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

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.

Keywords

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