Metabolic and antioxidant system alterations in an astrocytoma cell line challenged with mitochondrial DNA deletion
Metabolic and antioxidant system alterations in an astrocytoma cell line challenged with mitochondrial DNA deletion
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DOI：
10.1007/s11064-007-9380-3
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发表时间：
2007-11-01
影响因子：
4.4
通讯作者：
Lai, James C. K.
中科院分区：
文献类型：
--
作者：
Isaac, Alfred Orina;Dukhande, Vikas V.;Lai, James C. K.
氧化应激可导致线粒体功能障碍、线粒体DNA(MtDNA)耗竭和神经变性，尽管其潜在机制尚不清楚。线粒体保护细胞的主要抗氧化系统包括锰超氧化物歧化酶(MnSOD)、谷胱甘肽过氧化物酶(GPX)和谷胱甘肽(GSH)。为了研究线粒体DNA耗竭时抗氧化酶蛋白表达和线粒体的适应性变化，我们用溴化乙锭(EB，50 ng/ml)慢性处理U87星形细胞瘤细胞，使其线粒体DNA逐渐耗尽。细胞内MnSOD蛋白表达呈时间依赖性增加，而GPX蛋白表达呈时间依赖性下降。线粒体DNA的缺失也改变了GPX的靶向性或亚细胞分布，表明完整的线粒体DNA在线粒体基因组-核基因组信号/通讯中的重要性。细胞NADP(+)-ICDH活性也表现出明显的时间相关的增加，而其GSH含量下降。因此，我们的研究结果表明，提高MnSOD、GPX、NADP(+)-ICDH和GSH水平的干预措施可能会保护脑细胞免受氧化应激的影响。
Oxidative stress can induce mitochondrial dysfunction, mitochondrial DNA (mtDNA) depletion, and neurodegeneration, although the underlying mechanisms are poorly understood. The major mitochondrial antioxidant system that protects cells consists of manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx) and glutathione (GSH). To investigate the putative adaptive changes in antioxidant enzyme protein expression and targeting to mitochondria as mtDNA depletion occurs, we progressively depleted U87 astrocytoma cells of mtDNA by chronic treatment with ethidium bromide (EB, 50 ng/ml). Cellular MnSOD protein expression was markedly increased in a time-related manner while that of GPx showed time-related decreases. The mtDNA depletion also altered targeting or subcellular distribution of GPx, suggesting the importance of intact mtDNA in mitochondrial genome-nuclear genome signaling/communication. Cellular NADP(+)-ICDH activity also showed marked, time-related increases while their GSH content decreased. Thus, our findings suggest that interventions to elevate MnSOD, GPx, NADP(+)-ICDH, and GSH levels may protect brain cells from oxidative stress.