Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis
Abstract Acute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial ca...
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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/s41419-024-07231-2 |
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| author | Xin Su Mi Bai Yaqiong Shang Yang Du Shuang Xu Xiuli Lin Yunzhi Xiao Yue Zhang Huimei Chen Aihua Zhang |
| author_facet | Xin Su Mi Bai Yaqiong Shang Yang Du Shuang Xu Xiuli Lin Yunzhi Xiao Yue Zhang Huimei Chen Aihua Zhang |
| author_sort | Xin Su |
| collection | DOAJ |
| description | Abstract Acute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial carrier, as a potential target for AKI intervention. Renal Slc25a21 expression is negatively associated with kidney function in both AKI patients and cisplatin-induced murine models. Sustaining renal expression of Slc25a21 slowed down AKI progression by reducing cellular apoptosis, necroptosis, and the inflammatory response, likely through its regulation of 2-oxoadipate conversion. Slc25a21 is highly expressed in proximal tubular epithelial cells, and its down-regulation contributes to compromised mitochondrial biogenesis and integrity, as well as impaired oxidative phosphorylation. Mechanistically, reduced Slc25a21 in AKI disrupts mitochondrial 2-oxoadipate transport, affecting related metabolites influx and the tricarboxylic acid cycle. These findings demonstrate a previously unappreciated metabolic function of Slc25a21 in tubular cells, and suggest that targeting mitochondrial metabolic homeostasis by sustaining Slc25a21 expression could be a potential novel therapeutic strategy for AKI. |
| format | Article |
| id | doaj-art-adeb9d11c4614b16bedc4e2a39ef56fb |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-adeb9d11c4614b16bedc4e2a39ef56fb2025-08-20T01:57:13ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211610.1038/s41419-024-07231-2Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasisXin Su0Mi Bai1Yaqiong Shang2Yang Du3Shuang Xu4Xiuli Lin5Yunzhi Xiao6Yue Zhang7Huimei Chen8Aihua Zhang9Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityDepartment of Nephrology, Children’s Hospital of Nanjing Medical UniversityDepartment of Nephrology, Children’s Hospital of Nanjing Medical UniversityDepartment of Nephrology, Children’s Hospital of Nanjing Medical UniversityDepartment of Nephrology, Children’s Hospital of Nanjing Medical UniversityDepartment of Nephrology, Children’s Hospital of Nanjing Medical UniversityCentre for Computational Biology and Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolDepartment of Nephrology, Children’s Hospital of Nanjing Medical UniversityCentre for Computational Biology and Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolDepartment of Nephrology, Children’s Hospital of Nanjing Medical UniversityAbstract Acute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial carrier, as a potential target for AKI intervention. Renal Slc25a21 expression is negatively associated with kidney function in both AKI patients and cisplatin-induced murine models. Sustaining renal expression of Slc25a21 slowed down AKI progression by reducing cellular apoptosis, necroptosis, and the inflammatory response, likely through its regulation of 2-oxoadipate conversion. Slc25a21 is highly expressed in proximal tubular epithelial cells, and its down-regulation contributes to compromised mitochondrial biogenesis and integrity, as well as impaired oxidative phosphorylation. Mechanistically, reduced Slc25a21 in AKI disrupts mitochondrial 2-oxoadipate transport, affecting related metabolites influx and the tricarboxylic acid cycle. These findings demonstrate a previously unappreciated metabolic function of Slc25a21 in tubular cells, and suggest that targeting mitochondrial metabolic homeostasis by sustaining Slc25a21 expression could be a potential novel therapeutic strategy for AKI.https://doi.org/10.1038/s41419-024-07231-2 |
| spellingShingle | Xin Su Mi Bai Yaqiong Shang Yang Du Shuang Xu Xiuli Lin Yunzhi Xiao Yue Zhang Huimei Chen Aihua Zhang Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis Cell Death and Disease |
| title | Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis |
| title_full | Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis |
| title_fullStr | Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis |
| title_full_unstemmed | Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis |
| title_short | Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis |
| title_sort | slc25a21 in cisplatin induced acute kidney injury a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis |
| url | https://doi.org/10.1038/s41419-024-07231-2 |
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