2. Academic Validation
  3. Ionizing radiation triggers the release of mitochondrial DNA into the cytosol as a signal of mitochondrial damage

Ionizing radiation triggers the release of mitochondrial DNA into the cytosol as a signal of mitochondrial damage

  • Sci Rep. 2025 Jul 2;15(1):23191. doi: 10.1038/s41598-025-04845-0.
Tsutomu Shimura 1,  Yui Takahashi 2,  Chihiro Saito 2,  Riko Maida 2,  Megumi Sasatani 3,  Tatsuki Kunoh 4,  Akira Ushiyama 5
Affiliations

Affiliations

  • 1 Department of Environmental Health, National Institute of Public Health, 2-3-6 Minami, Wako, 351-0197, Saitama, Japan. simura.t.aa@niph.go.jp.
  • 2 Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, 204-8588, Tokyo, Japan.
  • 3 Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, 734-8553, Japan.
  • 4 Microbial and Genetic Resources Research Group, National Institute of Advanced Industrial Science and Technology, Tsukuba, 305-8566, Ibaraki, Japan.
  • 5 Department of Environmental Health, National Institute of Public Health, 2-3-6 Minami, Wako, 351-0197, Saitama, Japan.
PMID: 40603988 DOI: 10.1038/s41598-025-04845-0
Abstract

Inflammatory responses are crucial for repairing radiation-induced tissue damage. Excessive tissue remodeling in response to severe tissue injury causes chronic inflammation associated with various diseases including Cardiovascular Disease and Cancer. Fibroblasts are major components of the stroma and play key roles in tissue remodeling. However, causes of inflammatory response activation remain unclear. This study focused on cytosolic mitochondrial DNA (mtDNA) release and its role in inflammation following irradiation. Cytosolic mtDNA leakage increased 3 h after irradiation of normal human fibroblasts and persisted for at least 7 days. H2O2 treatment of fibroblasts increased Reactive Oxygen Species (ROS) levels, the number of cytosolic DNA per cell, and the number of senescent cells, indicating that ROS trigger cytosolic DNA release in association with cellular senescence. The cytosolic mtDNA was then recognized by the DNA sensor Cyclic GMP-AMP Synthase (cGAS), activating the cGAS/stimulator of interferon genes (STING) signaling pathway. DNA-PK and AMPK inhibitors prevented cytosolic mtDNA release and its colocalization with cGAS following irradiation. Cytosolic and extracellular mtDNA release was also induced in mouse upon whole-body irradiation. Our results demonstrated that mitochondrial damage signals spread throughout the body via exosomes or as cell-free DNA. Released mtDNA act as danger signals that trigger inflammation.

Keywords

Cytosolic DNA; Exosome; Mitochondrial DNA; Radiation; cGAS.

Figures
Products