Nuclear receptor corepressor SMRT regulates mitochondrial oxidative metabolism and mediates aging-related metabolic deterioration.
Nuclear receptor corepressor SMRT regulates mitochondrial oxidative metabolism and mediates aging-related metabolic deterioration.
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DOI：
10.1016/j.cmet.2010.11.007
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发表时间：
2010-12-01
期刊：
影响因子：
29
通讯作者：
Lee CH
中科院分区：
文献类型：
--
作者：
Reilly SM;Bhargava P;Liu S;Gangl MR;Gorgun C;Nofsinger RR;Evans RM;Qi L;Hu FB;Lee CH
转录辅阻遏物SMRT利用两个主要的受体相互作用结构域（RID 1和RID 2）通过表观遗传修饰介导核受体（NR）信号传导。这种相互作用的生理意义尚不清楚。我们发现SMRT的表达和它在过氧化物酶体增殖物激活受体（PPAR）靶基因启动子上的占有率随着年龄的增长而增加。选择性禁用RID 1（SMRTmRID 1）的遗传操作表明，将SMRT抑制转移到RID 2相关的NR，特别是PPARs，会导致早衰和相关的代谢疾病，伴随着线粒体功能和抗氧化基因表达的降低。SMRTmRID 1细胞表现出对氧化损伤的敏感性增加，这可以通过PPAR激活或抗氧化剂治疗来挽救。在音乐会上，几个人类SMRT基因多态性被发现名义上与2型糖尿病和脂联素水平。这些数据揭示了SMRT在线粒体氧化代谢和衰老过程中的作用，这可能是改善健康寿命的药物靶点。
The transcriptional co-repressor SMRT utilizes two major receptor interacting domains (RID1 and RID2) to mediate nuclear receptor (NR) signaling through epigenetic modification. The physiological significance of such interaction remains unclear. We find SMRT expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Genetic manipulations to selectively disable RID1 (SMRTmRID1) demonstrate that shifting SMRT repression to RID2-associated NRs, notably PPARs, causes premature aging and related metabolic diseases accompanied by reduced mitochondrial function and anti-oxidant gene expression. SMRTmRID1 cells exhibit increased susceptibility to oxidative damage, which could be rescued by PPAR activation or anti-oxidant treatment. In concert, several human SMRT gene polymorphisms are found to nominally associate with type 2 diabetes and adiponectin levels. These data uncover a role for SMRT in mitochondrial oxidative metabolism and the aging process, which may serve as a drug target to improve health span.
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