Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells
Abstract Cervical cancer is one of the leading causes of cancer death in women. Mitochondrial-mediated ferroptosis (MMF) is a recently discovered form of cancer cell death. However, the role and the underlying mechanism of MMF in cervical cancer remain elusive. Here, using an unbiased screening for...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06033-2 |
| _version_ | 1797743961967689728 |
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| author | Xuan Wang Yuting Ji Jingyi Qi Shuaishuai Zhou Sitong Wan Chang Fan Zhenglong Gu Peng An Yongting Luo Junjie Luo |
| author_facet | Xuan Wang Yuting Ji Jingyi Qi Shuaishuai Zhou Sitong Wan Chang Fan Zhenglong Gu Peng An Yongting Luo Junjie Luo |
| author_sort | Xuan Wang |
| collection | DOAJ |
| description | Abstract Cervical cancer is one of the leading causes of cancer death in women. Mitochondrial-mediated ferroptosis (MMF) is a recently discovered form of cancer cell death. However, the role and the underlying mechanism of MMF in cervical cancer remain elusive. Here, using an unbiased screening for mitochondrial transmembrane candidates, we identified mitochondrial carrier 1 (MTCH1) as a central mediator of MMF in cervical cancers. MTCH1-deficiency disrupted mitochondrial oxidative phosphorylation while elevated mitochondrial reactive oxygen species (ROS) by decreasing NAD+ levels. This mitochondrial autonomous event initiated a mitochondria-to-nucleus retrograde signaling involving reduced FoxO1 nuclear translocation and subsequently downregulation of the transcription and activity of a key anti-ferroptosis enzyme glutathione peroxidase 4 (GPX4), thereby elevating ROS and ultimately triggering ferroptosis. Strikingly, targeting MTCH1 in combination with Sorafenib effectively and synergistically inhibited the growth of cervical cancer in a nude mouse xenograft model by actively inducing ferroptosis. In conclusion, these findings enriched our understanding of the mechanisms of MMF in which MTCH1 governed ferroptosis though retrograde signaling to FoxO1-GPX4 axis, and provided a potential therapeutic target for treating cervical cancer. |
| first_indexed | 2024-03-12T15:03:02Z |
| format | Article |
| id | doaj.art-05ced6b191b34b418e00428b8c79d6a8 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T15:03:02Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-05ced6b191b34b418e00428b8c79d6a82023-08-13T11:24:44ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811310.1038/s41419-023-06033-2Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cellsXuan Wang0Yuting Ji1Jingyi Qi2Shuaishuai Zhou3Sitong Wan4Chang Fan5Zhenglong Gu6Peng An7Yongting Luo8Junjie Luo9Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityGreater Bay Area Institute of Precision Medicine (Guangzhou), Fudan UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityDepartment of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural UniversityAbstract Cervical cancer is one of the leading causes of cancer death in women. Mitochondrial-mediated ferroptosis (MMF) is a recently discovered form of cancer cell death. However, the role and the underlying mechanism of MMF in cervical cancer remain elusive. Here, using an unbiased screening for mitochondrial transmembrane candidates, we identified mitochondrial carrier 1 (MTCH1) as a central mediator of MMF in cervical cancers. MTCH1-deficiency disrupted mitochondrial oxidative phosphorylation while elevated mitochondrial reactive oxygen species (ROS) by decreasing NAD+ levels. This mitochondrial autonomous event initiated a mitochondria-to-nucleus retrograde signaling involving reduced FoxO1 nuclear translocation and subsequently downregulation of the transcription and activity of a key anti-ferroptosis enzyme glutathione peroxidase 4 (GPX4), thereby elevating ROS and ultimately triggering ferroptosis. Strikingly, targeting MTCH1 in combination with Sorafenib effectively and synergistically inhibited the growth of cervical cancer in a nude mouse xenograft model by actively inducing ferroptosis. In conclusion, these findings enriched our understanding of the mechanisms of MMF in which MTCH1 governed ferroptosis though retrograde signaling to FoxO1-GPX4 axis, and provided a potential therapeutic target for treating cervical cancer.https://doi.org/10.1038/s41419-023-06033-2 |
| spellingShingle | Xuan Wang Yuting Ji Jingyi Qi Shuaishuai Zhou Sitong Wan Chang Fan Zhenglong Gu Peng An Yongting Luo Junjie Luo Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells Cell Death and Disease |
| title | Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells |
| title_full | Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells |
| title_fullStr | Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells |
| title_full_unstemmed | Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells |
| title_short | Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells |
| title_sort | mitochondrial carrier 1 mtch1 governs ferroptosis by triggering the foxo1 gpx4 axis mediated retrograde signaling in cervical cancer cells |
| url | https://doi.org/10.1038/s41419-023-06033-2 |
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