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We investigated whether mitochondrial\u2010derived vesicles (MDVs) released by human valvular interstitial cells (hVICs) exert pro\u2010calcific effects on recipient cells and how MDV release is regulated. Using ex\u00a0vivo hemodynamic perfusion of human CAVD tissue, multi\u2010omics profiling, live\u2010cell single\u2010organelle tracking, MDV transfer assays, and in\u00a0vivo Gas6 deletion, we found that calcifying hVICs hypersecreted MDVs that exerted pro\u2010calcific effects in recipient hVICs. High\u2010resolution imaging showed that mitochondria remodeled into donut\u2010shaped structures under pro\u2010osteogenic conditions; these structures served as physical platforms for MDV budding. Human CAVD valve tissues and hVICs treated with pro\u2010osteogenic medium also exhibited senescence\u2010associated features. Multi\u2010omics profiling identified growth arrest\u2010specific 6 (Gas6), a senokine, among 36 concordantly upregulated candidates. Functional analyzes showed that Gas6 promoted terminal MDV scission while leaving donut\u2010shaped mitochondrial precursor formation intact. Mechanistically, Gas6 promoted intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    accumulation, calcium\/calmodulin\u2010dependent protein kinase II (CaMKII) activation, and dynamin\u2010related protein 1 (DRP1) phosphorylation at Ser616, supporting a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2013CaMKII\u2013DRP1 axis that facilitates terminal MDV scission. Pharmacological inhibition of CaMKII or DRP1 reduced MDV hypersecretion and subsequent recipient\u2010cell calcification, and Gas6 deletion in\u00a0vivo attenuated valvular stenosis, calcification, and fibrotic remodeling. These findings identify Gas6\u2010dependent terminal MDV scission as a mechanism contributing to the intercellular propagation of valvular calcification in a CAVD context characterized by senescence\u2010associated features.\n                  <\/jats:p>","DOI":"10.1111\/acel.70758","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:52:16Z","timestamp":1792565536000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII\u2013DRP1\u2013Mediated Terminal Scission of Mitochondrial\u2010Derived Vesicles"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3263-3617","authenticated-orcid":false,"given":"Yaoyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital Sichuan 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