BACKGROUND: Mitochondrial DNA (mtDNA), acting as a critical damage associated molecular pattern (DAMP), can translocate into the cytoplasm and directly activate the cGAS-STING signaling pathway. This activation induces the production of type I interferons and senescence associated secretory phenotype (SASP), positioning mtDNA as a key regulator of both inflammation and cellular senescence, namely mtDNA-cGAS-STING signaling axis.
MAIN TEXT: Here, we summarize the molecular mechanisms by which cytoplasmic escape of mtDNA and activation of the cGAS-STING pathway trigger a series of downstream cascade reactions. In addition, we discuss the role of the mtDNA-cGAS-STING axis in various inflammation-related pathologies, including ocular diseases, neurodegenerative disorders, pulmonary inflammation, cardiovascular diseases, and oral diseases.
CONCLUSIONS: Although interventions targeting the mtDNA-cGAS-STING signaling axis have shown promise in preclinical models, challenges regarding specificity, targeted delivery, and potential side effects remain and require further investigation before clinical translation. A deeper mechanistic understanding of the mtDNA-cGAS-STING axis may provide innovative therapeutic strategies for managing inflammation and aging-associated diseases.
Longevity & Aging