MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients
Abstract Individuals with homozygous laminA/C p.R527C mutations manifest a severe form of Mandibuloacral dysplasia‐(MAD) and exhibit overlapping progeroid symptoms, for which the underlying molecular pathology remains unknown. Herein, it is shown that MAD patients achieved inflammaging with differen...
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| Language: | English |
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407398 |
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| author | Arshad Ahmed Padhiar Xiaohong Yang Syed Aqib Ali Zaidi Zhu Li Jinqi Liao Wei Shu Arif Ali Chishti Liangge He Gulzar Alam Abdullah Faqeer Ilyas Ali Shuai Zhang Ting Wang Tao Liu Meiling Zhou Gang Wang Yan Zhou Guangqian Zhou |
| author_facet | Arshad Ahmed Padhiar Xiaohong Yang Syed Aqib Ali Zaidi Zhu Li Jinqi Liao Wei Shu Arif Ali Chishti Liangge He Gulzar Alam Abdullah Faqeer Ilyas Ali Shuai Zhang Ting Wang Tao Liu Meiling Zhou Gang Wang Yan Zhou Guangqian Zhou |
| author_sort | Arshad Ahmed Padhiar |
| collection | DOAJ |
| description | Abstract Individuals with homozygous laminA/C p.R527C mutations manifest a severe form of Mandibuloacral dysplasia‐(MAD) and exhibit overlapping progeroid symptoms, for which the underlying molecular pathology remains unknown. Herein, it is shown that MAD patients achieved inflammaging with different pro‐inflammatory cytokines compared to progeria‐(HGPS) patient. Characterization of MAD iPSC‐derived Mesenchymal stem cells (MAD‐iMSC) uncovers deregulated mitochondrial Ca+2 as the primary cause of inflammaging, mediated through inflammasome formation rather than the cGAS‐STING pathway. Moreover, MAD‐iMSCs extracellular vesicles (EVs) can also upregulate mitochondrial Ca+2 in healthy cells. This deregulated Ca+2 homeostasis is indirectly mediated by mitochondrial calcium mediator, signal transducer, and activator of transcription‐3 (STAT3), situated on the mitochondrial associated membrane (MAM). Inflammaging is mitigated by various FDA‐approved MAM‐STAT3 upstream inhibitors, such as (Tocilizumab) or by correcting R527C mutation with CRISPR/CAS9. These results provide new insights into MAD disease and propose targeting defective mitochondrial Ca+2 homeostasis as a promising therapy for reversing immunosenescence. |
| format | Article |
| id | doaj-art-03e67f2f96f147c496ee8dea787f38a8 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-03e67f2f96f147c496ee8dea787f38a82025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202407398MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia PatientsArshad Ahmed Padhiar0Xiaohong Yang1Syed Aqib Ali Zaidi2Zhu Li3Jinqi Liao4Wei Shu5Arif Ali Chishti6Liangge He7Gulzar Alam8Abdullah Faqeer9Ilyas Ali10Shuai Zhang11Ting Wang12Tao Liu13Meiling Zhou14Gang Wang15Yan Zhou16Guangqian Zhou17Guangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaSenotherapeutics Ltd. Hangzhou 311100 ChinaThe Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath Guilin Medical University Guilin 541004 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaSenotherapeutics Ltd. Hangzhou 311100 ChinaDepartment of Tumor Immunotherapy Shenzhen Luohu People's Hospital The Third Affiliated Hospital of Shenzhen University Shenzhen Guangdong 518001 ChinaDepartment of Tumor Immunotherapy Shenzhen Luohu People's Hospital The Third Affiliated Hospital of Shenzhen University Shenzhen Guangdong 518001 ChinaSenotherapeutics Ltd. Hangzhou 311100 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaGuangdong Key Laboratory of Genomic Stability and Disease Prevention Shenzhen Key Laboratory of Anti‐Aging and Regenerative Medicine Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases Department of Medical Cell Biology and Genetics Health Science Center Shenzhen University Shenzhen 518060 ChinaAbstract Individuals with homozygous laminA/C p.R527C mutations manifest a severe form of Mandibuloacral dysplasia‐(MAD) and exhibit overlapping progeroid symptoms, for which the underlying molecular pathology remains unknown. Herein, it is shown that MAD patients achieved inflammaging with different pro‐inflammatory cytokines compared to progeria‐(HGPS) patient. Characterization of MAD iPSC‐derived Mesenchymal stem cells (MAD‐iMSC) uncovers deregulated mitochondrial Ca+2 as the primary cause of inflammaging, mediated through inflammasome formation rather than the cGAS‐STING pathway. Moreover, MAD‐iMSCs extracellular vesicles (EVs) can also upregulate mitochondrial Ca+2 in healthy cells. This deregulated Ca+2 homeostasis is indirectly mediated by mitochondrial calcium mediator, signal transducer, and activator of transcription‐3 (STAT3), situated on the mitochondrial associated membrane (MAM). Inflammaging is mitigated by various FDA‐approved MAM‐STAT3 upstream inhibitors, such as (Tocilizumab) or by correcting R527C mutation with CRISPR/CAS9. These results provide new insights into MAD disease and propose targeting defective mitochondrial Ca+2 homeostasis as a promising therapy for reversing immunosenescence.https://doi.org/10.1002/advs.202407398calcium homeostasisextracellular vesicles (EVs)inflammagingmandibuloacral dysplasia (MADA)mitochondrial dysfunctionprogeroid symptoms |
| spellingShingle | Arshad Ahmed Padhiar Xiaohong Yang Syed Aqib Ali Zaidi Zhu Li Jinqi Liao Wei Shu Arif Ali Chishti Liangge He Gulzar Alam Abdullah Faqeer Ilyas Ali Shuai Zhang Ting Wang Tao Liu Meiling Zhou Gang Wang Yan Zhou Guangqian Zhou MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients Advanced Science calcium homeostasis extracellular vesicles (EVs) inflammaging mandibuloacral dysplasia (MADA) mitochondrial dysfunction progeroid symptoms |
| title | MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients |
| title_full | MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients |
| title_fullStr | MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients |
| title_full_unstemmed | MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients |
| title_short | MAM‐STAT3‐Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients |
| title_sort | mam stat3 driven mitochondrial ca 2 upregulation contributes to immunosenescence in type a mandibuloacral dysplasia patients |
| topic | calcium homeostasis extracellular vesicles (EVs) inflammaging mandibuloacral dysplasia (MADA) mitochondrial dysfunction progeroid symptoms |
| url | https://doi.org/10.1002/advs.202407398 |
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