cDivision of Psychiatry and Behavioral Proteomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871 Japan.
Mitochondrial ALDH2 Deficiency as an Oxidative Stress
Article first published online: 12 JAN 2006
Annals of the New York Academy of Sciences
Volume 1011, Mitochondrial Pathogenesis: From Genes and Apoptosis to Aging and Disease pages 36–44, April 2004
How to Cite
OHTA, S., OHSAWA, I., KAMINO, K., Ando, F. and SHIMOKATA, H. (2004), Mitochondrial ALDH2 Deficiency as an Oxidative Stress. Annals of the New York Academy of Sciences, 1011: 36–44. doi: 10.1196/annals.1293.004
- Issue published online: 12 JAN 2006
- Article first published online: 12 JAN 2006
- aldehyde dehydrogenase;
- ethanol metabolism;
- Alzheimer's disease;
- oxidative stress;
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-ε4), 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-ε4 than in those without it. These results indicate that the ALDH2 deficiency is a risk factor for LOAD, acting synergistically with the APOE-ε 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.