Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury
Abstract An important pathophysiological process of acute kidney injury (AKI) is mitochondrial fragmentation in renal tubular epithelial cells, which leads to cell death. Pyruvate kinase M2 (PKM2) is an active protein with various biological functions that participates in regulating glycolysis and p...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06195-z |
| _version_ | 1797659789190234112 |
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| author | Wenjia Xie Qingyun He Yan Zhang Xinxin Xu Ping Wen Hongdi Cao Yang Zhou Jing Luo Junwei Yang Lei Jiang |
| author_facet | Wenjia Xie Qingyun He Yan Zhang Xinxin Xu Ping Wen Hongdi Cao Yang Zhou Jing Luo Junwei Yang Lei Jiang |
| author_sort | Wenjia Xie |
| collection | DOAJ |
| description | Abstract An important pathophysiological process of acute kidney injury (AKI) is mitochondrial fragmentation in renal tubular epithelial cells, which leads to cell death. Pyruvate kinase M2 (PKM2) is an active protein with various biological functions that participates in regulating glycolysis and plays a key role in regulating cell survival. However, the role and mechanism of PKM2 in regulating cell survival during AKI remain unclear. Here, we found that the phosphorylation of PKM2 contributed to the formation of the PKM2 dimer and translocation of PKM2 into the mitochondria after treatment with staurosporine or cisplatin. Mitochondrial PKM2 binds myosin heavy chain 9 (MYH9) to promote dynamin-related protein 1 (DRP1)-mediated mitochondrial fragmentation. Both in vivo and in vitro, PKM2-specific loss or regulation PKM2 activity partially limits mitochondrial fragmentation, alleviating renal tubular injury and cell death, including apoptosis, necroptosis, and ferroptosis. Moreover, staurosporine or cisplatin-induced mitochondrial fragmentation and cell death were reversed in cultured cells by inhibiting MYH9 activity. Taken together, our results indicate that the regulation of PKM2 abundance and activity to inhibit mitochondrial translocation may maintain mitochondrial integrity and provide a new therapeutic strategy for treating AKI. |
| first_indexed | 2024-03-11T18:21:19Z |
| format | Article |
| id | doaj.art-9c23e06ccd1844ceb74d54130b36a983 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T18:21:19Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9c23e06ccd1844ceb74d54130b36a9832023-10-15T11:30:12ZengNature Publishing GroupCell Death and Disease2041-48892023-10-01141011110.1038/s41419-023-06195-zPyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injuryWenjia Xie0Qingyun He1Yan Zhang2Xinxin Xu3Ping Wen4Hongdi Cao5Yang Zhou6Jing Luo7Junwei Yang8Lei Jiang9Center for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical UniversityAbstract An important pathophysiological process of acute kidney injury (AKI) is mitochondrial fragmentation in renal tubular epithelial cells, which leads to cell death. Pyruvate kinase M2 (PKM2) is an active protein with various biological functions that participates in regulating glycolysis and plays a key role in regulating cell survival. However, the role and mechanism of PKM2 in regulating cell survival during AKI remain unclear. Here, we found that the phosphorylation of PKM2 contributed to the formation of the PKM2 dimer and translocation of PKM2 into the mitochondria after treatment with staurosporine or cisplatin. Mitochondrial PKM2 binds myosin heavy chain 9 (MYH9) to promote dynamin-related protein 1 (DRP1)-mediated mitochondrial fragmentation. Both in vivo and in vitro, PKM2-specific loss or regulation PKM2 activity partially limits mitochondrial fragmentation, alleviating renal tubular injury and cell death, including apoptosis, necroptosis, and ferroptosis. Moreover, staurosporine or cisplatin-induced mitochondrial fragmentation and cell death were reversed in cultured cells by inhibiting MYH9 activity. Taken together, our results indicate that the regulation of PKM2 abundance and activity to inhibit mitochondrial translocation may maintain mitochondrial integrity and provide a new therapeutic strategy for treating AKI.https://doi.org/10.1038/s41419-023-06195-z |
| spellingShingle | Wenjia Xie Qingyun He Yan Zhang Xinxin Xu Ping Wen Hongdi Cao Yang Zhou Jing Luo Junwei Yang Lei Jiang Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury Cell Death and Disease |
| title | Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury |
| title_full | Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury |
| title_fullStr | Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury |
| title_full_unstemmed | Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury |
| title_short | Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury |
| title_sort | pyruvate kinase m2 regulates mitochondrial homeostasis in cisplatin induced acute kidney injury |
| url | https://doi.org/10.1038/s41419-023-06195-z |
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