Faculty, Staff and Student Publications
Language
English
Publication Date
12-2-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-65845-2
PMID
41330919
PMCID
PMC12689632
PubMedCentral® Posted Date
12-2-2025
PubMedCentral® Full Text Version
Post-print
Abstract
We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.
Keywords
Humans, DNA Methylation, DNA, Mitochondrial, Female, Male, CpG Islands, Aged, Heteroplasmy, Genome-Wide Association Study, Cell Nucleus, HEK293 Cells, Epigenesis, Genetic, Epigenome, Mitochondria, Aged, 80 and over, Middle Aged, Cohort Studies
Published Open-Access
yes
Recommended Citation
Lai, Meng; Kim, Kyeezu; Zheng, Yinan; et al., "Epigenome-Wide Association Study of Nuclear DNA Methylation in Relation to Mitochondrial Heteroplasmy" (2025). Faculty, Staff and Student Publications. 1215.
https://digitalcommons.library.tmc.edu/uthsph_docs/1215