Padhiar Arshad Ahmed, Yang Xiaohong, Zaidi Syed Aqib Ali, Li Zhu, Liao Jinqi, Shu Wei, Chishti Arif Ali, He Liangge, Alam Gulzar, Faqeer Abdullah, Ali Ilyas, Zhang Shuai, Wang Ting, Liu Tao, Zhou Meiling, Wang Gang, Zhou Yan, Zhou Guangqian
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.
Adv Sci (Weinh). 2025 Feb;12(5):e2407398. doi: 10.1002/advs.202407398. Epub 2024 Dec 11.
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 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 in healthy cells. This deregulated Ca 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 homeostasis as a promising therapy for reversing immunosenescence.
携带纯合性核纤层蛋白A/C p.R527C突变的个体表现出严重形式的下颌骨发育不全症（MAD），并呈现出重叠的早衰样症状，其潜在的分子病理学仍不清楚。本文表明，与早衰症（HGPS）患者相比，MAD患者通过不同的促炎细胞因子实现了炎症衰老。对MAD诱导多能干细胞衍生的间充质干细胞（MAD-iMSC）的表征揭示，线粒体钙失调是炎症衰老的主要原因，其通过炎性小体形成而非cGAS-STING途径介导。此外，MAD-iMSC细胞外囊泡（EVs）也可上调健康细胞中的线粒体钙。这种失调的钙稳态是由位于线粒体相关膜（MAM）上的线粒体钙介质、信号转导子和转录激活因子3（STAT3）间接介导的。通过各种FDA批准的MAM-STAT3上游抑制剂，如（托珠单抗）或通过用CRISPR/CAS9纠正R527C突变，可减轻炎症衰老。这些结果为MAD疾病提供了新的见解，并提出将靶向缺陷的线粒体钙稳态作为逆转免疫衰老的一种有前景的治疗方法。
