Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide-mediated S-nitrosylation.
Mitochondrial aldehyde dehydrogenase (ALDH2) is responsible for the metabolism of acetaldehyde and other toxic lipid aldehydes. Despite many reports about the inhibition of ALDH2 by toxic chemicals, it is unknown whether nitric oxide (NO) can alter the ALDH2 activity in intact cells or in vivo animals. The aim of this study was to investigate the effects of NO on ALDH2 activity in H4IIE-C3 rat hepatoma cells. NO donors such as S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine, and 3-morpholinosydnonimine significantly increased the nitrite concentration while they inhibited the ALDH2 activity. Addition of GSH-ethylester (GSH-EE) completely blocked the GSNO-mediated ALDH2 inhibition and increased nitrite concentration. To directly demonstrate the NO-mediated S-nitrosylation and inactivation, ALDH2 was immunopurified from control or GSNO-treated cells and subjected to immunoblot analysis. The anti-nitrosocysteine antibody recognized the immunopurified ALDH2 only from the GSNO-treated samples. All these results indicate that S-nitrosylation of ALDH2 in intact cells leads to reversible inhibition of ALDH2 activity.
Moon
Kwan-Hoon
KH
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
Kim
Bong-Jo
BJ
Song
Byoung J
BJ
D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000906:Antibodies / Q000276:immunology; D003545:Cysteine / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009573:Nitrites / Q000032:analysis; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D024101:Mitochondrial Proteins; D020030:Nitric Oxide Donors; D009573:Nitrites; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D003545:Cysteine