mtDNA extramitochondrial replication mediates mitochondrial defect effects
Summary: A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-02-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224001913 |
| _version_ | 1797338203778187264 |
|---|---|
| author | Zhaoliang Shan Shengnan Li Yuxue Gao Chunhua Jian Xiuxiu Ti Hui Zuo Ying Wang Guochun Zhao Yan Wang Qing Zhang |
| author_facet | Zhaoliang Shan Shengnan Li Yuxue Gao Chunhua Jian Xiuxiu Ti Hui Zuo Ying Wang Guochun Zhao Yan Wang Qing Zhang |
| author_sort | Zhaoliang Shan |
| collection | DOAJ |
| description | Summary: A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases. |
| first_indexed | 2024-03-08T09:27:36Z |
| format | Article |
| id | doaj.art-238ab26abaa847a5869a1c747c478277 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-08T09:27:36Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-238ab26abaa847a5869a1c747c4782772024-01-31T05:45:22ZengElsevieriScience2589-00422024-02-01272108970mtDNA extramitochondrial replication mediates mitochondrial defect effectsZhaoliang Shan0Shengnan Li1Yuxue Gao2Chunhua Jian3Xiuxiu Ti4Hui Zuo5Ying Wang6Guochun Zhao7Yan Wang8Qing Zhang9State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, ChinaDepartment of Cardiovascular Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China; Corresponding authorState Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, China; Corresponding authorSummary: A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases.http://www.sciencedirect.com/science/article/pii/S2589004224001913Biological sciencesMolecular biologyMolecular geneticsMolecular interaction |
| spellingShingle | Zhaoliang Shan Shengnan Li Yuxue Gao Chunhua Jian Xiuxiu Ti Hui Zuo Ying Wang Guochun Zhao Yan Wang Qing Zhang mtDNA extramitochondrial replication mediates mitochondrial defect effects iScience Biological sciences Molecular biology Molecular genetics Molecular interaction |
| title | mtDNA extramitochondrial replication mediates mitochondrial defect effects |
| title_full | mtDNA extramitochondrial replication mediates mitochondrial defect effects |
| title_fullStr | mtDNA extramitochondrial replication mediates mitochondrial defect effects |
| title_full_unstemmed | mtDNA extramitochondrial replication mediates mitochondrial defect effects |
| title_short | mtDNA extramitochondrial replication mediates mitochondrial defect effects |
| title_sort | mtdna extramitochondrial replication mediates mitochondrial defect effects |
| topic | Biological sciences Molecular biology Molecular genetics Molecular interaction |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224001913 |
| work_keys_str_mv | AT zhaoliangshan mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT shengnanli mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT yuxuegao mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT chunhuajian mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT xiuxiuti mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT huizuo mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT yingwang mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT guochunzhao mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT yanwang mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects AT qingzhang mtdnaextramitochondrialreplicationmediatesmitochondrialdefecteffects |