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.
Biochem Biophys Res Commun. 2011 Jan 7;404(1):400-6. doi: 10.1016/j.bbrc.2010.11.131. Epub 2010 Dec 3.
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.
衰老过程是由活性氧引起的有害损伤引起的，特别是各种代谢性醛。醛脱氢酶 2（ALDH2）是在氧化条件下解毒各种醛的代谢酶之一。AMP 激活的蛋白激酶（AMPK）在控制代谢过程中起着关键作用。然而，在氧化条件下，ALDH2 与 AMPK 之间的关系知之甚少。在这里，我们使用 MDA 特异性单克隆抗体，筛选了年轻和老年大鼠的组织，以筛选 MDA 修饰的蛋白质，并在老年大鼠肾脏组织中鉴定出 ALDH2 作为 MDA 修饰的突出蛋白带。ALDH2 与 AMPK 结合并被 AMPK 磷酸化。此外，AMP 激活的蛋白激酶激活剂 AICAR 诱导 ALDH2 的核转位。核内的 ALDH2 通过与组蛋白去乙酰化酶结合参与一般转录抑制。此外，MDA 修饰抑制了 ALDH2 的易位和与 AMPK 的结合，并最终导致报告基因系统分析中转录的去抑制。在这项研究中，我们证明 ALDH2 作为一种转录抑制剂，对 AMPK 激活作出反应，MDA 修饰 ALDH2 并抑制一般转录中的 ALDH2 的抑制活性。因此，我们认为衰老过程中 MDA 含量的增加可能会中断由 AMPK 调节的 ALDH2 的核功能。
