The role of reactive oxygen species and mitochondria in human neuromusclar diseases.

为了深入了解氧化损伤在线粒体DNA （mtDNA）突变或生理衰老过程中引起的人类疾病中的作用，我们研究了携带正常mtDNA （p^+）、缺乏mtDNA （p^0）或携带线粒体tRNA基因突变（syn^-）的培养细胞系对高浓度氧气环境（氧应激）的易感性和mtDNA的氧化损伤，这些细胞系负责人类神经肌肉疾病。线粒体肌病、脑病、乳酸酸中毒和卒中样发作（MELAS）或肌阵挛性癫痫与红纤维褴褛（MERRF）综合征相关。与亲本p +细胞相比，这些syn -细胞系对氧胁迫具有更高的易感性，并表现出更高的羟基自由基生成。在syn^-细胞中，与亲本p^+细胞中较少数量的mtdna缺失相比，证实了大量缺失mtdna的积累。这些体外培养研究表明，有缺陷的呼吸链对mtDNA的氧化损伤可能是决定mtDNA突变或衰老引起的人类疾病中细胞死亡的潜在分子机制。

To gain an insight into the role of oxidative damages in the human diseases caused by mitochondrial DNA (mtDNA) mutations or during the physiological aging process, we have investigated the vulnerability to a high concentration of oxygen atmosphere (oxygen stress) and the oxidative damage to mtDNA in cultured cell lines carrying normal mtDNA (p^+), lacking mtDNA (p^0), or harboring mitochondrial tRNA gene mutations (syn^-) which are responsible for human neuromuscular disorders : mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) or myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome. These syn^- cell lines possessed higher vulnerability to the oxygen stress and exhibited higher production of hydroxyl radical than the parental p^+ cells. In the syn^- cells, extensive accumulation of deleted mtDNAs was demonstrated, compared with a smaller number of deleted mtDNAs in the parental p^+ cell. These in vitro culture studies demonstrate that the oxidative damage to mtDNA by the defective respiratory chain can be an underlying molecular mechanism in determining the cell death in human diseases caused by mtDNA mutations, or in aging.