Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy
Abstract Homocysteine can cause damage to cardiomyocytes. However, Mitophagy is essential for preserving homeostasis in cardiomyocytes. So, we focused on investigating the impact of homocysteine on cardiomyocyte mitophagy and cardiac hypertrophy through the β-catenin/FUNDC1 pathway. Mice were admini...
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Nature Portfolio
2025-07-01
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| author | Yanping Lei Hengjing Hu Huifang Tang Hui Sun Rui Liu Yue Zhao |
| author_facet | Yanping Lei Hengjing Hu Huifang Tang Hui Sun Rui Liu Yue Zhao |
| author_sort | Yanping Lei |
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| description | Abstract Homocysteine can cause damage to cardiomyocytes. However, Mitophagy is essential for preserving homeostasis in cardiomyocytes. So, we focused on investigating the impact of homocysteine on cardiomyocyte mitophagy and cardiac hypertrophy through the β-catenin/FUNDC1 pathway. Mice were administered water containing homocysteine (1.8 g/L) to induce hyperhomocysteinemia for 4 weeks. The overexpression of specific genes, including β-catenin and FUNDC1, were performed by gene delivery mediated with adeno-associated virus. In vitro, cardiomyocytes were exposed to homocysteine (1 mmol/L) and then transfected with plasmids to overexpress β-catenin and FUNDC1, respectively. The duration of cell experiments was 48 h. Western blotting was employed to assess the expression levels of β-catenin, active β-catenin, FUNDC1, LC3, p62, α-actin, and β-MHC. Immunohistochemistry and immunofluorescence techniques were applied to measure β-catenin and FUNDC1 in cardiomyocytes. Cell viability was assessed using a CCK-8 assay kit, and mitophagy was observed under transmission electron microscopy. The interaction between β-catenin protein and the promoter of the FUNDC1 gene was examined using ChIP assay and dual-luciferase reporter gene assay. Homocysteine inhibited β-catenin signaling and the FUNDC1-mediated mitophagy in the cardiomyocytes, simultaneously promoting cardiac hypertrophy in vitro and in vivo. Elevated β-catenin signaling promoted FUNDC1 expression, then restored the normal level of mitophagy, and consequently inhibited homocysteine-induced cardiac hypertrophy. Similarly, overexpression of FUNDC1 restored mitophagy and protected cardiomyocytes from hypertrophy. In addition, FUNDC1 served as a target gene of β-catenin. In summary, homocysteine induces cardiomyocyte hypertrophy by inhibiting β-catenin signaling and suppressing FUNDC1-mediated mitophagy. |
| format | Article |
| id | doaj-art-350681677ce14fdebafb48ab3a8d2ddf |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-350681677ce14fdebafb48ab3a8d2ddf2025-08-20T03:37:27ZengNature PortfolioScientific Reports2045-23222025-07-0115111310.1038/s41598-025-06772-6Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagyYanping Lei0Hengjing Hu1Huifang Tang2Hui Sun3Rui Liu4Yue Zhao5Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South ChinaThe First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South ChinaThe First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South ChinaInstitute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South ChinaThe First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South ChinaThe First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South ChinaAbstract Homocysteine can cause damage to cardiomyocytes. However, Mitophagy is essential for preserving homeostasis in cardiomyocytes. So, we focused on investigating the impact of homocysteine on cardiomyocyte mitophagy and cardiac hypertrophy through the β-catenin/FUNDC1 pathway. Mice were administered water containing homocysteine (1.8 g/L) to induce hyperhomocysteinemia for 4 weeks. The overexpression of specific genes, including β-catenin and FUNDC1, were performed by gene delivery mediated with adeno-associated virus. In vitro, cardiomyocytes were exposed to homocysteine (1 mmol/L) and then transfected with plasmids to overexpress β-catenin and FUNDC1, respectively. The duration of cell experiments was 48 h. Western blotting was employed to assess the expression levels of β-catenin, active β-catenin, FUNDC1, LC3, p62, α-actin, and β-MHC. Immunohistochemistry and immunofluorescence techniques were applied to measure β-catenin and FUNDC1 in cardiomyocytes. Cell viability was assessed using a CCK-8 assay kit, and mitophagy was observed under transmission electron microscopy. The interaction between β-catenin protein and the promoter of the FUNDC1 gene was examined using ChIP assay and dual-luciferase reporter gene assay. Homocysteine inhibited β-catenin signaling and the FUNDC1-mediated mitophagy in the cardiomyocytes, simultaneously promoting cardiac hypertrophy in vitro and in vivo. Elevated β-catenin signaling promoted FUNDC1 expression, then restored the normal level of mitophagy, and consequently inhibited homocysteine-induced cardiac hypertrophy. Similarly, overexpression of FUNDC1 restored mitophagy and protected cardiomyocytes from hypertrophy. In addition, FUNDC1 served as a target gene of β-catenin. In summary, homocysteine induces cardiomyocyte hypertrophy by inhibiting β-catenin signaling and suppressing FUNDC1-mediated mitophagy.https://doi.org/10.1038/s41598-025-06772-6Homocysteineβ-cateninFUNDC1MitophagyCardiomyocyte hypertrophy |
| spellingShingle | Yanping Lei Hengjing Hu Huifang Tang Hui Sun Rui Liu Yue Zhao Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy Scientific Reports Homocysteine β-catenin FUNDC1 Mitophagy Cardiomyocyte hypertrophy |
| title | Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy |
| title_full | Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy |
| title_fullStr | Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy |
| title_full_unstemmed | Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy |
| title_short | Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy |
| title_sort | homocysteine promotes cardiomyocyte hypertrophy through inhibiting β catenin fundc1 mediated mitophagy |
| topic | Homocysteine β-catenin FUNDC1 Mitophagy Cardiomyocyte hypertrophy |
| url | https://doi.org/10.1038/s41598-025-06772-6 |
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