Mitochondrial genomic integrity and the nuclear epigenome in health and disease

Abstract

Bidirectional crosstalk between the nuclear and mitochondrial genomes is essential for proper cell functioning. Mitochondrial DNA copy number (mtDNA-CN) and heteroplasmy influence mitochondrial function, which can influence the nuclear genome and contribute to health and disease.Evidence shows that mtDNA-CN and heteroplasmic variation are associated with aging, complex disease, and all-cause mortality. Further, the nuclear epigenome may mediate the effects of mtDNA variation on disease. In this way, mitochondria act as an environmental biosensor translating vital information about the state of the cell to the nuclear genome.Cellular communication between mtDNA variation and the nuclear epigenome can be achieved by modification of metabolites and intermediates of the citric acid cycle and oxidative phosphorylation. These essential molecules (e.g. ATP, acetyl-CoA, ɑ-ketoglutarate and S-adenosylmethionine) act as substrates and cofactors for enzymes involved in epigenetic modifications.The role of mitochondria as an environmental biosensor is emerging as a critical modifier of disease states. Uncovering the mechanisms of these dynamics in disease processes is expected to lead to earlier and improved treatment for a variety of diseases. However, the influence of mtDNA-CN and heteroplasmy variation on mitochondrially-derived epigenome-modifying metabolites and intermediates is poorly understood. This perspective will focus on the relationship between mtDNA-CN, heteroplasmy, and epigenome modifying cofactors and substrates, and the influence of their dynamics on the nuclear epigenome in health and disease.

Reduced mitochondrial DNA content correlate with poor clinical outcomes in cryotransfers with day 6 single euploid embryos

“…Evaluation of the relative mtDNA quantity lacks the evidence of gene integrity and functional assessment. Mitochondria display uniparental inheritance to reduce heteroplasmy, exhibiting a genetic bottleneck to prevent possible deleterious mutants in offspring ( 43 , 44 ). However, mtDNA has a higher mutation frequency due to the insufficient repairing system and higher oxidative stress, the effect derived from these heteroplasmic mitochondria involving de novo variants in early-stage embryos derived from women without inherited mitochondrial disease remained uncertain.…”

Mitochondrial DNA copy number reduction viain vitro TFAMknockout remodels the nuclear epigenome and transcriptome

“…These dynamics have also been found to be influenced by environmental stimuli [76]. It has been proposed that these environmental stimuli affect the bidirectional cross-talk between the mitochondrial and nuclear genome through several key mitochondrial metabolites [77]. Here, we identify biological pathways in relation to these associations and highlight key targets for further research.…”

Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions

“…Interestingly, the dynamic interplay between nuclear and mitochondrial genomes can also influence an organism's phenotype [26]. Using cultured cybrid cell lines harboring a mitochondrial tRNA Leu(UUR) mutation (A3243G), Kopinski et al [26] showed that heteroplasmy leads to diminished acetyl coA generation and concomitant alterations in histone acetylation (i.e., retrograde signaling; mitochondria to the nucleus) [27]. Heteroplasmy frequency has also been shown to play a role in the corresponding phenotype in humans, with low levels (20-30%) in the mitochondrial tRNA Leu(UUR) gene (A3243G) leading to the development of type 2 diabetes and high levels (80-90%) leading to deadly perinatal diseases [7].…”