β-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy
Abstract Background In perinatal dairy cows, ketosis is a prevalent metabolic disorder that lowers milk output and performance. Mitochondrial dysfunction and chronic inflammation in mammary tissue are linked to elevated blood ketone levels, particularly β-hydroxybutyrate (BHB). Recent research has l...
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BMC
2025-02-01
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| Series: | Journal of Animal Science and Biotechnology |
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| Online Access: | https://doi.org/10.1186/s40104-024-01143-z |
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| author | Yihui Huo Taiyu Shen Tianyin Feng Moli Li Wanli Zhao Juan J. Loor Ben Aernouts Androniki Psifidi Chuang Xu |
| author_facet | Yihui Huo Taiyu Shen Tianyin Feng Moli Li Wanli Zhao Juan J. Loor Ben Aernouts Androniki Psifidi Chuang Xu |
| author_sort | Yihui Huo |
| collection | DOAJ |
| description | Abstract Background In perinatal dairy cows, ketosis is a prevalent metabolic disorder that lowers milk output and performance. Mitochondrial dysfunction and chronic inflammation in mammary tissue are linked to elevated blood ketone levels, particularly β-hydroxybutyrate (BHB). Recent research has linked cytosolic mitochondrial DNA (mtDNA) with chronic aseptic inflammation by activating the cGAS-STING pathway during metabolic disorders, while autophagy activation effectively reverses this process. However, whether it is involved in mammary gland damage during ketosis is poorly understood. Therefore, this study aimed to explore the underlying mechanisms of mtDNA-induced inflammation under BHB stress and evaluate the potential therapeutic strategy of autophagy activation in mitigating this damage. Results Our study found an increased cytoplasmic mtDNA abundance in mammary gland tissues of dairy cows with ketosis and bovine mammary epithelial cell line (MAC-T) subjected to BHB stress. Further investigations revealed the activation of the cGAS-STING pathway and inflammatory response, indicated by elevated levels of cGAS and STING, along with increased phosphorylation levels of TBK1, P65, and IκB, and higher transcript levels of pro-inflammatory factors (IL-1B, IL-6, and TNF-α) in both in vivo and in vitro experiments. Notably, STING inhibition via si-STING transfection reversed BHB-induced inflammation. Additionally, autophagy activation appeared to protect against BHB stress by facilitating the removal of cytoplasmic mtDNA and preventing cGAS-STING pathway-mediated inflammation. Conclusions The findings illustrate that elevated BHB levels lead to the release of cytoplasmic mtDNA, which in turn activates the cGAS-STING pathway and triggers an inflammatory response in the mammary glands during hyperketonemia. Conversely, autophagy activation has been shown to alleviate this process by promoting cytoplasmic mtDNA degradation. Graphical Abstract |
| format | Article |
| id | doaj-art-c5b0d7dc371d4197b52d0a6c956d9a61 |
| institution | Kabale University |
| issn | 2049-1891 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Animal Science and Biotechnology |
| spelling | doaj-art-c5b0d7dc371d4197b52d0a6c956d9a612025-02-02T12:35:50ZengBMCJournal of Animal Science and Biotechnology2049-18912025-02-0116111510.1186/s40104-024-01143-zβ-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagyYihui Huo0Taiyu Shen1Tianyin Feng2Moli Li3Wanli Zhao4Juan J. Loor5Ben Aernouts6Androniki Psifidi7Chuang Xu8College of Veterinary Medicine, China Agricultural UniversityCollege of Veterinary Medicine, China Agricultural UniversityCollege of Veterinary Medicine, China Agricultural UniversityCollege of Veterinary Medicine, China Agricultural UniversityCollege of Veterinary Medicine, China Agricultural UniversityDepartment of Animal Sciences, University of Illinois at Urbana-ChampaignDepartment of Biosystems, Division of Animal and Human Health Engineering, KU LeuvenDepartment of Clinical Science and Services, Queen Mother Hospital for Animals, The Royal Veterinary CollegeCollege of Veterinary Medicine, China Agricultural UniversityAbstract Background In perinatal dairy cows, ketosis is a prevalent metabolic disorder that lowers milk output and performance. Mitochondrial dysfunction and chronic inflammation in mammary tissue are linked to elevated blood ketone levels, particularly β-hydroxybutyrate (BHB). Recent research has linked cytosolic mitochondrial DNA (mtDNA) with chronic aseptic inflammation by activating the cGAS-STING pathway during metabolic disorders, while autophagy activation effectively reverses this process. However, whether it is involved in mammary gland damage during ketosis is poorly understood. Therefore, this study aimed to explore the underlying mechanisms of mtDNA-induced inflammation under BHB stress and evaluate the potential therapeutic strategy of autophagy activation in mitigating this damage. Results Our study found an increased cytoplasmic mtDNA abundance in mammary gland tissues of dairy cows with ketosis and bovine mammary epithelial cell line (MAC-T) subjected to BHB stress. Further investigations revealed the activation of the cGAS-STING pathway and inflammatory response, indicated by elevated levels of cGAS and STING, along with increased phosphorylation levels of TBK1, P65, and IκB, and higher transcript levels of pro-inflammatory factors (IL-1B, IL-6, and TNF-α) in both in vivo and in vitro experiments. Notably, STING inhibition via si-STING transfection reversed BHB-induced inflammation. Additionally, autophagy activation appeared to protect against BHB stress by facilitating the removal of cytoplasmic mtDNA and preventing cGAS-STING pathway-mediated inflammation. Conclusions The findings illustrate that elevated BHB levels lead to the release of cytoplasmic mtDNA, which in turn activates the cGAS-STING pathway and triggers an inflammatory response in the mammary glands during hyperketonemia. Conversely, autophagy activation has been shown to alleviate this process by promoting cytoplasmic mtDNA degradation. Graphical Abstracthttps://doi.org/10.1186/s40104-024-01143-zAutophagyBovine mammary glandInflammationMitochondria DNA |
| spellingShingle | Yihui Huo Taiyu Shen Tianyin Feng Moli Li Wanli Zhao Juan J. Loor Ben Aernouts Androniki Psifidi Chuang Xu β-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy Journal of Animal Science and Biotechnology Autophagy Bovine mammary gland Inflammation Mitochondria DNA |
| title | β-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy |
| title_full | β-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy |
| title_fullStr | β-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy |
| title_full_unstemmed | β-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy |
| title_short | β-Hydroxybutyrate-induced mitochondrial DNA (mtDNA) release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy |
| title_sort | β hydroxybutyrate induced mitochondrial dna mtdna release mediated innate inflammatory response in bovine mammary epithelial cells by inhibiting autophagy |
| topic | Autophagy Bovine mammary gland Inflammation Mitochondria DNA |
| url | https://doi.org/10.1186/s40104-024-01143-z |
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