If there’s one thing we can all agree on, it’s that mitochondria are the powerhouse of the cell. Adding to this prowess is a new finding showing that the amount of mitochondrial DNA impacts nuclear DNA methylation and gene expression, ultimately influencing mortality and cardiovascular disease. While we’ve seen how mutant mitochondria can influence histone modifications, this report targets DNA methylation and adds to the epigenetic influence of mitochondria.
Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and may impact epigenetic changes to the genome. In their well-powered publication, the Arking Lab from Johns Hopkins University School of Medicine found more evidence of the might of mitochondria. Here’s what they found when applying methylation arrays to human cohorts and cell culture:
- In a discovery cohort EWAS, 34 independent CpGs associate with mitochondrial DNA copy number (mtDNA-CN)
- The neuroactive ligand-receptor interaction pathway is overrepresented
- Using a meta-analysis including three cohorts and two self-reported race groups, six CpGs robustly associate with mtDNA-CN
Then, to see if variation in mtDNA-CN causes the nuclear DNA methylation changes, the team used CRISPR-Cas9 to knock out the mitochondrial DNA replication regulator, TFAM, in cell culture.
- The TFAM knockout results in reduced mtDNA-CN, and three of the associated CpGs found in the human cohorts are also differentially methylated in cell culture
- Five genes near the three differentially methylated CpGs are differentially expressed in the knockout lines
- Mendelian randomization suggests that nuclear DNA methylation at these CpGs isn’t causative of changes in mtDNA-CN
Finally, since mtDNA-CN has been associated with aging-related diseases, these strong scientists set their sights on significant phenotype associations for each of their six CpGs. They found four of the six CpGs associate with prevalent coronary heart disease and cardiovascular disease, as well as all-cause mortality.
First author Christina Castellani concludes, “Our results show that one way that mitochondrial variation may influence disease is through regulation of nuclear gene expression via the modification of nuclear DNA methylation. These exciting results will form the basis of future research on how mitochondrial variation can influence complex diseases like cardiovascular disease.”
If you’re interested in being part of this powerhouse, the Castellani Lab will be opening at Western University in Canada in January 2021. See the might of this mitochondrial manuscript in Genome Medicine, September 2020.