Abstract
BackgroundMitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.MethodsTo investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.ResultsThirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10− 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10− 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10− 12), as well as the TFAM knockout methylation (P = 4.41 × 10− 4) and expression (P = 4.30 × 10− 4) studies.ConclusionsThese results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
Highlights
Mitochondrial DNA copy number has been associated with a variety of aging-related diseases, including all-cause mortality
Mitochondrial DNA copy number, a measure of mitochondrial DNA levels per cell, while not a direct measure of mitochondrial function, is associated with mitochondrial enzyme activity and adenosine triphosphate production. mtDNA-CN is regulated in a tissue-specific manner and in contrast to the nuclear genome, is present in multiple copies per cell, with the number being highly dependent on cell type [3, 4]. mtDNA-CN estimates can be derived from DNA isolated from blood and is a relatively attainable biomarker of mitochondrial function
Results mtDNA-CN is associated with nuclear DNA methylation at independent genome-wide loci in cross-sectional analysis We performed an epigenome-wide association study (EWAS) in DNA derived from blood for 2507 individuals from the Atherosclerosis Risk in Communities (ARIC) study, comprised of 1567 African American (AA) and 940 European American (EA) subjects (Additional file 2: Table S1, Additional file 3: Table S2)
Summary
Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. The mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. MtDNA-CN is regulated in a tissue-specific manner and in contrast to the nuclear genome, is present in multiple copies per cell, with the number being highly dependent on cell type [3, 4]. Cells with reduced mtDNA-CN show reduced expression of vital complex proteins, altered cellular morphology, and lower respiratory enzyme activity [5]. Lower mtDNA-CN has been found to be associated with frailty and all-cause mortality [10]
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