Mitochondrial DNA methylation and mitochondria-related epigenetics in neurodegeneration

Mitochondria are cytoplasmic organelles referred to as the powerhouse of the cell because they are primarily involved in oxidative phosphorylation and energy production. They are particularly abundant in tissues with high energy demands, including muscle, liver, and brain, and mitochondrial dysfunction, oxidative mitochondrial DNA (mtDNA) damage, and impaired mitochondrial dynamics have often been associated with neurodegeneration. The mtDNA is a circular, double-stranded molecule present in two to ten copies per mitochondrion and encodes 13 subunits of the mitochondrial respiratory chain as well as 22 transfer RNAs and two ribosomal RNAs. The existence of mitochondrial epigenetics, and in particular mtDNA methylation, has been largely debated, but a growing body of literature suggests that impaired mtDNA methylation may be involved in neurodegeneration (Coppedè and Stoccoro, 2019). Furthermore, there is increasing evidence for bidirectional crosstalk between the nuclear and mitochondrial genomes to allow coordinated gene expression in response to different cellular stressors. This crosstalk is mainly mediated by epigenetic mechanisms, but is unfortunately still poorly understood in neurodegenerative diseases (Coppedè, 2021). In this perspective, after a brief description of the available literature on impaired mtDNA methylation in neurodegenerative diseases, the author discusses the potential factors contributing to these alterations and their crosstalk with nuclear epigenetics.