A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans
A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans
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DOI：
10.1074/jbc.m104718200
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发表时间：
2001-11-09
影响因子：
4.8
通讯作者：
Ishii, N
中科院分区：
文献类型：
--
作者：
Senoo-Matsuda, N;Yasuda, K;Ishii, N
秀丽隐杆线虫mev-1（kn1）突变体在线粒体电子传递链复合体II的细胞色素b大亚基（Cyt-1/ceSDHC）中存在缺陷。我们之前已经证明，mev-1的突变会导致寿命缩短，并以依赖氧的方式快速积累老化标记物，如荧光材料和蛋白质羰基。然而，目前尚不清楚这种超敏反应是由外源性氧的直接毒性引起的，还是由线粒体来源的内源性活性氧的损伤引起的。在这里，我们报告了mev-1动物的重要生化变化，这些变化有助于解释它们在常氧条件下的异常：(i)线粒体超氧阴离子的过量产生；（ii）即使在大气氧气下，谷胱甘肽含量也会相互减少。此外，与野生型不同，mev-1线粒体产生的超氧阴离子水平在高氧条件下显著升高。一般情况下，众所周知，在电子传递系统中，超氧阴离子在配合物I和III处产生。我们的数据表明mev-1（kn1）突变增加了复合物II本身的超氧阴离子产生，而不是复合物I和III。mev-1突变体的乳酸水平也比野生型高2倍，表明乳酸酸中毒，这是人类线粒体疾病的标志。这些数据表明，Cyt-1/ceSDHC不仅在能量代谢中发挥重要作用，而且在超氧阴离子的产生中发挥重要作用，超氧阴离子是对大气氧敏感性的关键因素。
A mev-1(kn1) mutant of the nematode Caenorhabditis elegans is defective in the cytochrome b large subunit (Cyt-1/ceSDHC) in complex II of the mitochondrial electron transport chain. We have previously shown that a mutation in mev-1 causes shortened life span and rapid accumulation of aging markers such as fluorescent materials and protein carbonyls in an oxygen-dependent fashion. However, it remains unclear as to whether this hypersensitivity is caused by direct toxicity of the exogenous oxygen or by the damage of endogenous reactive oxygen species derived from mitochondria. Here we report important biochemical changes in mev-1 animals that serve to explain their abnormalities under normoxic conditions: (i) an overproduction of superoxide anion from mitochondria; and (ii) a reciprocal reduction in glutathione content even under atmospheric oxygen. In addition, unlike wild type, the levels of superoxide anion production from mev-1 mitochondria were significantly elevated under hyperoxia. Under normal circumstances, it is well known that superoxide anion is produced at complexes I and III in the electron transport system. Our data suggest that the mev-1(kn1) mutation increases superoxide anion production at complex II itself rather than at complexes I and III. The mev-1 mutant also had a lactate level 2-fold higher than wild type, indicative of lactic acidosis, a hallmark of human mitochondrial diseases. These data indicate that Cyt-1/ceSDHC plays an important role not only in energy metabolism but also in superoxide anion production that is critically involved in sensitivity to atmospheric oxygen.