Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells |
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Authors: | Ohsawa Ikuroh Nishimaki Kiyomi Yasuda Chie Kamino Kouzin Ohta Shigeo |
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Institution: | Department of Biochemistry and Cell Biology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nahakara-ku, Kawasaki 211-8533, Japan. |
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Abstract: | 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. |
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Keywords: | aldehyde dehydrogenase Alzheimer's disease 4-hydroxy-2-nonenal mitochondria oxidative stress |
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