Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL

Clinical Epigenetics

Shuyi Wang¹  Pingping Bai²  Yanliang Wang³  Junkui Shang⁴  Dandan Gao⁴  Ruihua Sun⁴  Wan Wang⁴  Jiewen Zhang⁴  Ruijie Liu⁴  Xuejing Huo⁴  Zhixia Ren⁴  Fengyu Wang⁴  Miaomiao Yang⁴  Gai Li⁴  Xi Yan⁴ 

[1] Department of General Practice, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, 450003, Zhengzhou, Henan, China;Department of Health Management, Henan Key Laboratory of Chronic Disease Management, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, 450003, Zhengzhou, Henan, China;Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, 450003, Zhengzhou, Henan, China;Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, 450003, Zhengzhou, Henan, China;

关键词: CADASIL;    Mitochondrial D-loop region;    Mitochondrial DNA copy number;    Methylation;   

DOI  :  10.1186/s13148-021-01225-z

来源: Springer

【 摘 要 】

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a typical neurodegenerative disease associated with mitochondrial dysfunction. Methylation of the D-loop region and mitochondrial DNA copy number (mtDNAcn) play a critical role in the maintenance of mitochondrial function. However, the association between D-loop region methylation, mtDNAcn and CADASIL remains unclear.MethodsOverall, 162 individuals were recruited, including 66 CADASIL patients and 96 age- and sex-matched controls. After extracting genomic DNA from the peripheral white blood cells, levels of D-loop methylation and mtDNAcn were assessed using MethylTarget sequencing and real-time PCR, respectively.ResultsWe observed increased mtDNAcn and decreased D-loop methylation levels in CADASIL patients compared to the control group, regardless of gender stratification. Besides, we found a negative correlation between D-loop methylation levels and mtDNAcn. Mediation effect analysis shows that the proportion of the association between mtDNAcn and CADASIL that is mediated by D-loop methylation is 11.6% (95% CI 5.6, 22.6). After gender stratification, the proportions of such associations that are mediated by D-loop methylation in males and females were 7.2% (95% CI 2.4, 19.8) and 22.0% (95% CI 7.4, 50.1), respectively.ConclusionDecreased methylation of the D-loop region mediates increased mtDNAcn in CADASIL, which may be caused by a compensatory mechanism of mitochondrial dysfunction in patients with CADASIL.

【 授权许可】

CC BY