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MSCs can perceive variations in the firmness of the extracellular matrix and respond by regulating mitochondrial function. Diminished mitochondrial function is intricately linked to cellular aging, and studies have shown that mitochondria\u2010lysosome contacts (M\u2010L contacts) can regulate mitochondrial function to sustain cellular equilibrium. Nonetheless, the influence of M\u2010L contacts on MSC aging under varying matrix stiffness remains unclear. In this study, utilizing single\u2010cell RNA sequencing and atomic force microscopy, we further demonstrate that reduced matrix stiffness in older individuals leads to MSC aging and subsequent decline in osteogenic ability. Mechanistically, augmented M\u2010L contacts under low matrix stiffness exacerbate MSC aging by escalating mitochondrial oxidative stress and peripheral division. Moreover, under soft matrix stiffness, cytoskeleton reorganization facilitates rapid movement of lysosomes. The M\u2010L contacts inhibitor ML282 ameliorates MSC aging by reinstating mitochondrial network and function. Overall, our findings confirm that MSC aging is instigated by disruption of the mitochondrial network and function induced by matrix stiffness, while also elucidating the potential mechanism by which M\u2010L Contact regulates mitochondrial homeostasis. Crucially, this presents promise for cellular anti\u2010aging strategies centred on mitochondria, particularly in the realm of stem cell therapy.<\/jats:p>","DOI":"10.1111\/cpr.13746","type":"journal-article","created":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T00:43:56Z","timestamp":1727829836000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Matrix stiffness regulates mitochondria\u2010lysosome contacts to modulate the mitochondrial network, alleviate the senescence of <scp>MSCs<\/scp>"],"prefix":"10.1111","volume":"58","author":[{"given":"Kang","family":"Wang","sequence":"first","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology Sun Yat\u2010sen University  Guangzhou People's Republic of China"},{"name":"Guangdong Provincial Key Laboratory of Stomatology  Guangzhou People's Republic of 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