mtDNA regulates cGAS-STING signaling pathway in adenomyosis

  • Free Radic Biol Med. 2024 Mar 15:216:80-88. doi: 10.1016/j.freeradbiomed.2024.03.012.
Kun Wang  1 ,  Yi Wen  2 ,  Xianyun Fu  3 ,  Shaobin Wei  4 ,  Shidan Liu  1 ,  Minmin Chen  1
Affiliations
  • 1. Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yi Chang, 443000, China; College of Medicine and Health Sciences, China Three Gorges University, Yi Chang, 443000, China.
  • 2. TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China; Department of Gynecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China.
  • 3. Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yi Chang, 443000, China; College of Medicine and Health Sciences, China Three Gorges University, Yi Chang, 443000, China. Electronic address: [email protected].
  • 4. TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China; Department of Gynecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China. Electronic address: [email protected].
PMID: 38494142 DOI: 10.1016/j.freeradbiomed.2024.03.012
Abstract

In various hyperproliferative disorders, damaged mitochondria can release mitochondrial DNA (mtDNA) into the cytoplasm, activating the cGAS-STING signaling pathway and subsequent immune imbalances. Our previous research has demonstrated that hypoxia plays a role in the development of adenomyosis (AM) by inducing mitochondrial dysfunction. However, the precise involvement of the cGAS-STING signaling pathway and mtDNA in AM remains unclear. Therefore, this study aims to investigate the relationship between mtDNA secretion, changes in the cGAS-STING signaling pathway, and the abnormal cellular proliferation observed in AM. We found the cGAS, STING, TBK1, p-TBK1, IRF3, and p-IRF3 proteins levels were significantly elevated in the tissues of patients with AM compared to the control group. Additionally, there was an increase in the expression of the pro-inflammatory cytokines IL-6 and IFN-α in the AM tissues. Hypoxia-induced an increase in the proliferation and migration abilities of endometrial stromal cells (ESCs), accompanied by the activation of the cGAS-STING signaling pathway and elevated levels of IFN-α. Furthermore, hypoxia promoted the leakage of mtDNA into the cytoplasm in AM ESCs, and the deletion of mtDNA reduced the activation of the cGAS-STING pathway. Moreover, knockdown of the STING gene inhibited the expression of TBK1, p-TBK1, IRF3, and p-IRF3 and suppressed the secretion of the inflammatory cytokines IL-6 and IFN-α. Furthermore, the migration and invasion abilities of AM ESCs were significantly diminished after STING knockdown. These findings provide valuable insights into the role of mtDNA release and the cGAS-STING signaling pathway in the pathogenesis of AM.

Keywords
Adenomyosis; cGAS-STING signaling; mtDNA.
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