Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes

Abstract

Mitochondria are controlled by the coordination of two genomes: the mitochondrial and the nuclear DNA. As such, variations in nuclear gene expression as a consequence of mutations and epigenetic modifications can affect mitochondrial functionality. Conversely, the opposite could also be true. However, the relationship between mitochondrial dysfunction and epigenetics, such as nuclear DNA methylation, remains largely unexplored. Mitochondria function as central metabolic hubs controlling some of the main substrates involved in nuclear DNA methylation, via the one carbon metabolism, the tricarboxylic acid cycle and the methionine pathway. Here, we review key findings and highlight new areas of focus, with the ultimate goal of getting one step closer to understanding the genomic effects of mitochondrial dysfunction on nuclear epigenetic landscapes.

Keywords: DNA; DNA methylation; Haplogroups; Metabolism; Mitochondria; Nucleus.

Fig. 1

Interactions between DNA methylation and mitochondria. Arrows refer to different phenomena. (1) nDNAm: Nuclear DNA methylation impact on mitochondrial metabolism. (2) nDNA expression: Influence of nuclear gene expression on enzymes which may cause mtDNA methylation. (3) Metabolites: Effect of mitochondrial metabolites on nDNA methylation. (4) mtDNA SNPs: Burden of mtDNA mutations and haplogroups on nDNA methylation. Metabolites are presented in purple; DNA methylation sites are shown in yellow; DNA mutations are displayed in pink; orange refers to enzymes

Fig. 2

Metabolic processes tightly intertwined with DNA methylation. The yellow pathway refers to the folate cycle which mainly takes place in the mitochondria, and generates methionine. The red cycle is the methionine cycle which is important for the production of SAM in the cytoplasm. The blue network represents DNA methylation, and highlights the modification that happens on the genome, for example, in the nucleus. The transsulfuration pathway shown in green involves the irreversible transformation of homocysteine, leading to gluconeogenesis which takes place in the mitochondria, cytosol and the endoplasmic reticulum

Fig. 3

Interaction of Krebs cycle intermediates and AMPK with DNA methylation. Diagram shows how cytoplasmic glycolysis connects to the Krebs cycle, which occurs in the mitochondria. The latter affects the levels of TETs that are involved in DNA methylation, and which are regulated also by AMPK. AMPK modulates DNA methylation via DNMT directly and indirectly, and by interacting with the Krebs cycle. Different colours refer to the terms metabolic processes (green), DNA processes (purple), metabolites (blue), enzymes (yellow), proteins (red) and miRNA (black)