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Peer-reviewedCC BYAging cell

The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII-DRP1-Mediated Terminal Scission of Mitochondrial-Derived Vesicles.

  • Yaoyu Zhang1,2,3
  • Jialiang Zhang1,2,3
  • Yanjiani Xu1,2,3
  • Wenhua Lei1,2,3
  • Fei Xu1,2,3
  • Junli Li1,2,3
  • Zisong Wei1,2,3
  • Bo Su4
  • Shuang Liu1,2,3
  • Jing Zhou1,2,3
  • Hongde Li1,2,3
  • Junpeng Ran1,2,3
6 more authors
  • Weiya Li1,2,3
  • Tuerhongjiang Tuerdi1,2,3
  • Xiaojiao Wang4
  • Zhi Fang5
  • Fangyang Huang1,2,3
  • Mao Chen1,2,3
5 affiliations
  1. 1Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
  2. 2Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
  3. 3Cardiac Structure and Function Research Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
  4. 4Core Facilities of West China Hospital, Chengdu, Sichuan, China.
  5. 5Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
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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.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026senokine,
  title = {{The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII-DRP1-Mediated Terminal Scission of Mitochondrial-Derived Vesicles.}},
  author = {Yaoyu Zhang and Jialiang Zhang and Yanjiani Xu and Wenhua Lei and Fei Xu and Junli Li and Zisong Wei and Bo Su and Shuang Liu and Jing Zhou and Hongde Li and Junpeng Ran and Weiya Li and Tuerhongjiang Tuerdi and Xiaojiao Wang and Zhi Fang and Fangyang Huang and Mao Chen},
  journal = {Aging cell},
  year = {2026},
  month = oct,
  doi = {10.1111/acel.70758},
  url = {https://europepmc.org/article/MED/42902865},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII-DRP1-Mediated Terminal Scission of Mitochondrial-Derived Vesicles.
AU  - Yaoyu Zhang
AU  - Jialiang Zhang
AU  - Yanjiani Xu
AU  - Wenhua Lei
AU  - Fei Xu
AU  - Junli Li
AU  - Zisong Wei
AU  - Bo Su
AU  - Shuang Liu
AU  - Jing Zhou
AU  - Hongde Li
AU  - Junpeng Ran
AU  - Weiya Li
AU  - Tuerhongjiang Tuerdi
AU  - Xiaojiao Wang
AU  - Zhi Fang
AU  - Fangyang Huang
AU  - Mao Chen
PY  - 2026
DA  - 2026/10/30
JO  - Aging cell
DO  - 10.1111/acel.70758
UR  - https://europepmc.org/article/MED/42902865
AB  - 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.
SN  - 1474-9718
SN  - 1474-9726
ER  -