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Although Mcu has been studied in various physiological contexts, its role in skeletal homeostasis remains poorly understood. Here we investigate how\n                    <jats:italic>Mcu<\/jats:italic>\n                    deficiency affects osteoblast differentiation and bone formation under aging-related stress. Using an inducible whole-body\n                    <jats:italic>Mcu<\/jats:italic>\n                    -knockout mouse model, we found that\n                    <jats:italic>Mcu<\/jats:italic>\n                    deletion resulted in impaired mitochondrial calcium uptake, reduced oxidative phosphorylation, fragmented mitochondrial morphology and decreased expression of osteogenic genes, leading to defective osteogenesis. Concurrently, adipogenic markers were elevated in\n                    <jats:italic>Mcu<\/jats:italic>\n                    -deficient bone marrow cells, indicating altered mesenchymal lineage commitment. Mechanistically,\n                    <jats:italic>Mcu<\/jats:italic>\n                    -deficient cells exhibited enhanced TGF-\u03b2 signaling and reduced BMP\/Wnt pathway activity. In vivo, inducible whole-body\n                    <jats:italic>Mcu<\/jats:italic>\n                    -knockout mice exhibited reduced trabecular bone volume and density while maintaining normal skeletal growth. Pharmacological modulation of mitochondrial calcium influx using kaempferol enhanced osteogenic differentiation and mitochondrial respiration in wild-type, but not\n                    <jats:italic>Mcu<\/jats:italic>\n                    -deficient, cells. Consistently, analysis of publicly available human datasets revealed age- and osteoporosis-associated downregulation of\n                    <jats:italic>MCU<\/jats:italic>\n                    expression in bone tissues. These findings suggest that Mcu regulates bone formation by controlling mitochondrial calcium uptake and mesenchymal lineage allocation. Targeting mitochondrial calcium signaling may offer novel therapeutic strategies for age-related skeletal disorders.\n                  <\/jats:p>","DOI":"10.1038\/s12276-026-01705-3","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:17:43Z","timestamp":1777605463000},"page":"1439-1448","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mcu regulates bone formation via mitochondrial calcium uptake and lineage allocation"],"prefix":"10.1038","volume":"58","author":[{"given":"Suji","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tue","family":"Nguyen Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0322-9807","authenticated-orcid":false,"given":"Kyu-sang","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0515-0860","authenticated-orcid":false,"given":"Jun","family":"Namkung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"1705_CR1","doi-asserted-by":"publisher","unstructured":"Kim, J. 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