Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice
Mitochondrion is an important organelle of eukaryotic cells and a critical target of ionizing radiation (IR) outside the nucleus. The biological significance and mechanism of the non-target effect originating from mitochondria have received much attention in the field of radiation biology and protec...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/4020 |
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| author | Hua Guan Wen Zhang Dafei Xie Yuehua Nie Shi Chen Xiaoya Sun Hongling Zhao Xiaochang Liu Hua Wang Xin Huang Chenjun Bai Bo Huang Pingkun Zhou Shanshan Gao |
| author_facet | Hua Guan Wen Zhang Dafei Xie Yuehua Nie Shi Chen Xiaoya Sun Hongling Zhao Xiaochang Liu Hua Wang Xin Huang Chenjun Bai Bo Huang Pingkun Zhou Shanshan Gao |
| author_sort | Hua Guan |
| collection | DOAJ |
| description | Mitochondrion is an important organelle of eukaryotic cells and a critical target of ionizing radiation (IR) outside the nucleus. The biological significance and mechanism of the non-target effect originating from mitochondria have received much attention in the field of radiation biology and protection. In this study, we investigated the effect, role, and radioprotective significance of cytosolic mitochondrial DNA (mtDNA) and its associated cGAS signaling on hematopoietic injury induced by IR in vitro culture cells and in vivo total body irradiated mice in this study. The results demonstrated that γ-ray exposure increases the release of mtDNA into the cytosol to activate cGAS signaling pathway, and the voltage-dependent anion channel (VDAC) may contribute to IR-induced mtDNA release. VDAC1 inhibitor DIDS and cGAS synthetase inhibitor can alleviate bone marrow injury and ameliorate hematopoietic suppression induced by IR via protecting hematopoietic stem cells and adjusting subtype distribution of bone marrow cells, such as attenuating the increase of the F4/80<sup>+</sup> macrophage proportion in bone marrow cells. The present study provides a new mechanistic explanation for the radiation non-target effect and an alternative technical strategy for the prevention and treatment of hematopoietic acute radiation syndrome. |
| first_indexed | 2024-03-11T08:40:32Z |
| format | Article |
| id | doaj.art-2c9b4d7ec80a444fb57878dbd712c4e6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:40:32Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2c9b4d7ec80a444fb57878dbd712c4e62023-11-16T21:08:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244402010.3390/ijms24044020Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of MiceHua Guan0Wen Zhang1Dafei Xie2Yuehua Nie3Shi Chen4Xiaoya Sun5Hongling Zhao6Xiaochang Liu7Hua Wang8Xin Huang9Chenjun Bai10Bo Huang11Pingkun Zhou12Shanshan Gao13Hengyang Medical School, University of South China, Hengyang 421001, ChinaHengyang Medical School, University of South China, Hengyang 421001, ChinaBeijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaBeijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaHengyang Medical School, University of South China, Hengyang 421001, ChinaHengyang Medical School, University of South China, Hengyang 421001, ChinaBeijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaBeijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaBeijing Key Laboratory for Radiobiology, Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaBeijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaBeijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaSchool of Public Health, University of South China, Hengyang 421001, ChinaHengyang Medical School, University of South China, Hengyang 421001, ChinaBeijing Key Laboratory for Radiobiology, Department of Radiation Biology, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaMitochondrion is an important organelle of eukaryotic cells and a critical target of ionizing radiation (IR) outside the nucleus. The biological significance and mechanism of the non-target effect originating from mitochondria have received much attention in the field of radiation biology and protection. In this study, we investigated the effect, role, and radioprotective significance of cytosolic mitochondrial DNA (mtDNA) and its associated cGAS signaling on hematopoietic injury induced by IR in vitro culture cells and in vivo total body irradiated mice in this study. The results demonstrated that γ-ray exposure increases the release of mtDNA into the cytosol to activate cGAS signaling pathway, and the voltage-dependent anion channel (VDAC) may contribute to IR-induced mtDNA release. VDAC1 inhibitor DIDS and cGAS synthetase inhibitor can alleviate bone marrow injury and ameliorate hematopoietic suppression induced by IR via protecting hematopoietic stem cells and adjusting subtype distribution of bone marrow cells, such as attenuating the increase of the F4/80<sup>+</sup> macrophage proportion in bone marrow cells. The present study provides a new mechanistic explanation for the radiation non-target effect and an alternative technical strategy for the prevention and treatment of hematopoietic acute radiation syndrome.https://www.mdpi.com/1422-0067/24/4/4020mitochondrial DNAbone marrow tissuehematopoietic stem cellsradiation injurynon-target effectcGAS signaling |
| spellingShingle | Hua Guan Wen Zhang Dafei Xie Yuehua Nie Shi Chen Xiaoya Sun Hongling Zhao Xiaochang Liu Hua Wang Xin Huang Chenjun Bai Bo Huang Pingkun Zhou Shanshan Gao Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice International Journal of Molecular Sciences mitochondrial DNA bone marrow tissue hematopoietic stem cells radiation injury non-target effect cGAS signaling |
| title | Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice |
| title_full | Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice |
| title_fullStr | Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice |
| title_full_unstemmed | Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice |
| title_short | Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice |
| title_sort | cytosolic release of mitochondrial dna and associated cgas signaling mediates radiation induced hematopoietic injury of mice |
| topic | mitochondrial DNA bone marrow tissue hematopoietic stem cells radiation injury non-target effect cGAS signaling |
| url | https://www.mdpi.com/1422-0067/24/4/4020 |
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