Cell response to oxidative stress induced apoptosis in patients with Leber's hereditary optic neuropathy
Cell response to oxidative stress induced apoptosis in patients with Leber's hereditary optic neuropathy
复制标题
DOI：
10.1136/jnnp.2003.024372
复制
发表时间：
2004-12-01
影响因子：
11
通讯作者：
Federico, A
中科院分区：
文献类型：
--
作者：
Battisti, C;Formichi, P;Federico, A
目的：Leber's遗传性视神经病变（LHON）是一种以年轻男性为主的急性或亚急性双侧视力丧失的母系遗传性疾病。超过95%的LHON病例与三种线粒体DNA （mtDNA）点突变中的一种有关，但只有50%的男性和10%的女性携带致病性mtDNA突变发展为视神经病变。这种不完全外显率和对男性的偏好表明，额外的遗传（核或线粒体）和/或环境因素必须调节LHON的表型表达。活性氧（ROS）在线粒体疾病中的作用，继发于mtDNA突变，或作为ROS细胞毒性的直接作用，已涉及许多线粒体疾病，包括LHON。本研究旨在探讨氧化应激诱导的细胞凋亡在LHON中的作用。方法：采用光镜、流式细胞术、琼脂糖凝胶电泳、线粒体膜电位测定等方法观察6例LHON患者和6例正常人外周血淋巴细胞2-脱氧d核糖诱导的凋亡反应。结果：LHON患者细胞凋亡率高于对照组，凋亡级联活化过程中有线粒体参与。结论：氧化应激诱导细胞凋亡的这些差异与氧化还原稳态可能在不同个体的基因突变表达中发挥作用的假设一致，并可能代表开发新的治疗策略的潜在靶点。
Objectives: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease in which acute or subacute bilateral visual loss occurs preferentially in young men. Over 95% of LHON cases are associated with one of three mitochondrial DNA (mtDNA) point mutations, but only 50% of men and 10% of women who harbour a pathogenetic mtDNA mutation develop optic neuropathy. This incomplete penetrance and preference for men suggests that additional genetic (nuclear or mitochondrial) and/or environmental factors must modulate phenotype expression in LHON. A role for reactive oxygen species (ROS) in mitochondrial diseases, secondary to mtDNA mutations, or as a result of the direct effect of ROS cytotoxicity, has been implicated in many mitochondrial disorders, including LHON. The purpose of this study was to investigate the role of oxidative stress induced apoptosis in LHON.Methods: The 2-deoxy-D-ribose induced apoptotic response of peripheral blood lymphocytes from six patients with LHON and six healthy subjects was investigated using light microscopy, flow cytometry, agarose gel electrophoresis, and the measurement of mitochondrial membrane potential.Results: Cells of patients with LHON had a higher rate of apoptosis than those of controls and there was evidence of mitochondrial involvement in the activation of the apoptotic cascade.Conclusions: These differences in oxidative stress induced apoptosis are in line with the hypothesis that redox homeostasis could play a role in the expression of genetic mutations in different individuals and could represent a potential target in the development of new therapeutic strategies.