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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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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 |
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author | 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 |
author_facet | 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 |
author_sort | Zhang, Jiewen |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8725280 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-87252802022-01-06 Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL 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 Clin Epigenetics Research 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. BioMed Central 2022-01-04 /pmc/articles/PMC8725280/ /pubmed/34983647 http://dx.doi.org/10.1186/s13148-021-01225-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research 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 Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL |
title | Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL |
title_full | Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL |
title_fullStr | Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL |
title_full_unstemmed | Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL |
title_short | Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL |
title_sort | decreased mitochondrial d-loop region methylation mediates an increase in mitochondrial dna copy number in cadasil |
topic | Research |
url | 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 |
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