Mitochondrial DNA as a driver of inflammation via the cGAS-STING pathway

Mar 31, 2026Inflammation research : official journal of the European Histamine Research Society ... [et al.]

Mitochondrial DNA may trigger inflammation through the cGAS-STING immune pathway

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Abstract

Mitochondrial DNA can translocate into the cytoplasm and activate the cGAS-STING signaling pathway.

Activation of the cGAS-STING pathway by cytoplasmic mtDNA induces type I interferon production.
This signaling pathway is associated with the senescence associated secretory phenotype (SASP).
The mtDNA-cGAS-STING signaling axis may play a role in various inflammation-related conditions.
Challenges such as specificity and potential side effects of interventions targeting this axis remain to be addressed.
A deeper understanding of this signaling axis could lead to new therapeutic strategies for inflammation and aging-related diseases.

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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.

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Mitochondrial DNA as a driver of inflammation via the cGAS-STING pathway

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