Hypermethylation of mitochondrial DNA in vascular smooth muscle cells impairs cell contractility
Hypermethylation of mitochondrial DNA in vascular smooth muscle cells impairs cell contractility
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血管平滑肌细胞线粒体 DNA 的高甲基化损害细胞收缩性
DOI：
10.1038/s41419-020-2240-7
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发表时间：
2020-01-20
影响因子：
9
通讯作者：
Zhou, Jing
中科院分区：
文献类型：
--
作者：
Liu, Yue-Feng;Zhu, Juan-Juan;Zhou, Jing
动脉狭窄闭塞症患者的血管平滑肌细胞(SMC)以线粒体呼吸不足和细胞收缩功能丧失为特征。然而，SMC中线粒体基因和线粒体能量代谢的调控机制仍不清楚。在此，我们描述了DNA甲基转移酶1(DNMT1)在血小板衍生生长因子-BB(PDGF-BB)作用下移位到线粒体并催化血管内皮细胞线粒体DNA D-环甲基化。线粒体特异性表达的DNMT1抑制线粒体基因的表达，导致功能损伤，降低SMC的收缩能力。在血流停止或机械内皮损伤的小鼠颈动脉内膜中层，以及颈动脉闭塞性疾病患者的血管标本中，都检测到线粒体D-loop区域的高甲基化。同样，结扎的小鼠动脉显示DNMT1的线粒体结合增强，线粒体基因表达受抑，线粒体呼吸障碍，收缩能力受损。结扎血管的收缩功能受损可以通过DNMT1缺失的线粒体的体外移植恢复。综上所述，我们发现了DNMT1介导的线粒体D-loop甲基化在线粒体基因转录调控中的作用。在血管闭塞性疾病中，线粒体D-loop的甲基化是导致线粒体功能受损和收缩表型丧失的原因之一。
Vascular smooth muscle cell (SMC) from arterial stenotic-occlusive diseases is featured with deficiency in mitochondrial respiration and loss of cell contractility. However, the regulatory mechanism of mitochondrial genes and mitochondrial energy metabolism in SMC remains elusive. Here, we described that DNA methyltransferase 1 (DNMT1) translocated to the mitochondria and catalyzed D-loop methylation of mitochondrial DNA in vascular SMCs in response to platelet-derived growth factor-BB (PDGF-BB). Mitochondrial-specific expression of DNMT1 repressed mitochondrial gene expression, caused functional damage, and reduced SMC contractility. Hypermethylation of mitochondrial D-loop regions were detected in the intima-media layer of mouse carotid arteries subjected to either cessation of blood flow or mechanical endothelial injury, and also in vessel specimens from patients with carotid occlusive diseases. Likewise, the ligated mouse arteries exhibited an enhanced mitochondrial binding of DNMT1, repressed mitochondrial gene expression, defects in mitochondrial respiration, and impaired contractility. The impaired contractility of a ligated vessel could be restored by ex vivo transplantation of DNMT1-deleted mitochondria. In summary, we discovered the function of DNMT1-mediated mitochondrial D-loop methylation in the regulation of mitochondrial gene transcription. Methylation of mitochondrial D-loop in vascular SMCs contributes to impaired mitochondrial function and loss of contractile phenotype in vascular occlusive disease.