Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

Abstract

Background Mitochondrial 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. Methods To 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. Results Thirty-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. Conclusions These 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.

The genetic constituent of varicose vein pathogenesis as a key for future treatment option development

“…Recently, it was shown that mitochondrial DNA copy number (mtDNA-CN) was inversely associated with incident and prevalent cardiovascular disease outcomes in 21,870 participants from three independent cohorts [36] . Shortly after, in our laboratory, we found that mtDNA-CN was decreased in varicose vein vs. non-varicose vein tissue samples [37] . Then, Castellani et al [38] demonstrated across multiple independent cohorts that changes in mtDNA-CN influence nuclear DNA methylation at specific CpG loci and result in differential expression of specific genes that may impact human health and disease (namely, cardiovascular disease and all-cause mortality) via altered cell signaling [38] .…”

Mitochondrial DNA Methylation and Human Diseases

“…Moreover, mtDNA variants may have effects on the transcription of genes in the nuclear genome through epigenetic mechanisms, as the removal of mtDNA or changes in mtDNA haplogroups have been found to be associated with differences in nuclear DNA methylation levels [ 27 , 28 , 29 ], suggesting an important epigenetic interplay between the two genomes. Recently, it has also been observed that changes in the mtDNA copy number influence nuclear DNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling [ 30 ]. On the other hand, nuclear epigenetics modulates mitochondrial function, as many of the mitochondrial proteins are nuclear-encoded.…”

Mitochondrial DNA Copy Number and Developmental Origins of Health and Disease (DOHaD)

“…As shown in previous studies, the number of mtDNA copies in the peripheral blood decreases with age [ 38 ], and the decrease is negatively associated with age-related events, such as all-cause mortality [ 39 ]. In addition, mtDNA copy number loss is associated with cognitive function [ 40 ], cardiovascular diseases [ 41 ], and infectious morbidity and mortality in patients with chronic kidney disease [ 42 ]. Mitochondrial DNA depletion syndrome (MTDPS) refers to diseases in which the mtDNA copy number is reduced, and mitochondrial energy metabolism is impaired [ 43 ].…”