast, in galactose, GSSG concentrations increased significantly in all cells, indicating severe oxidative stress, whereas GR and MnSOD activities further decreased in all LHON cybrids. These data suggest that, in cells carrying LHON mutations, there is a decrease in antioxidant defences, which is especially evident in cells with mutations associated with the most severe clinical phenotype. This is magnified by stressful conditions such as exposure to galactose.
机译：氧化应激和自由基生成与解毒之间的不平衡可能在Leber遗传性视神经病变（LHON）的发病机理中起关键作用。携带与LHON相关的同质11778 / ND4、3460 / ND1和14484 / ND6 mtDNA点突变的线粒体用于产生骨肉瘤来源的混合体。最近在这些杂种中证明了增强的线粒体活性氧的产生[贝雷塔S，马塔维利L，萨拉G，特雷莫利佐L，沙皮拉AHV，马丁努奇A，卡雷利VO Ferrarese C（2004）Brain 127，2183-2192]。这项研究的目的是表征这些受LHON影响的细胞的抗氧化防御能力。在富含葡萄糖的培养基和半乳糖中培养的混合体中，测定了谷胱甘肽过氧化物酶（GPx），谷胱甘肽还原酶（GR）超氧化物歧化酶（SOD）和过氧化氢酶的活性以及谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）的量。丰富的媒体。已知后者会引起氧化应激并触发这些细胞的凋亡死亡。尽管所有LHON杂种中的SOD活性均降低，并且具有最严重3460 / ND1和11778 / ND4突变的细胞中GPx和GR活性较低，但在葡萄糖培养基中培养的LHON杂种中GSH和GSSG的含量并未显着改变。相反，在半乳糖中，所有细胞中的GSSG浓度均显着增加，表明存在严重的氧化应激，而在所有LHON杂种中，GR和MnSOD活性进一步降低。这些数据表明，在携带LHON突变的细胞中，抗​​氧化剂防御能力下降，这在具有与最严重的临床表型相关的突变的细胞中尤为明显。压力条件（例如暴露于半乳糖）将其放大。

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