Malondialdehyde inhibits an AMPK-mediated nuclear translocation and repression activity of ALDH2 in transcription.
Aging process results from deleterious damages by reactive oxygen species, in particular, various metabolic aldehydes. Aldehyde dehydrogenase 2 (ALDH2) is one of metabolic enzymes detoxifying various aldehydes under oxidative conditions. AMP-activated protein kinase (AMPK) plays a key role in controlling metabolic process. However, little was known about the relationship of ALDH2 with AMPK under oxidative conditions. Here, we, by using MDA-specific monoclonal antibody, screened the tissues of young and old rats for MDA-modified proteins and identified an ALDH2 as a prominent MDA-modified protein band in the old rat kidney tissue. ALDH2 associates with AMPK and is phosphorylated by AMPK. In addition, AICAR, an activator of AMP-activated protein kinase, induces the nuclear translocation of ALDH2. ALDH2 in nucleus is involved in general transcription repression by association with histone deacetylases. Furthermore, MDA modification inhibited the translocation of ALDH2 and the association with AMPK, and ultimately led to de-repression of transcription in the reporter system analysis. In this study, we have demonstrated that ALDH2 acts as a transcriptional repressor in response to AMPK activation, and MDA modifies ALDH2 and inhibits repressive activity of ALDH2 in general transcription. We thus suggest that increasing amount of MDA during aging process may interrupt the nuclear function of ALDH2, modulated by AMPK.
Department of Biomedical Sciences and Biochemistry and Molecular Biology, Seoul National University College of Medicine, 28 Yongon-dong, Chongro-gu, Seoul 110-799, Republic of Korea.
Ji-Woong
JW
Choi
Jae-Hwan
JH
Kim
Sung-Chun
SC
Cho
Moon-Kyung
MK
Ha
Kye-Yong
KY
Song
Hong-Duk
HD
Youn
Sang Chul
SC
Park
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology*; D005260:Female; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D008315:Malondialdehyde / Q000032:analysis / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D024101:Mitochondrial Proteins; D012097:Repressor Proteins; D008315:Malondialdehyde; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D055372:AMP-Activated Protein Kinases; D006655:Histone Deacetylases