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journal article·2025-02Open access

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

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

Advanced Science· Volume 12· Issue 5
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Abstract

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.
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Research context

OpenAlex topics: Nuclear Structure and Function · Mitochondrial Function and Pathology · RNA modifications and cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

Department of Ecology and Evolutionary Biology University of Connecticut Storrs CT 06269‐3043 USA

Senotherapeutics Ltd. Hangzhou 311100 China

Department of Laboratory Medicine Puning Traditional Chinese Medicine Hospital Puning Guangdong 515343 China

Lungene Biotech Ltd. Yinxing Scientific Building Shenzhen 510086 China

The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath Guilin Medical University Guilin 541004 China

Brain Research Centre and Department of Biology Southern University of Science and Technology 1088 Xueyuan Blvd, Nanshan District Shenzhen Guangdong 518055 China

Department of Tumor Immunotherapy Shenzhen Luohu People's Hospital The Third Affiliated Hospital of Shenzhen University Shenzhen Guangdong 518001 China

Funding

National Natural Science Foundation of China

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