Mitochondrial disease in mouse results in increased oxidative stress
Mitochondrial disease in mouse results in increased oxidative stress
复制标题
DOI：
10.1073/pnas.96.9.4820
复制
发表时间：
1999-04-27
影响因子：
11.1
通讯作者：
Wallace, DC
中科院分区：
文献类型：
--
作者：
Esposito, LA;Melov, S;Wallace, DC
据推测，氧化磷酸化缺陷（OXPHOS）导致线粒体疾病进展的一个主要因素是线粒体产生活性氧（ROS）的刺激以及由此导致的mtDNA损伤。为了验证这一假设，我们检测了缺乏腺嘌呤核苷酸转位子（Ant1）心脏/肌肉异构体的小鼠的线粒体，命名为An1(tm2Mgr)（-/-）小鼠。Anti的缺失阻断了ADP和ATP在线粒体内膜上的交换，从而抑制了OXPHOS。与Anti的表达一致，从ant1缺陷小鼠的骨骼肌、心脏和大脑中分离的线粒体产生了明显增加的ROS过氧化氢，而表达不同Ant亚型的肝脏线粒体产生了正常低水平的过氧化氢。骨骼肌和心脏产生ROS的增加与肌肉组织和肌肉线粒体中ROS解毒酶锰超氧化物歧化酶（Sod2，也称为MnSod）的急剧增加有关，心脏组织中Sod2的适度增加，心脏线粒体中不增加，两组织线粒体中第二种ROS解毒酶谷胱甘肽过氧化物酶-1 （Gpx1）的水平适度增加。与心脏中较低的抗氧化防御一致，ant1缺陷小鼠的心脏mtDNA重排的积累显著增加，而具有较高抗氧化防御的骨骼肌的mtDNA重排较少。因此，抑制OXPHOS确实会增加线粒体ROS的产生，引发抗氧化防御。如果抗氧化防御不足以解毒ROS，则会导致mtDNA突变率增加。
It has been hypothesized that a major factor in the progression of mitochondrial disease resulting from defects in oxidative phosphorylation (OXPHOS) is the stimulation of the mitochondrial production of reactive oxygen species (ROS) and the resulting damage to the mtDNA. To test this hypothesis, we examined the mitochondria from mice lacking the heart/muscle isoform of the adenine nucleotide translocator (Ant1), designated An1(tm2Mgr) (-/-) mice. The absence of Anti blocks the exchange of ADP and ATP across the mitochondrial inner membrane, thus inhibiting OXPHOS, Consistent with Anti expression, mitochondria isolated from skeletal muscle, heart, and brain of the Ant1-deficient mice produced markedly increased amounts of the ROS hydrogen peroxide, whereas liver mitochondria, which express a different Ant isoform, produced normally low levels of hydrogen peroxide, The increased production of ROS by the skeletal muscle and heart was associated with a dramatic increase in the ROS detoxification enzyme manganese superoxide dismutase (Sod2, also known as MnSod) in muscle tissue and muscle mitochondria, a modest increase in Sod2 in heart tissue, and no increase in heart mitochondria, The level of glutathione peroxidase-1 (Gpx1), a second ROS detoxifying enzyme, was increased moderately in the mitochondria of both tissues. Consistent with the lower antioxidant defenses in heart, the heart mtDNAs of the Ant1-deficient mice showed a striking increase in the accumulation of mtDNA rearrangements, whereas skeletal muscle, with higher antioxidant defenses, had fewer mtDNA rearrangements. Hence, inhibition of OXPHOS does increase mitochondrial ROS production, eliciting antioxidant defenses, If the antioxidant defenses are insufficient to detoxify the ROS, then an increased mtDNA mutation rate can result.