{
  "abstract": "Calcific aortic valve disease (CAVD) is an age-associated valvular disorder in which calcification expands from discrete foci into adjacent tissue. We investigated whether mitochondrial-derived vesicles (MDVs) released by human valvular interstitial cells (hVICs) exert pro-calcific effects on recipient cells and how MDV release is regulated. Using ex vivo hemodynamic perfusion of human CAVD tissue, multi-omics profiling, live-cell single-organelle tracking, MDV transfer assays, and in vivo Gas6 deletion, we found that calcifying hVICs hypersecreted MDVs that exerted pro-calcific effects in recipient hVICs. High-resolution imaging showed that mitochondria remodeled into donut-shaped structures under pro-osteogenic conditions; these structures served as physical platforms for MDV budding. Human CAVD valve tissues and hVICs treated with pro-osteogenic medium also exhibited senescence-associated features. Multi-omics profiling identified growth arrest-specific 6 (Gas6), a senokine, among 36 concordantly upregulated candidates. Functional analyzes showed that Gas6 promoted terminal MDV scission while leaving donut-shaped mitochondrial precursor formation intact. Mechanistically, Gas6 promoted intracellular Ca²⁺ accumulation, calcium/calmodulin-dependent protein kinase II (CaMKII) activation, and dynamin-related protein 1 (DRP1) phosphorylation at Ser616, supporting a Ca²⁺-CaMKII-DRP1 axis that facilitates terminal MDV scission. Pharmacological inhibition of CaMKII or DRP1 reduced MDV hypersecretion and subsequent recipient-cell calcification, and Gas6 deletion in vivo attenuated valvular stenosis, calcification, and fibrotic remodeling. These findings identify Gas6-dependent terminal MDV scission as a mechanism contributing to the intercellular propagation of valvular calcification in a CAVD context characterized by senescence-associated features.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, People's Republic of China.",
    "Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.",
    "Cardiac Structure and Function Research Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, People's Republic of China.",
    "Core Facilities of West China Hospital, Chengdu, Sichuan, China.",
    "Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yaoyu Zhang",
      "orcid": "0009-0001-3263-3617"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Jialiang Zhang",
      "orcid": "0000-0001-7737-0323"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yanjiani Xu",
      "orcid": "0000-0002-7765-514X"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Wenhua Lei",
      "orcid": "0000-0002-5324-3503"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Fei Xu"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Junli Li"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Zisong Wei",
      "orcid": "0009-0004-4710-5333"
    },
    {
      "affs": [
        3
      ],
      "name": "Bo Su"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Shuang Liu"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Jing Zhou"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Hongde Li",
      "orcid": "0009-0008-0701-2393"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Junpeng Ran",
      "orcid": "0009-0003-1381-6797"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Weiya Li"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Tuerhongjiang Tuerdi",
      "orcid": "0009-0000-7101-351X"
    },
    {
      "affs": [
        3
      ],
      "name": "Xiaojiao Wang",
      "orcid": "0000-0002-7091-9923"
    },
    {
      "affs": [
        4
      ],
      "name": "Zhi Fang",
      "orcid": "0000-0002-0724-8485"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Fangyang Huang",
      "orcid": "0000-0002-3049-2996"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Mao Chen",
      "orcid": "0000-0002-7352-0563"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dt0rtzyks1dxp.bib",
  "cited_by": 0,
  "doi": "10.1111/acel.70758",
  "fulltext_url": "https://europepmc.org/articles/PMC13684317",
  "id": "dt0rtzyks1dxp",
  "issns": [
    "1474-9718",
    "1474-9726"
  ],
  "landing_url": "https://europepmc.org/article/MED/42902865",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Mitochondrial Function and Pathology"
    ]
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  "openalex": "W7223081610",
  "pdf_url": "https://europepmc.org/articles/PMC13684317?pdf=render",
  "pmcid": "PMC13684317",
  "pmid": "42902865",
  "published": "2026-10-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dt0rtzyks1dxp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:53Z",
      "native_id": "MED:42902865",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42902865"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Mitochondrial Function and Pathology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII-DRP1-Mediated Terminal Scission of Mitochondrial-Derived Vesicles.",
  "title_text": "The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII-DRP1-Mediated Terminal Scission of Mitochondrial-Derived Vesicles.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:53Z",
  "url": "https://research.draconitic.com/paper/dt0rtzyks1dxp",
  "venue": "Aging cell",
  "versions": []
}