Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells
Objective: Diabetes, characterized by childhood-onset, autoantibody-negativity and insulin-deficiency, is a major manifestation of Wolfram syndrome 2 (WFS2), which is caused by recessive mutations of CISD2. Nevertheless, the mechanism underlying β-cell dysfunction in WFS2 remains elusive. Here we de...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782500047X |
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| author | Zhao-Qing Shen Wen-Tai Chiu Cheng-Heng Kao Yu-Chen Chen Li-Hsien Chen Tsai-Wen Teng Shao-Yu Hsiung Tsai-Yu Tzeng Chien-Yi Tung Chi-Chang Juan Ting-Fen Tsai |
| author_facet | Zhao-Qing Shen Wen-Tai Chiu Cheng-Heng Kao Yu-Chen Chen Li-Hsien Chen Tsai-Wen Teng Shao-Yu Hsiung Tsai-Yu Tzeng Chien-Yi Tung Chi-Chang Juan Ting-Fen Tsai |
| author_sort | Zhao-Qing Shen |
| collection | DOAJ |
| description | Objective: Diabetes, characterized by childhood-onset, autoantibody-negativity and insulin-deficiency, is a major manifestation of Wolfram syndrome 2 (WFS2), which is caused by recessive mutations of CISD2. Nevertheless, the mechanism underlying β-cell dysfunction in WFS2 remains elusive. Here we delineate the essential role of CISD2 in β-cells. Methods: We use β-cell specific Cisd2 knockout (Cisd2KO) mice, a CRISPR-mediated Cisd2KO MIN6 β-cell line and transcriptomic analysis. Results: Four findings are pinpointed. Firstly, β-cell specific Cisd2KO in mice disrupts systemic glucose homeostasis via impairing β-granules synthesis and insulin secretion; hypertrophy of the β-islets and the presence of a loss of identity that affects certain β-cells. Secondly, Cisd2 deficiency leads to impairment of glucose-induced extracellular Ca2+ influx, which compromises Ca2+-mediated insulin secretory signaling, causing mitochondrial dysfunction and, thereby impairing insulin secretion in the MIN6-Cisd2KO β-cells. Thirdly, transcriptomic analysis of β-islets reveals that Cisd2 modulates proteostasis and ER stress, mitochondrial function, insulin secretion and vesicle transport. Finally, the activated state of two potential upstream regulators, Glis3 and Hnf1a, is significantly suppressed under Cisd2 deficiency; notably, their downstream target genes are deeply involved in β-cell function and identity. Conclusions: These findings provide mechanistic insights and form a basis for developing therapeutics for the effective treatment of diabetes in WFS2 patients. |
| format | Article |
| id | doaj-art-e5cbdecb855a46e5b9c8411bf26e84ed |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-e5cbdecb855a46e5b9c8411bf26e84ed2025-08-20T03:48:47ZengElsevierMolecular Metabolism2212-87782025-06-019610214010.1016/j.molmet.2025.102140Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cellsZhao-Qing Shen0Wen-Tai Chiu1Cheng-Heng Kao2Yu-Chen Chen3Li-Hsien Chen4Tsai-Wen Teng5Shao-Yu Hsiung6Tsai-Yu Tzeng7Chien-Yi Tung8Chi-Chang Juan9Ting-Fen Tsai10Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanDepartment of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 701, TaiwanCenter of General Education, Chang Gung University, Taoyuan 333, TaiwanDepartment of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanDepartment of Pharmacology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, TaiwanDepartment of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanDepartment of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanThe National Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112, TaiwanThe National Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112, TaiwanInstitutes of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, TaiwanDepartment of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 350, Taiwan; Corresponding author. 155 Li-Nong St., Sec. 2, Peitou, Taipei 11221, Taiwan.Objective: Diabetes, characterized by childhood-onset, autoantibody-negativity and insulin-deficiency, is a major manifestation of Wolfram syndrome 2 (WFS2), which is caused by recessive mutations of CISD2. Nevertheless, the mechanism underlying β-cell dysfunction in WFS2 remains elusive. Here we delineate the essential role of CISD2 in β-cells. Methods: We use β-cell specific Cisd2 knockout (Cisd2KO) mice, a CRISPR-mediated Cisd2KO MIN6 β-cell line and transcriptomic analysis. Results: Four findings are pinpointed. Firstly, β-cell specific Cisd2KO in mice disrupts systemic glucose homeostasis via impairing β-granules synthesis and insulin secretion; hypertrophy of the β-islets and the presence of a loss of identity that affects certain β-cells. Secondly, Cisd2 deficiency leads to impairment of glucose-induced extracellular Ca2+ influx, which compromises Ca2+-mediated insulin secretory signaling, causing mitochondrial dysfunction and, thereby impairing insulin secretion in the MIN6-Cisd2KO β-cells. Thirdly, transcriptomic analysis of β-islets reveals that Cisd2 modulates proteostasis and ER stress, mitochondrial function, insulin secretion and vesicle transport. Finally, the activated state of two potential upstream regulators, Glis3 and Hnf1a, is significantly suppressed under Cisd2 deficiency; notably, their downstream target genes are deeply involved in β-cell function and identity. Conclusions: These findings provide mechanistic insights and form a basis for developing therapeutics for the effective treatment of diabetes in WFS2 patients.http://www.sciencedirect.com/science/article/pii/S221287782500047XCISD2Wolfram syndrome 2DiabetesCa2+ homeostasisMitochondrial function |
| spellingShingle | Zhao-Qing Shen Wen-Tai Chiu Cheng-Heng Kao Yu-Chen Chen Li-Hsien Chen Tsai-Wen Teng Shao-Yu Hsiung Tsai-Yu Tzeng Chien-Yi Tung Chi-Chang Juan Ting-Fen Tsai Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells Molecular Metabolism CISD2 Wolfram syndrome 2 Diabetes Ca2+ homeostasis Mitochondrial function |
| title | Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells |
| title_full | Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells |
| title_fullStr | Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells |
| title_full_unstemmed | Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells |
| title_short | Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells |
| title_sort | wolfram syndrome 2 gene cisd2 deficiency disrupts ca2 mediated insulin secretion in β cells |
| topic | CISD2 Wolfram syndrome 2 Diabetes Ca2+ homeostasis Mitochondrial function |
| url | http://www.sciencedirect.com/science/article/pii/S221287782500047X |
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