Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells.
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.
Ohsawa
Ikuroh
I
Department of Biochemistry and Cell Biology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nahakara-ku, Kawasaki 211-8533, Japan.
Nishimaki
Kiyomi
K
Yasuda
Chie
C
Kamino
Kouzin
K
Ohta
Shigeo
S
D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D005799:Genes, Dominant; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy / Q000201:enzymology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
D000447:Aldehydes; D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D000968:Antimycin A; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C027576:4-hydroxy-2-nonenal