Mitochondrial DNA: cellular genotoxic stress sentinel

High copy number, damage prone, and lean on repair mechanisms are unique features of mitochondrial DNA (mtDNA) that are hard to reconcile with its essentiality for oxidative phosphorylation, the primary function ascribed to this maternally inherited component of our genome. We propose that mtDNA is also a genotoxic stress sentinel, as well as a direct second messenger of this type of cellular stress. Here, we discuss existing evidence for this sentinel/effector role through the ability of mtDNA to escape the confines of the mitochondrial matrix and activate nuclear DNA damage/repair responses via interferon-stimulated gene products and other downstream effectors. However, this arrangement may come at a cost, leading to cancer chemoresistance and contributing to inflammation, disease pathology, and aging.

Automated summary

Mitochondrial DNA (mtDNA) is characterized by high copy number, damage prone tendencies, and reliance on repair mechanisms, making it difficult to reconcile its essential role in oxidative phosphorylation. However, evidence suggests that mtDNA also serves as a genotoxic stress sentinel and a direct second messenger. It can escape the mitochondrial matrix to activate nuclear DNA damage/repair responses through interferon-stimulated gene products and other downstream effectors, potentially leading to cancer chemoresistance, inflammation, disease pathology, and aging.