Hahn, Anne et al. (2021) International Worm Meeting "Mis-regulation of mtDNA 6mdA methylation causes enhanced oxidative stress and ageing in C. elegans"

Hahn, Anne, Onraet, Tessa, Zuryn, Steven, Dai, Chuan Yang, Hung, Grace Ching Ching, Ahier, Arnaud, Kirmes, Ina

[International Worm Meeting, 2021]

Cellular energy production, ion balance, innate immunity, and metabolite synthesis are heavily reliant on mitochondrial function, which is dependent on the transcription, replication and maintenance of the mitochondrial genome (mtDNA). Owing to the compartmentalization of mitochondria and the proteobacterial ancestry of mtDNA, regulatory mechanisms applicable to nuclear DNA are not compatible within mitochondria. The most prominent epigenetic modification on bacterial DNA is adenosine methylation (m6dA), which is associated with DNA repair and transcriptional regulation. Using multiple highly sensitive and sequence-specific assays, we detected m6dA modifications on the C. elegans mtDNA that were distributed throughout the genome and enriched within certain regions. We identified potential m6dA methyltransferases and demethylases in the C. elegans genome that localize to mitochondria, and when overexpressed, reduce growth rates and cause premature ageing. Our results suggest that mis-regulation of mitochondrial m6dA can perturb correct mtDNA expression resulting in mito-nuclear protein imbalance, enhanced oxidative stress production, and activation of the mitochondrial unfolded protein response. Importantly, we have discovered the presence of mtDNA m6dA in a wide range of animal and plant species suggesting that its existence and biological role may be evolutionarily conserved.