ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3
Abstract Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using col...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56444-2 |
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| author | Shiyang Wang Xi Wu Wenxin Bi Jiuzhi Xu Liyuan Hou Guilin Li Yuwei Pan Hanfu Zhang Mengzhen Li Sujuan Du Mingxin Zhang Di Liu Shuiling Jin Xiaojing Shi Yuhua Tian Jianwei Shuai Maksim V. Plikus Moshi Song Zhaocai Zhou Lu Yu Cong Lv Zhengquan Yu |
| author_facet | Shiyang Wang Xi Wu Wenxin Bi Jiuzhi Xu Liyuan Hou Guilin Li Yuwei Pan Hanfu Zhang Mengzhen Li Sujuan Du Mingxin Zhang Di Liu Shuiling Jin Xiaojing Shi Yuhua Tian Jianwei Shuai Maksim V. Plikus Moshi Song Zhaocai Zhou Lu Yu Cong Lv Zhengquan Yu |
| author_sort | Shiyang Wang |
| collection | DOAJ |
| description | Abstract Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics. |
| format | Article |
| id | doaj-art-eefa967da41946a3ae0902a241e04396 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-eefa967da41946a3ae0902a241e043962025-02-09T12:45:14ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-025-56444-2ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3Shiyang Wang0Xi Wu1Wenxin Bi2Jiuzhi Xu3Liyuan Hou4Guilin Li5Yuwei Pan6Hanfu Zhang7Mengzhen Li8Sujuan Du9Mingxin Zhang10Di Liu11Shuiling Jin12Xiaojing Shi13Yuhua Tian14Jianwei Shuai15Maksim V. Plikus16Moshi Song17Zhaocai Zhou18Lu Yu19Cong Lv20Zhengquan Yu21State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityKey Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural UniversityKey Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityDepartment of Oncology, the First Affiliated Hospital of Zhengzhou UniversityTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversityTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversityWenzhou Institute, University of Chinese Academy of SciencesDepartment of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California, IrvineState Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityKey Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural UniversityState Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural UniversityAbstract Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.https://doi.org/10.1038/s41467-025-56444-2 |
| spellingShingle | Shiyang Wang Xi Wu Wenxin Bi Jiuzhi Xu Liyuan Hou Guilin Li Yuwei Pan Hanfu Zhang Mengzhen Li Sujuan Du Mingxin Zhang Di Liu Shuiling Jin Xiaojing Shi Yuhua Tian Jianwei Shuai Maksim V. Plikus Moshi Song Zhaocai Zhou Lu Yu Cong Lv Zhengquan Yu ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3 Nature Communications |
| title | ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3 |
| title_full | ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3 |
| title_fullStr | ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3 |
| title_full_unstemmed | ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3 |
| title_short | ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3 |
| title_sort | ros induced cytosolic release of mitochondrial pgam5 promotes colorectal cancer progression by interacting with mst3 |
| url | https://doi.org/10.1038/s41467-025-56444-2 |
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