2. Academic Validation
  3. MAM-STAT3-Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients

MAM-STAT3-Driven Mitochondrial Ca+2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients

  • Adv Sci (Weinh). 2025 Feb;12(5):e2407398. doi: 10.1002/advs.202407398.
Arshad Ahmed Padhiar 1 2 3,  Xiaohong Yang 1 4,  Syed Aqib Ali Zaidi 1,  Zhu Li 1,  Jinqi Liao 3 5,  Wei Shu 6,  Arif Ali Chishti 1,  Liangge He 1,  Gulzar Alam 1,  Abdullah Faqeer 1,  Ilyas Ali 1,  Shuai Zhang 1 7,  Ting Wang 3 5 6,  Tao Liu 8,  Meiling Zhou 8,  Gang Wang 3,  Yan Zhou 1 3 5,  Guangqian Zhou 1 3 5
Affiliations

Affiliations

  • 1 Guangdong 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, China.
  • 2 Department of Ecology and Evolutionary Biology, University of Connecticut, Storrs, CT, 06269-3043, USA.
  • 3 Senotherapeutics Ltd., Hangzhou, 311100, China.
  • 4 Department of Laboratory Medicine, Puning Traditional Chinese Medicine Hospital, Puning, Guangdong, 515343, China.
  • 5 Lungene Biotech Ltd., Yinxing Scientific Building, Shenzhen, 510086, China.
  • 6 The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, 541004, China.
  • 7 Brain Research Centre and Department of Biology, Southern University of Science and Technology, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong, 518055, China.
  • 8 Department of Tumor Immunotherapy, Shenzhen Luohu People's Hospital, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, 518001, China.
PMID: 39661729 DOI: 10.1002/advs.202407398
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.

Keywords

calcium homeostasis; extracellular vesicles (EVs); inflammaging; mandibuloacral dysplasia (MADA); mitochondrial dysfunction; progeroid symptoms.

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