TAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytes
Abstract Background TGF-β-activated kinase 1 binding protein 2 (TAB2) is an intermediary protein that links Tumor necrosis factor receptor 1 (TNFR1) and other receptor signals to the TGF-β-activated kinase 1 (TAK1) signaling complex. TAB2 frameshift mutations have been linked to dilated cardiomyopat...
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| Language: | English |
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BMC
2025-02-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01103-x |
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| author | Wenrui Sun Jianchao Zhang Shuang Li Wanrong Fu Yangyang Liu Mengduan Liu Jianzeng Dong Xiaoyan Zhao Xiaowei Li |
| author_facet | Wenrui Sun Jianchao Zhang Shuang Li Wanrong Fu Yangyang Liu Mengduan Liu Jianzeng Dong Xiaoyan Zhao Xiaowei Li |
| author_sort | Wenrui Sun |
| collection | DOAJ |
| description | Abstract Background TGF-β-activated kinase 1 binding protein 2 (TAB2) is an intermediary protein that links Tumor necrosis factor receptor 1 (TNFR1) and other receptor signals to the TGF-β-activated kinase 1 (TAK1) signaling complex. TAB2 frameshift mutations have been linked to dilated cardiomyopathy (DCM), while the exact mechanism needs further investigation. Methods In this study, we generated a TAB2 compound heterozygous knockout cell line in induced pluripotent stem cells (iPSCs) derived from a healthy individual using CRISPR/Cas9 technology. IPSCs are not species-dependent, are readily accessible, and raise fewer ethical concerns. Results TAB2 disruption had no impact on the cardiac differentiation of iPSCs and led to confirmed TAB2 deficiency in human iPSC-derived cardiomyocytes (hiPSC-CMs). TAB2-deficient hiPSC-CMs were found to develop phenotypic features of DCM, such as distorted sarcomeric ultrastructure, decreased contractility and energy production, and mitochondrial damage at day 30 post differentiation. Paradoxically, TAB2 knockout cell lines showed abnormal calcium handling after 40 days, later than reduced contractility, suggesting that the main cause of impaired contractility was abnormal energy production due to mitochondrial damage. As early as day 25, TAB2 knockout cardiomyocytes showed significant mitochondrial calcium overload, which can lead to mitochondrial damage. Furthermore, TAB2 knockout activated receptor-interacting protein kinase 1 (RIPK1), leading to an increase in mitochondrial calcium uniporter (MCU) expression, thereby augmenting the uptake of mitochondrial calcium ions. Finally, the application of the RIPK1 inhibitor Nec-1s prevents the progression of these phenotypes. Conclusions In summary, TAB2 abatement cardiomyocytes mimic dilated cardiomyopathy in vitro. This finding emphasizes the importance of using a human model to study the underlying mechanisms of this specific disease. More importantly, the discovery of a unique pathogenic pathway introduces a new notion for the future management of dilated cardiomyopathy. |
| format | Article |
| id | doaj-art-5d351cdb74c74a318e28c7aece5238ca |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-5d351cdb74c74a318e28c7aece5238ca2025-02-09T12:42:13ZengBMCMolecular Medicine1528-36582025-02-0131111710.1186/s10020-025-01103-xTAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytesWenrui Sun0Jianchao Zhang1Shuang Li2Wanrong Fu3Yangyang Liu4Mengduan Liu5Jianzeng Dong6Xiaoyan Zhao7Xiaowei Li8Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversityDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityAbstract Background TGF-β-activated kinase 1 binding protein 2 (TAB2) is an intermediary protein that links Tumor necrosis factor receptor 1 (TNFR1) and other receptor signals to the TGF-β-activated kinase 1 (TAK1) signaling complex. TAB2 frameshift mutations have been linked to dilated cardiomyopathy (DCM), while the exact mechanism needs further investigation. Methods In this study, we generated a TAB2 compound heterozygous knockout cell line in induced pluripotent stem cells (iPSCs) derived from a healthy individual using CRISPR/Cas9 technology. IPSCs are not species-dependent, are readily accessible, and raise fewer ethical concerns. Results TAB2 disruption had no impact on the cardiac differentiation of iPSCs and led to confirmed TAB2 deficiency in human iPSC-derived cardiomyocytes (hiPSC-CMs). TAB2-deficient hiPSC-CMs were found to develop phenotypic features of DCM, such as distorted sarcomeric ultrastructure, decreased contractility and energy production, and mitochondrial damage at day 30 post differentiation. Paradoxically, TAB2 knockout cell lines showed abnormal calcium handling after 40 days, later than reduced contractility, suggesting that the main cause of impaired contractility was abnormal energy production due to mitochondrial damage. As early as day 25, TAB2 knockout cardiomyocytes showed significant mitochondrial calcium overload, which can lead to mitochondrial damage. Furthermore, TAB2 knockout activated receptor-interacting protein kinase 1 (RIPK1), leading to an increase in mitochondrial calcium uniporter (MCU) expression, thereby augmenting the uptake of mitochondrial calcium ions. Finally, the application of the RIPK1 inhibitor Nec-1s prevents the progression of these phenotypes. Conclusions In summary, TAB2 abatement cardiomyocytes mimic dilated cardiomyopathy in vitro. This finding emphasizes the importance of using a human model to study the underlying mechanisms of this specific disease. More importantly, the discovery of a unique pathogenic pathway introduces a new notion for the future management of dilated cardiomyopathy.https://doi.org/10.1186/s10020-025-01103-xTAB2 knockoutIPSCsDilated cardiomyopathyMitochondrial calcium overload |
| spellingShingle | Wenrui Sun Jianchao Zhang Shuang Li Wanrong Fu Yangyang Liu Mengduan Liu Jianzeng Dong Xiaoyan Zhao Xiaowei Li TAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytes Molecular Medicine TAB2 knockout IPSCs Dilated cardiomyopathy Mitochondrial calcium overload |
| title | TAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytes |
| title_full | TAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytes |
| title_fullStr | TAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytes |
| title_full_unstemmed | TAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytes |
| title_short | TAB2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human iPSC-derived cardiomyocytes |
| title_sort | tab2 deficiency induces dilated cardiomyopathy by promoting mitochondrial calcium overload in human ipsc derived cardiomyocytes |
| topic | TAB2 knockout IPSCs Dilated cardiomyopathy Mitochondrial calcium overload |
| url | https://doi.org/10.1186/s10020-025-01103-x |
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