Hypermethylation of mitochondrial DNA in vascular smooth muscle cells impairs cell contractility

Yue Feng Liu, Juan Juan Zhu, Xiao Yu Tian, Han Liu, Tao Zhang, Yun Peng Zhang, Si An Xie, Ming Zheng, Wei Kong, Wei Juan Yao, Wei Pang, Chuan Rong Zhao, Yuan Jun Tang, Jing Zhou

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Article number35
JournalCell Death and Disease
Volume11
Issue number1
DOIs
StatePublished - 1 Jan 2020
Externally publishedYes

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