Mitochondrial DNA and other cellular nucleic acids (mtDNA/nDNA)

Mitochondrial DNA (mtDNA) and other cellular nucleic acids, such as nuclear DNA (nDNA) and various RNA species, are the primary repositories of genetic information and essential templates for protein synthesis within eukaryotic cells (Alberts B, et al., Molecular Biology of the Cell, 2014). While nDNA is sequestered in the nucleus, mtDNA resides within the mitochondria and is particularly susceptible to oxidative damage due to its proximity to the electron transport chain (West AP, Shadel GS, Nat Rev Immunol, 2017). In therapeutic contexts, these nucleic acids are the direct targets of many anti-cancer drugs, including alkylating agents and intercalators, which disrupt DNA integrity to trigger programmed cell death (Dasari S, Tchounwou PB, Eur J Pharmacol, 2014). Furthermore, the release of mtDNA or nDNA into the cytoplasm acts as a danger signal or Damage-Associated Molecular Pattern (DAMP), activating innate immune pathways like the cGAS-STING axis, which is increasingly targeted for treating inflammatory and autoimmune disorders (Hopfner KP, Hornung V, Nat Rev Mol Cell Biol, 2020). However, off-target damage to mtDNA by certain antibiotics and chemotherapeutics can lead to significant toxicities, such as mitotoxicity and organ failure (Kalghatgi S, et al., Sci Transl Med, 2013).

Other names

Mitochondrial DNANuclear DNACytosolic DNAGenomic DNACellular nucleic acidsDamage-associated molecular patterns (DAMPs)

Drugs interact with these nucleic acids through covalent adduct formation, intercalation, or oxidative damage, leading to the inhibition of replication and transcription, or by acting as ligands for pattern recognition receptors when released into the cytosol (Dasari S, Tchounwou PB, Eur J Pharmacol, 2014; West AP, Shadel GS, Nat Rev Immunol, 2017).