Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells
Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells
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DOI：
10.1046/j.1471-4159.2003.01619.x
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发表时间：
2003-03-01
影响因子：
4.7
通讯作者：
Ohta, S
中科院分区：
文献类型：
--
作者：
Ohsawa, I;Nishimaki, K;Ohta, S
线粒体乙醛脱氢酶2(ALDH2)在乙醛解毒中起重要作用。酒精敏感性与ALDH2的遗传缺陷有关。我们之前已经报道过，这种缺陷会影响迟发性阿尔茨海默病的风险。然而，这种缺陷对神经细胞的生物学影响还知之甚少。因此，我们将小鼠突变型ALDH2基因导入PC12细胞，获得了ALDH2基因缺失的细胞系。突变体ALDH2以显性负性方式抑制线粒体ALDH活性，但不抑制胞浆活性。由此产生的ALDH2缺陷的转染体非常容易受到外源4-羟基-2-壬烯醛的影响，这是一种由超氧化物与不饱和脂肪酸反应生成的醛衍生物。此外，ALDH2缺陷的转染体对抗霉素A诱导的氧化损伤很敏感，并伴有4-羟基-2-壬烯醛修饰的蛋白质的积累。因此，这些发现表明，线粒体ALDH2对氧化应激具有保护作用。
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in acetaldehyde detoxification. The alcohol sensitivity is associated with a genetic deficiency of ALDH2. We have previously reported that this deficiency influences the risk for late-onset Alzheimer's disease. However, the biological effects of the deficiency on neuronal cells are poorly understood. Thus, we obtained ALDH2-deficient cell lines by introducing mouse mutant Aldh2 cDNA into PC12 cells. The mutant ALDH2 repressed mitochondrial ALDH activity in a dominant negative fashion, but not cytosolic activity. The resultant ALDH2-deficient transfectants were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative generated by the reaction of superoxide with unsaturated fatty acid. In addition, the ALDH2-deficient transfectants were sensitive to oxidative insult induced by antimycin A, accompanied by an accumulation of proteins modified with 4-hydroxy-2-nonenal. Thus, these findings suggest that mitochondrial ALDH2 functions as a protector against oxidative stress.