Mitochondrial DNA methylation drift and postoperative delirium in mice
Mitochondrial DNA methylation drift and postoperative delirium in mice
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DOI：
10.1097/eja.0000000000001620
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发表时间：
2021-11
影响因子：
3.6
通讯作者：
Yue Liu;F. Song;Yan Yang;Shuai Yang;M. Jiang;Wei Zhang;Zhengliang Ma;X. Gu
中科院分区：
文献类型：
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作者：
Yue Liu;F. Song;Yan Yang;Shuai Yang;M. Jiang;Wei Zhang;Zhengliang Ma;X. Gu
线粒体功能障碍与术后谵妄（POD）的发病机制有关，这严重影响了接受手术的老年患者的预后。线粒体DNA（mtDNA）甲基化是一种调节线粒体结构和功能的新的和不完全描述的现象，与衰老有关。然而，线粒体DNA甲基化与POD的关系尚未建立。目的探讨线粒体表观遗传调控在过氧化物酶（POD）中的作用。设计：随机动物实验。对象：6月龄雄性C57 BL/6 N小鼠88只，18月龄雄性C57 BL/6 N小鼠176只。干预：采用1.4%异氟醚麻醉2 h诱导POD。在手术前24小时和手术后6、9和24小时进行行为测试。主要观察指标采用亚硫酸氢盐焦磷酸测序法检测6月龄和18月龄小鼠海马、前额叶皮质、杏仁核和前扣带皮质手术后线粒体基因组中位移环（D-loop）的5个CpG位点和编码基因位点的60个CpG位点的5-甲基胞嘧啶（5-mC）。应用电镜和真实的时间PCR检测线粒体结构、线粒体基因表达和线粒体DNA拷贝数，分析线粒体DNA甲基化与线粒体DNA甲基化的关系。结果手术后海马和前额皮质线粒体DNA甲基化漂移表现为D环甲基化水平降低和多个编码基因位点甲基化水平升高或降低，最终导致线粒体DNA拷贝数减少，线粒体基因表达改变，线粒体结构受损。沉默信息调节因子-1（SIRT 1）的激活通过调节mtDNA甲基转移酶介导的mtDNA甲基化来改善麻醉诱导和手术诱导的线粒体功能障碍和谵妄样行为。结论POD中存在线粒体DNA的表观遗传调控，但具体机制有待进一步研究。试验注册号20181204鼓楼医院。
Supplemental Digital Content is available in the text BACKGROUND Mitochondrial dysfunction is linked to the etiopathogenesis of postoperative delirium (POD), which severely affects the prognosis of elderly patients undergoing surgery. The methylation of mitochondrial DNA (mtDNA), a new and incompletely described phenomenon that regulates the structure and function of mitochondria, is associated with ageing. However, the relationship between mtDNA methylation and POD has not been established. OBJECTIVE To explore the potential roles of mitochondrial epigenetic regulation in POD. DESIGN A randomised animal study. PARTICIPANTS Eighty-eight 6-month-old and one hundred seventy-six 18-month-old male C57BL/6N mice. INTERVENTIONS POD was induced by abdominal surgery under 1.4% isoflurane for 2 h. Behavioural tests were performed at 24 h before surgery and at 6, 9 and 24 h after surgery. MAIN OUTCOME MEASURES 5-methylcytosine (5-mC) at five CpG sites of the displacement loop (D-loop) and at 60 CpG sites of coding gene loci in the mitochondrial genome after surgery of the hippocampus, prefrontal cortex, amygdala and anterior cingulate cortex in 6 and 18-month-old mice were detected using bisulfite pyrosequencing. Mitochondrial structure, mitochondrial gene expression and mtDNA copy number were also examined using Electron microscopy and real time PCR to find the association with mtDNA methylation. RESULTS The mtDNA methylation drift manifested as a decrease in the methylation levels at the D-loop and an increase or decrease in the methylation levels at several coding gene loci, ultimately resulting in reduced mtDNA copy numbers, altered mitochondrial gene expression and damaged mitochondrial structures in the hippocampus and prefrontal cortex after surgery. The activation of Silent information regulator-1 (SIRT1) ameliorated anaesthesia-induced and surgery-induced mitochondrial dysfunction and delirium-like behaviours by regulating mtDNA methyltransferase-mediated mtDNA methylation. CONCLUSION These data support the existence of epigenetic mtDNA regulation in POD; however, further studies are required to explore the specific mechanisms. TRIAL REGISTRATION No 20181204 Drum tower hospital.