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

BACKGROUND: Cerebral 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...

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Detalles Bibliográficos
Autores principales: Zhang, Jiewen, Shang, Junkui, Wang, Fengyu, Huo, Xuejing, Sun, Ruihua, Ren, Zhixia, Wang, Wan, Yang, Miaomiao, Li, Gai, Gao, Dandan, Liu, Ruijie, Bai, Pingping, Wang, Shuyi, Wang, Yanliang, Yan, Xi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725280/
https://www.ncbi.nlm.nih.gov/pubmed/34983647
http://dx.doi.org/10.1186/s13148-021-01225-z
Descripción
Sumario:BACKGROUND: Cerebral 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. METHODS: Overall, 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. RESULTS: We 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. CONCLUSION: Decreased 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-021-01225-z.