piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1
Abstract Ovarian cancer (OC) is a heterogeneous cancer. In contrast to other tumor cells, which rely primarily on aerobic glycolysis (Warburg effect) as their energy source, oxidative phosphorylation (OXPHOS) is also one of its major metabolic modes. Piwi-interacting RNAs (piRNAs) play a regulatory...
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07340-6 |
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| author | Jing Yuan Bu-Min Xie Yu-Meng Ji Hai-Juan Bao Jie-Lin Wang Jia-Chen Cheng Xiang-Chun Huang Yang Zhao Shuo Chen |
| author_facet | Jing Yuan Bu-Min Xie Yu-Meng Ji Hai-Juan Bao Jie-Lin Wang Jia-Chen Cheng Xiang-Chun Huang Yang Zhao Shuo Chen |
| author_sort | Jing Yuan |
| collection | DOAJ |
| description | Abstract Ovarian cancer (OC) is a heterogeneous cancer. In contrast to other tumor cells, which rely primarily on aerobic glycolysis (Warburg effect) as their energy source, oxidative phosphorylation (OXPHOS) is also one of its major metabolic modes. Piwi-interacting RNAs (piRNAs) play a regulatory function in various biological processes in tumor cells. However, the role and mechanisms of piRNAs in OC and mitochondrial OXPHOS remain to be elucidated. Here, we found that piR-26441 was aberrantly downregulated in OC, and its overexpression suppressed the malignant features of OC cells and tumor growth in a xenograft model. Moreover, overexpression of piR-26441 significantly reduced mitochondrial OXPHOS levels in OC cells. Furthermore, piR-26441 directly binds to and upregulates the expression of YTHDC1 in OC cells. piR-26441 also increased m6A levels, thereby interacting with YTHDC1 to destabilize the mRNA of TSFM. The resultant TSFM loss reduced mitochondrial complex I activity and mitochondrial OXPHOS, leading to mitochondrial dysfunction in OC cells, increased reactive oxygen species levels, and thus, DNA damage and apoptosis in OC cells, thereby inhibiting OC progression. Additionally, ago-piR-26441 suppressed tumor growth and mitochondrial metabolism in the patient-derived organoid model. Altogether, piR-26441 could inhibit OC cell growth via the YTHDC1/TSFM signaling axis, underscoring its significant importance in the context of OC, as well as offering potential as a therapeutic target. |
| format | Article |
| id | doaj-art-87dc5b14c2544bdba3e8f308092fb76e |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-87dc5b14c2544bdba3e8f308092fb76e2025-01-19T12:40:50ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111310.1038/s41419-025-07340-6piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1Jing Yuan0Bu-Min Xie1Yu-Meng Ji2Hai-Juan Bao3Jie-Lin Wang4Jia-Chen Cheng5Xiang-Chun Huang6Yang Zhao7Shuo Chen8Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical UniversityAbstract Ovarian cancer (OC) is a heterogeneous cancer. In contrast to other tumor cells, which rely primarily on aerobic glycolysis (Warburg effect) as their energy source, oxidative phosphorylation (OXPHOS) is also one of its major metabolic modes. Piwi-interacting RNAs (piRNAs) play a regulatory function in various biological processes in tumor cells. However, the role and mechanisms of piRNAs in OC and mitochondrial OXPHOS remain to be elucidated. Here, we found that piR-26441 was aberrantly downregulated in OC, and its overexpression suppressed the malignant features of OC cells and tumor growth in a xenograft model. Moreover, overexpression of piR-26441 significantly reduced mitochondrial OXPHOS levels in OC cells. Furthermore, piR-26441 directly binds to and upregulates the expression of YTHDC1 in OC cells. piR-26441 also increased m6A levels, thereby interacting with YTHDC1 to destabilize the mRNA of TSFM. The resultant TSFM loss reduced mitochondrial complex I activity and mitochondrial OXPHOS, leading to mitochondrial dysfunction in OC cells, increased reactive oxygen species levels, and thus, DNA damage and apoptosis in OC cells, thereby inhibiting OC progression. Additionally, ago-piR-26441 suppressed tumor growth and mitochondrial metabolism in the patient-derived organoid model. Altogether, piR-26441 could inhibit OC cell growth via the YTHDC1/TSFM signaling axis, underscoring its significant importance in the context of OC, as well as offering potential as a therapeutic target.https://doi.org/10.1038/s41419-025-07340-6 |
| spellingShingle | Jing Yuan Bu-Min Xie Yu-Meng Ji Hai-Juan Bao Jie-Lin Wang Jia-Chen Cheng Xiang-Chun Huang Yang Zhao Shuo Chen piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1 Cell Death and Disease |
| title | piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1 |
| title_full | piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1 |
| title_fullStr | piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1 |
| title_full_unstemmed | piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1 |
| title_short | piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1 |
| title_sort | pir 26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6a modification by interacting with ythdc1 |
| url | https://doi.org/10.1038/s41419-025-07340-6 |
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