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

Xingyue Wen1,2, Fan Yang3, Lan Zhang4,5

  • 1State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Chengdu, 610041, Sichuan Province, China.

Inflammation Research : Official Journal of the European Histamine Research Society ... [Et Al.]
|March 31, 2026
PubMed
Abstract

Insights

Mitochondrial DNA (mtDNA) in the cytoplasm activates the cGAS-STING pathway, driving inflammation and cellular senescence. Understanding this mtDNA-cGAS-STING axis offers therapeutic potential for inflammatory and aging-related diseases.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cellular Biology

Background:

  • Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern (DAMP).
  • Cytoplasmic mtDNA activates the cGAS-STING signaling pathway.
  • This axis regulates type I interferons and cellular senescence (SASP).

Purpose of the Study:

  • To summarize the molecular mechanisms of mtDNA-induced cGAS-STING activation.
  • To discuss the role of the mtDNA-cGAS-STING axis in various pathologies.
  • To explore therapeutic potential for inflammation and aging.

Main Methods:

  • Literature review and synthesis of existing research.
  • Analysis of molecular pathways involved in mtDNA release and cGAS-STING activation.
  • Discussion of disease relevance and therapeutic strategies.

Main Results:

  • Cytoplasmic mtDNA triggers the cGAS-STING pathway, leading to downstream inflammatory and senescence responses.
  • The mtDNA-cGAS-STING axis is implicated in ocular, neurodegenerative, pulmonary, cardiovascular, and oral diseases.
  • Preclinical interventions show promise but face challenges in specificity and delivery.

Conclusions:

  • Targeting the mtDNA-cGAS-STING axis holds therapeutic promise for inflammatory and aging-related conditions.
  • Further research is needed to address challenges in clinical translation, including specificity and delivery.
  • A deeper mechanistic understanding can lead to novel therapeutic strategies.
Keywords:
AgingChronic inflammationMitochondrial DNAcGAS-STING signaling pathway

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