Mitochondrial DNA (mtDNA) plays an important role in regulating mitochondrial homeostasis, transcription, cell metabolism, and drug sensitivity. Patterns and regulations of mtDNA methylation vary among cell types, species, functions, and diseases. High-resolution mtDNA methylation maps of human and animal mitochondrial genomes addressed that the light (L)-strand non-CpG methylation of mtDNA varied among species, developing stages, and ages. Of DNA methyltransferases, DNMT3A was a critical enzyme in the dynamic regulation of mtDNA regional methylation patterns and strand bias. Altered mtDNA methylations may regulate dynamic occurrences of pathogenic mtDNA mutations. The number and sites of control regions, involved enzymes, and regulators during mtDNA methylation may vary among cell types and diseases. Specific regulatory and functional networks associated with mtDNA methylation mainly include mtDNA, regulatory factors, methyltransferases, nucleotides, mt-rRNAs, and other epigenetic modifications. Those carry out precise functions and regulations of mtDNA methylation-associated network, interactions with genome DNA and other signal pathways, and decisive roles in patient phenomes. A breakthrough in mtDNA methylation-associated networks will be a crucial milestone in the journey of understanding mitochondrial function at a higher level and discovering new mitochondria-based biomarkers and therapeutic targets.
Keywords: Epigenetics; Methylation; Mitochondria; Mitochondrial DNA; Networks.