TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression
Hepatic ischemia–reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2023-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0159 |
| _version_ | 1827297415136280576 |
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| author | Cheng Zhong Jing Yang Yiyin Zhang Xiaoxiao Fan Yang Fan Ning Hua Duguang Li Shengxi Jin Yirun Li Peng Chen Yongle Chen Xiaobo Cai Yi Zhang Linhua Jiang Wei Yang Peilin Yu Hui Lin |
| author_facet | Cheng Zhong Jing Yang Yiyin Zhang Xiaoxiao Fan Yang Fan Ning Hua Duguang Li Shengxi Jin Yirun Li Peng Chen Yongle Chen Xiaobo Cai Yi Zhang Linhua Jiang Wei Yang Peilin Yu Hui Lin |
| author_sort | Cheng Zhong |
| collection | DOAJ |
| description | Hepatic ischemia–reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation. |
| first_indexed | 2024-03-13T08:08:34Z |
| format | Article |
| id | doaj.art-9dd57fc864dd49c98fde430f99396002 |
| institution | Directory Open Access Journal |
| issn | 2639-5274 |
| language | English |
| last_indexed | 2024-04-24T14:55:50Z |
| publishDate | 2023-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj.art-9dd57fc864dd49c98fde430f993960022024-04-02T19:12:34ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742023-01-01610.34133/research.0159TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 ExpressionCheng Zhong0Jing Yang1Yiyin Zhang2Xiaoxiao Fan3Yang Fan4Ning Hua5Duguang Li6Shengxi Jin7Yirun Li8Peng Chen9Yongle Chen10Xiaobo Cai11Yi Zhang12Linhua Jiang13Wei Yang14Peilin Yu15Hui Lin16Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of Toxicology and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Xinxiang Medical University, 453003 Xinxiang, Henan, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, P.R. China.Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, P.R. China.Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Xinxiang Medical University, 453003 Xinxiang, Henan, P.R. China.Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, P.R. China.Department of Toxicology and Department of Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.Hepatic ischemia–reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.https://spj.science.org/doi/10.34133/research.0159 |
| spellingShingle | Cheng Zhong Jing Yang Yiyin Zhang Xiaoxiao Fan Yang Fan Ning Hua Duguang Li Shengxi Jin Yirun Li Peng Chen Yongle Chen Xiaobo Cai Yi Zhang Linhua Jiang Wei Yang Peilin Yu Hui Lin TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression Research |
| title | TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression |
| title_full | TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression |
| title_fullStr | TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression |
| title_full_unstemmed | TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression |
| title_short | TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression |
| title_sort | trpm2 mediates hepatic ischemia reperfusion injury via ca2 induced mitochondrial lipid peroxidation through increasing alox12 expression |
| url | https://spj.science.org/doi/10.34133/research.0159 |
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