Epigenetic marks on nuclear DNA, such as DNA methylation, control the expression of specific genes, and thus the mix of proteins being manufactured by a cell, and thus the behavior of that cell. Epigenetic marks are added and removed constantly in response to changing circumstances inside and outside a cell, and differ between cell types, but some of these marks are quite characteristic of the altered environment of an aged tissue. So much so that epigenetic clocks have been established to produce quite accurate assessments of chronological age, and more importantly biological age, a representation of the burden of molecular damage and cellular dysfunction produced by aging.
A sizable minority of the research community sees epigenetic change as an evolved program, a fundamental cause of aging. A more mainstream view is that epigenetic change is a downstream consequence of deeper causes, various forms of molecular damage to cells and tissues that lead to an altered signaling environment. Some of these epigenetic changes are adaptive and helpful, some maladaptive and harmful. The question of how specific mechanisms and damage cause age-related epigenetic change remains largely open, however. Much of cellular biology remains a poorly explored maze of relationships and mechanisms; there are many, many epigenetic marks to investigate, and only so many researchers in the world.
Some progress has been made towards demonstrating that at least some age-related epigenetic alterations are an unfortunate side-effect of repeated cycles of repair of double strand breaks in DNA. Along the same lines, in today's open access paper, researchers provide evidence for some epigenetic alteration to be driven by loss of mitochondrial function in aging tissues. Mitochondria are the power plants of the cell, involved in many fundamental cellular processes, but their activity declines throughout the body with age. Research into this manifestation of aging, important in numerous age-related conditions, suggests that loss of mitochondrial function results from altered mitochondrial dynamics, an imbalance of fusion and fission of mitochondria that makes it harder for cells to remove and replace damaged mitochondria. That imbalance is in turn is caused by changes in protein levels related to fusion and fission - and those protein levels are controlled by epigenetic marks determining production from their DNA blueprints. Many of the relationships in the cellular biochemistry of aging are two-way streets at the very least, and possibly more complex than that in detail.
Mitochondria are cytoplasmic organelles primarily responsible for cellular metabolism and have pivotal roles in many cellular processes, including aging, apoptosis, and oxidative phosphorylation. Dysfunction of the mitochondria has been associated with complex disease presentation including susceptibility to disease and severity of disease. Mitochondrial DNA copy number (mtDNA-CN), a measure of mitochondrial DNA (mtDNA) 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. mtDNA-CN estimates can be derived from DNA isolated from blood and is therefore a relatively easily attainable biomarker of mitochondrial function. Cells with reduced mtDNA-CN show reduced expression of vital complex proteins, altered cellular morphology, and lower respiratory enzyme activity. Variation in mtDNA-CN has been associated with numerous diseases and traits, including cardiovascular disease, chronic kidney disease, diabetes, and liver disease. Lower mtDNA-CN has also been found to be associated with frailty and all-cause mortality.
Communication between the mitochondria and the nucleus is bi-directional and it has long been known that crosstalk between nuclear DNA (nDNA) and mtDNA is required for proper cellular functioning and homeostasis. However, the precise relationship between mtDNA and the nuclear epigenome has not been well defined despite a number of reports which have identified a relationship between mitochondria and the nuclear epigenome. For example, mtDNA polymorphisms have been previously demonstrated to be associated with nDNA methylation patterns. Further, mtDNA-CN has been previously associated with changes in nuclear gene expression.
Thus, gene expression changes identified as a result of mitochondrial variation may be mediated, at least in part, by nDNA methylation. Further, given that it has been well-established that mtDNA-CN influences a number of human diseases, we propose that one mechanism by which mtDNA-CN influences disease may be through regulation of nuclear gene expression via the modification of nDNA methylation. To this end, we report the results of cross-sectional analysis of this association between mtDNA-CN and nDNA methylation in 5035 individuals from the Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) cohorts.
Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance. Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance. 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. 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.