Chapter title |
Mitochondrial ALDH2 deficiency as an oxidative stress.
|
---|---|
Chapter number | 4 |
Book title |
Mitochondrial Pathogenesis
|
Published in |
Annals of the New York Academy of Sciences, May 2004
|
DOI | 10.1007/978-3-662-41088-2_4 |
Pubmed ID | |
Book ISBNs |
978-1-57331-491-6, 978-3-66-241088-2
|
Authors |
Ohta S, Ohsawa I, Kamino K, Ando F, Shimokata H, Ohta, Shigeo, Ohsawa, Ikuroh, Kamino, Kouzin, Ando, Fujiko, Shimokata, Hiroshi |
Abstract |
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in ethanol metabolism. It is involved in acetaldehyde detoxification. A polymorphism of the ALDH2 gene is specific to North-East Asians. Sensitivity to ethanol is highly associated with this polymorphism (ALDH2(*)2 allele), which is responsible for a deficiency of ALDH2 activity. We first show that this deficiency influences the risk for late-onset Alzheimer's disease (LOAD) by a case-control study in a Japanese population. In a comparison of 447 patients with sex, age, and region-matched non-demented controls, the genotype frequency for the ALDH2(*)2 allele was significantly higher in the patients than in the controls (P=0.001). Next, we examined the combined effect of the ALDH2(*)2 and the apolipoprotein E4 allele (APOE-epsilon4), which has been confirmed to be a risk factor for LOAD. The ALDH2(*)2 allele more significantly affected frequency and age at onset in patients with APOE-epsilon4 than in those without it. These results indicate that the ALDH2 deficiency is a risk factor for LOAD, acting synergistically with the APOE-epsilon allele. Next, to elucidate the molecular mechanism involved, we obtained ALDH2-deficient cell lines by introducing mouse mutant ALDH2 cDNA into PC12 cells. We speculate that ALDH2 may act to oxidize toxic aldehyde derivatives. Then, we found that the ALDH2-deficient transfectants were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative generated from peroxidized fatty acids. 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. Mitochondrial ALDH2 functions as a protector against oxidative stress. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United States | 1 | 8% |
Canada | 1 | 8% |
Unknown | 11 | 85% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 4 | 31% |
Researcher | 3 | 23% |
Student > Master | 2 | 15% |
Other | 1 | 8% |
Professor > Associate Professor | 1 | 8% |
Other | 1 | 8% |
Unknown | 1 | 8% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 9 | 69% |
Nursing and Health Professions | 2 | 15% |
Medicine and Dentistry | 1 | 8% |
Unknown | 1 | 8% |