Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation
Abstract Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the res...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55768-9 |
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| author | Yong Yi Guoqiang Wang Wenhua Zhang Shuhan Yu Junjie Fei Tingting An Jianqiao Yi Fengtian Li Ting Huang Jian Yang Mengmeng Niu Yang Wang Chuan Xu Zhi-Xiong Jim Xiao |
| author_facet | Yong Yi Guoqiang Wang Wenhua Zhang Shuhan Yu Junjie Fei Tingting An Jianqiao Yi Fengtian Li Ting Huang Jian Yang Mengmeng Niu Yang Wang Chuan Xu Zhi-Xiong Jim Xiao |
| author_sort | Yong Yi |
| collection | DOAJ |
| description | Abstract Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA. Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival. Furthermore, MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth, and elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients. Together, these findings reveal a role for MT-CO2 in adapting to metabolic stress and highlight MT-CO2 as a putative therapeutic target for Ras-driven cancers. |
| format | Article |
| id | doaj-art-2cfd0de8b3634d7b914c28b9dc43549b |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2cfd0de8b3634d7b914c28b9dc43549b2025-01-05T12:41:05ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-55768-9Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivationYong Yi0Guoqiang Wang1Wenhua Zhang2Shuhan Yu3Junjie Fei4Tingting An5Jianqiao Yi6Fengtian Li7Ting Huang8Jian Yang9Mengmeng Niu10Yang Wang11Chuan Xu12Zhi-Xiong Jim Xiao13Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversitySchool of Biosciences and Technology, Chengdu Medical CollegeDepartment of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityDepartment of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan UniversityAbstract Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA. Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival. Furthermore, MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth, and elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients. Together, these findings reveal a role for MT-CO2 in adapting to metabolic stress and highlight MT-CO2 as a putative therapeutic target for Ras-driven cancers.https://doi.org/10.1038/s41467-024-55768-9 |
| spellingShingle | Yong Yi Guoqiang Wang Wenhua Zhang Shuhan Yu Junjie Fei Tingting An Jianqiao Yi Fengtian Li Ting Huang Jian Yang Mengmeng Niu Yang Wang Chuan Xu Zhi-Xiong Jim Xiao Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation Nature Communications |
| title | Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation |
| title_full | Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation |
| title_fullStr | Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation |
| title_full_unstemmed | Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation |
| title_short | Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation |
| title_sort | mitochondrial cytochrome c oxidase ii promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation |
| url | https://doi.org/10.1038/s41467-024-55768-9 |
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