Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells
Excessive copper (Cu) has the potential risk to ecosystems and organism health, with its impact on dairy cow mammary glands being not well-defined. This study used a bovine mammary epithelial cell (MAC-T) model to explore how copper excess affects cellular oxidative stress, autophagy, ferroptosis, a...
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| Language: | English |
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Elsevier
2025-02-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325001198 |
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| author | Ya Ting Fan Dong Qiao Peng Jing Lin Shen Jun Hao Cui Xin Yue Yang Jin Ge Zhang Yong Cheng Jin |
| author_facet | Ya Ting Fan Dong Qiao Peng Jing Lin Shen Jun Hao Cui Xin Yue Yang Jin Ge Zhang Yong Cheng Jin |
| author_sort | Ya Ting Fan |
| collection | DOAJ |
| description | Excessive copper (Cu) has the potential risk to ecosystems and organism health, with its impact on dairy cow mammary glands being not well-defined. This study used a bovine mammary epithelial cell (MAC-T) model to explore how copper excess affects cellular oxidative stress, autophagy, ferroptosis, and protein and lipid biosynthesis in milk. Results showed the increased intracellular ROS, MDA, and CAT (P < 0.05), alongside decreased T-SOD and GSH in CuSO4-treated cells (P < 0.05). Transmission electron microscopy and Ad-mCherry-GFP-LC3B assays revealed significant autophagosome accumulation in CuSO4 exposed cells (P < 0.05). Additionally, CuSO4 exposure modulated autophagy markers, evidenced by upregulation of genes such as LC3, ATG5, JNK1, and Beclin1, and downregulation of genes such as ATG4B, and p62 (P < 0.05). CuSO4 also led to notable mitochondrial changes, including size reduction, membrane rupture, and cristae loss, and reduced expression of the ferroptosis inhibitor GPX4 (P < 0.05). The expression of mTOR, HIF-1α and β-catenin signaling pathway were inhibited in differentiated MAC-T cells by CuSO4 exposure (P < 0.05), activated autophagy through activation of the AMPK-mTOR pathway which in turn affected downstream levels of genes related to milk protein and lipid. In conclusion, excessive copper induces oxidative stress in MAC-T cells, promoting autophagy through JNK-Bcl2, Beclin1-Vps34 and AMPK-mTOR pathways, leading to cell ferroptosis, as well as inhibits the cellular biosynthesis of milk protein and lipid. |
| format | Article |
| id | doaj-art-3bb1a9721d3b4eb9bd23cbd25d1d5e3a |
| institution | OA Journals |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-3bb1a9721d3b4eb9bd23cbd25d1d5e3a2025-08-20T02:03:59ZengElsevierEcotoxicology and Environmental Safety0147-65132025-02-0129111778310.1016/j.ecoenv.2025.117783Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cellsYa Ting Fan0Dong Qiao Peng1Jing Lin Shen2Jun Hao Cui3Xin Yue Yang4Jin Ge Zhang5Yong Cheng Jin6College of Animal Science, Jilin University, Jilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding In Northeastern Frigid Area, Changchun 130062, ChinaCollege of Animal Science, Jilin University, Jilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding In Northeastern Frigid Area, Changchun 130062, ChinaCollege of Animal Science, Jilin University, Jilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding In Northeastern Frigid Area, Changchun 130062, ChinaCollege of Animal Science, Jilin University, Jilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding In Northeastern Frigid Area, Changchun 130062, ChinaCollege of Animal Science, Jilin University, Jilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding In Northeastern Frigid Area, Changchun 130062, ChinaCollege of Animal Science, Jilin University, Jilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding In Northeastern Frigid Area, Changchun 130062, ChinaCorresponding author.; College of Animal Science, Jilin University, Jilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding In Northeastern Frigid Area, Changchun 130062, ChinaExcessive copper (Cu) has the potential risk to ecosystems and organism health, with its impact on dairy cow mammary glands being not well-defined. This study used a bovine mammary epithelial cell (MAC-T) model to explore how copper excess affects cellular oxidative stress, autophagy, ferroptosis, and protein and lipid biosynthesis in milk. Results showed the increased intracellular ROS, MDA, and CAT (P < 0.05), alongside decreased T-SOD and GSH in CuSO4-treated cells (P < 0.05). Transmission electron microscopy and Ad-mCherry-GFP-LC3B assays revealed significant autophagosome accumulation in CuSO4 exposed cells (P < 0.05). Additionally, CuSO4 exposure modulated autophagy markers, evidenced by upregulation of genes such as LC3, ATG5, JNK1, and Beclin1, and downregulation of genes such as ATG4B, and p62 (P < 0.05). CuSO4 also led to notable mitochondrial changes, including size reduction, membrane rupture, and cristae loss, and reduced expression of the ferroptosis inhibitor GPX4 (P < 0.05). The expression of mTOR, HIF-1α and β-catenin signaling pathway were inhibited in differentiated MAC-T cells by CuSO4 exposure (P < 0.05), activated autophagy through activation of the AMPK-mTOR pathway which in turn affected downstream levels of genes related to milk protein and lipid. In conclusion, excessive copper induces oxidative stress in MAC-T cells, promoting autophagy through JNK-Bcl2, Beclin1-Vps34 and AMPK-mTOR pathways, leading to cell ferroptosis, as well as inhibits the cellular biosynthesis of milk protein and lipid.http://www.sciencedirect.com/science/article/pii/S0147651325001198AutophagyBovine Mammary Epithelial CellCopperFerroptosisMilk protein and lipid synthesis |
| spellingShingle | Ya Ting Fan Dong Qiao Peng Jing Lin Shen Jun Hao Cui Xin Yue Yang Jin Ge Zhang Yong Cheng Jin Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells Ecotoxicology and Environmental Safety Autophagy Bovine Mammary Epithelial Cell Copper Ferroptosis Milk protein and lipid synthesis |
| title | Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells |
| title_full | Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells |
| title_fullStr | Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells |
| title_full_unstemmed | Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells |
| title_short | Copper excess induces autophagy dysfunction and mitochondrial ROS-ferroptosis progression, inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells |
| title_sort | copper excess induces autophagy dysfunction and mitochondrial ros ferroptosis progression inhibits cellular biosynthesis of milk protein and lipid in bovine mammary epithelial cells |
| topic | Autophagy Bovine Mammary Epithelial Cell Copper Ferroptosis Milk protein and lipid synthesis |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325001198 |
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