Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction
Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction
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DOI：
10.1016/j.bbadis.2018.01.018
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发表时间：
2018-04-01
影响因子：
6.2
通讯作者：
Kotamraju, Srigiridhar
中科院分区：
文献类型：
--
作者：
Karnewar, Santosh;Neeli, Praveen Kumar;Kotamraju, Srigiridhar
内皮细胞衰老与线粒体功能障碍共同协调年龄相关性心血管疾病。在本研究中，我们研究了这两个过程之间的因果关系，并研究了二甲双胍通过增强线粒体生物发生/功能来协调延迟内皮衰老的分子机制。AMPK激活剂二甲双胍和AICAR通过SIRT 1介导的DOT 1 L上调延迟内皮衰老，导致H3 K79（H3 K79 me 3）的三甲基化增加。用siAMPK或siSIRT 1处理细胞抑制DOT 1 L介导的H3 K79 me 3增强。此外，AMPK激活剂引起的SIRT 3表达和线粒体生物发生/功能的增加是H3 K79 me依赖性的，因为H3 K79 N突变体或siDOT 1 L消除了这些作用。这通过在具有AMPK活化的SIRT 3启动子中H3 K79 me 3的富集来证实。有趣的是，SIRT 3通过AMPK激活增强PGC-1 α表达是增加hTERT表达和延迟内皮衰老的原因。与此相反，SIRT 3敲低引起氧化应激和过早衰老，可能是通过消耗hTERT表达。此外，长期低剂量二甲双胍给药可显著减轻ApoE（-/-）小鼠的血管老化并抑制年龄相关动脉粥样硬化斑块形成。总体而言，本研究的结果表明，H3 K79 me通过SIRT 3作用对线粒体生物发生/功能和细胞衰老进行了新的调节，从而为二甲双胍介导的延缓衰老作用提供了分子基础。
Endothelial senescence in conjunction with mitochondrial dysfunction orchestrates age-associated cardiovascular disorders. In this study we investigated the causal link between these two processes and studied the molecular mechanisms by which metformin acts to coordinate the delay of endothelial senescence via enhancing mitochondrial biogenesis/function. AMPK activators metformin and AICAR delayed endothelial senescence via SIRT1-mediated upregulation of DOT1L, leading to increased trimethylation of H3K79 (H3K79me3). Treatment of cells with either siAMPK or siSIRT1 repressed DOT1L-mediated enhancement of H3K79me3. Moreover, the increase in SIRT3 expression and mitochondrial biogenesis/function by AMPK activators was H3K79me-dependent as H3K79N mutant or siDOT1L abrogated these effects. This was confirmed by the enrichment of H3K79me3 in the SIRT3 promoter with AMPK activation. Intriguingly, enhanced PGC-1 alpha expression by SIRT3 via AMPK activation was responsible for increased hTERT expression and delayed endothelial senescence. In contrast, SIRT3 knockdown caused increased oxidative stress and premature senescence, possibly by depleting hTERT expression. Furthermore, a chronic low dose administration of metformin significantly attenuated vascular aging and inhibited age-associated atherosclerotic plaque formation in ApoE(-/-) mice. Overall, the results of this study show a novel regulation of mitochondrial biogenesis/function, and cellular senescence by H3K79me acting through SIRT3, thus providing a molecular basis for metformin-mediated age-delaying effects.