Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria
Abstract Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoi...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07237-w |
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| author | Yusuke Hirata Yuto Yamada Soma Taguchi Ryota Kojima Haruka Masumoto Shinnosuke Kimura Takuya Niijima Takashi Toyama Ryoji Kise Emiko Sato Yasunori Uchida Junya Ito Kiyotaka Nakagawa Tomohiko Taguchi Asuka Inoue Yoshiro Saito Takuya Noguchi Atsushi Matsuzawa |
| author_facet | Yusuke Hirata Yuto Yamada Soma Taguchi Ryota Kojima Haruka Masumoto Shinnosuke Kimura Takuya Niijima Takashi Toyama Ryoji Kise Emiko Sato Yasunori Uchida Junya Ito Kiyotaka Nakagawa Tomohiko Taguchi Asuka Inoue Yoshiro Saito Takuya Noguchi Atsushi Matsuzawa |
| author_sort | Yusuke Hirata |
| collection | DOAJ |
| description | Abstract Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy. |
| format | Article |
| id | doaj-art-03c5af266e5e42b0a6a6c297d28bbde4 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-03c5af266e5e42b0a6a6c297d28bbde42024-12-08T12:47:28ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211510.1038/s41419-024-07237-wConjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondriaYusuke Hirata0Yuto Yamada1Soma Taguchi2Ryota Kojima3Haruka Masumoto4Shinnosuke Kimura5Takuya Niijima6Takashi Toyama7Ryoji Kise8Emiko Sato9Yasunori Uchida10Junya Ito11Kiyotaka Nakagawa12Tomohiko Taguchi13Asuka Inoue14Yoshiro Saito15Takuya Noguchi16Atsushi Matsuzawa17Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityDivision of Clinical Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku UniversityLaboratory of Food Function Analysis, Graduate School of Agricultural Sciences, Tohoku UniversityLaboratory of Food Function Analysis, Graduate School of Agricultural Sciences, Tohoku UniversityLaboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku UniversityLaboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityAbstract Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy.https://doi.org/10.1038/s41419-024-07237-w |
| spellingShingle | Yusuke Hirata Yuto Yamada Soma Taguchi Ryota Kojima Haruka Masumoto Shinnosuke Kimura Takuya Niijima Takashi Toyama Ryoji Kise Emiko Sato Yasunori Uchida Junya Ito Kiyotaka Nakagawa Tomohiko Taguchi Asuka Inoue Yoshiro Saito Takuya Noguchi Atsushi Matsuzawa Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria Cell Death and Disease |
| title | Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria |
| title_full | Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria |
| title_fullStr | Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria |
| title_full_unstemmed | Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria |
| title_short | Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria |
| title_sort | conjugated fatty acids drive ferroptosis through chaperone mediated autophagic degradation of gpx4 by targeting mitochondria |
| url | https://doi.org/10.1038/s41419-024-07237-w |
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