Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis
Abstract Cancer development is associated with adaptation to various stressful conditions, such as extracellular acidosis. The adverse tumor microenvironment also selects for increased malignancy. Mitochondria are integral in stress sensing to allow for tumor cells to adapt to stressful conditions....
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02301-6 |
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| author | Xiaojie Liu Xue Sun Wenqing Mu Yanan Li Wenqing Bu Tingting Yang Jia Zhang Rui Liu Jiayu Ren Jin Zhou Peishan Li Yufang Shi Changshun Shao |
| author_facet | Xiaojie Liu Xue Sun Wenqing Mu Yanan Li Wenqing Bu Tingting Yang Jia Zhang Rui Liu Jiayu Ren Jin Zhou Peishan Li Yufang Shi Changshun Shao |
| author_sort | Xiaojie Liu |
| collection | DOAJ |
| description | Abstract Cancer development is associated with adaptation to various stressful conditions, such as extracellular acidosis. The adverse tumor microenvironment also selects for increased malignancy. Mitochondria are integral in stress sensing to allow for tumor cells to adapt to stressful conditions. Here, we show that colorectal cancer cells adapted to acidic microenvironment (CRC-AA) are more reliant on oxidative phosphorylation than their parental cells, and the acetyl-CoA in CRC-AA cells are generated from fatty acids and glutamine, but not from glucose. Consistently, CRC-AA cells exhibit increased mitochondrial mass and fitness that depends on an upregulated autophagic flux-lipid droplet axis. Lipid droplets (LDs) function as a buffering system to store the fatty acids derived from autophagy and to protect mitochondria from lipotoxicity in CRC-AA cells. Blockade of LD biogenesis causes mitochondrial dysfunction that can be rescued by inhibiting carnitine palmitoyltransferase 1 α (CPT1α). High level of mitochondrial superoxide is essential for the AMPK activation, resistance to apoptosis, high autophagic flux and mitochondrial function in CRC-AA cells. Thus, our results demonstrate that the cascade of autophagic flux and LD formation plays an essential role in sustaining mitochondrial fitness to promote cancer cell survival under chronic acidosis. Our findings provide insight into the pro-survival metabolic plasticity in cancer cells under microenvironmental or therapeutic stress and imply that this pro-survival cascade may potentially be targeted in cancer therapy. |
| format | Article |
| id | doaj-art-cf45f69349004cda91509bd419a460f8 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-cf45f69349004cda91509bd419a460f82025-01-26T12:15:26ZengNature Publishing GroupCell Death Discovery2058-77162025-01-0111111210.1038/s41420-025-02301-6Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosisXiaojie Liu0Xue Sun1Wenqing Mu2Yanan Li3Wenqing Bu4Tingting Yang5Jia Zhang6Rui Liu7Jiayu Ren8Jin Zhou9Peishan Li10Yufang Shi11Changshun Shao12The Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeDepartment of General Surgery, The First Affiliated Hospital of Soochow UniversityDepartment of General Surgery, The First Affiliated Hospital of Soochow UniversityThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeThe Third Affiliated of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical CollegeAbstract Cancer development is associated with adaptation to various stressful conditions, such as extracellular acidosis. The adverse tumor microenvironment also selects for increased malignancy. Mitochondria are integral in stress sensing to allow for tumor cells to adapt to stressful conditions. Here, we show that colorectal cancer cells adapted to acidic microenvironment (CRC-AA) are more reliant on oxidative phosphorylation than their parental cells, and the acetyl-CoA in CRC-AA cells are generated from fatty acids and glutamine, but not from glucose. Consistently, CRC-AA cells exhibit increased mitochondrial mass and fitness that depends on an upregulated autophagic flux-lipid droplet axis. Lipid droplets (LDs) function as a buffering system to store the fatty acids derived from autophagy and to protect mitochondria from lipotoxicity in CRC-AA cells. Blockade of LD biogenesis causes mitochondrial dysfunction that can be rescued by inhibiting carnitine palmitoyltransferase 1 α (CPT1α). High level of mitochondrial superoxide is essential for the AMPK activation, resistance to apoptosis, high autophagic flux and mitochondrial function in CRC-AA cells. Thus, our results demonstrate that the cascade of autophagic flux and LD formation plays an essential role in sustaining mitochondrial fitness to promote cancer cell survival under chronic acidosis. Our findings provide insight into the pro-survival metabolic plasticity in cancer cells under microenvironmental or therapeutic stress and imply that this pro-survival cascade may potentially be targeted in cancer therapy.https://doi.org/10.1038/s41420-025-02301-6 |
| spellingShingle | Xiaojie Liu Xue Sun Wenqing Mu Yanan Li Wenqing Bu Tingting Yang Jia Zhang Rui Liu Jiayu Ren Jin Zhou Peishan Li Yufang Shi Changshun Shao Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis Cell Death Discovery |
| title | Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis |
| title_full | Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis |
| title_fullStr | Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis |
| title_full_unstemmed | Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis |
| title_short | Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis |
| title_sort | autophagic flux lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis |
| url | https://doi.org/10.1038/s41420-025-02301-6 |
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