The role of cytosolic mitochondrial DNA as a mitochondrial danger signal for stromal fibroblasts in forming the tumor-promoting microenvironment following radiation exposure.

Inflammation plays an essential role in detecting foreign pathogens, which triggers a defensive response, eliminates infected tissue and facilitates tissue repair. However, when acute inflammation progresses to chronic inflammation, it contributes to the development of diseases, such as cancer. Both the inflammatory response and gene mutations are key elements of radiation-induced carcinogenesis; however, the molecular mechanisms underlying the initiation of the inflammatory response following radiation have not been fully understood yet. We hypothesize that cytosolic mitochondrial DNA is a mediator of the inflammatory response in radiation-induced tumor microenvironment formation. Using normal human fibroblasts and mice, we recently demonstrated that radiation fragmented mitochondrial DNA, which was subsequently released into the cytoplasm. Unlike nuclear DNA, cytosolic mitochondrial DNA is considered foreign by the DNA sensor cyclic GMP-AMP synthase, cGAS, and triggers an immune response similar to that evoked by viral DNA. Thus, cytosolic mitochondrial DNA is a mediator of inflammation in various physiological and pathological contexts. In addition, mitochondrial DNA fragments are released into the extracellular matrix. Such mitochondrial danger signals generated by fibroblasts in response to radiation exposure contribute to inflammation. Here, this review discusses the manner in which mitochondrial danger signals alter the microenvironment of tissue stem cells, or the stem cell niche, and contributes to the formation of the tumor microenvironment. In addition, the mechanisms underlying radiation-induced carcinogenesis are addressed.