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Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer

Author

Listed:
  • Yi Wang

    (China Pharmaceutical University)

  • Hao-Yuan Yu

    (China Pharmaceutical University)

  • Zi-Juan Yi

    (China Pharmaceutical University)

  • Lian-Yu Qi

    (China Pharmaceutical University)

  • Jing-Song Yang

    (China Pharmaceutical University)

  • Hai-Xin Xie

    (China Pharmaceutical University)

  • Min Zhao

    (China Pharmaceutical University)

  • Na-Hui Liu

    (China Pharmaceutical University)

  • Jia-Qi Chen

    (China Pharmaceutical University)

  • Tian-Jiao Zhou

    (China Pharmaceutical University)

  • Lei Xing

    (China Pharmaceutical University)

  • Xian-Wu Cheng

    (Yanbian University Hospital)

  • Hu-Lin Jiang

    (China Pharmaceutical University
    Yanbian University Hospital
    China Pharmaceutical University
    Sungkyunkwan University)

Abstract

Mitochondria transfer is a spontaneous process that releases functional mitochondria to damaged cells via different mechanisms including extracellular vesicle containing mitochondria (EV-Mito) to restore mitochondrial functions. However, the limited EV-Mito yield makes it challenging to supply a sufficient quantity of functional mitochondria to damaged cells, hindering their application in mitochondrial diseases. Here, we show that the release of EV-Mito from mesenchymal stem cells (MSCs) is regulated by a calcium-dependent mechanism involving CD38 and IP3R signaling (CD38/IP3R/Ca2+ pathway). Activating this pathway through our non-viral gene engineering approach generates super donor MSCs which produce Super-EV-Mito with a threefold increase in yield compared to Ctrl-EV-Mito from normal MSCs. Leber’s hereditary optic neuropathy (LHON), a classic mitochondrial disease caused by mtDNA mutations, is used as a proof-of-concept model. Super-EV-Mito rescues mtDNA defects and alleviates LHON-associated symptoms in LHON male mice. This strategy offers a promising avenue for enhancing mitochondria transfer efficiency and advancing its clinical application in mitochondrial disorders.

Suggested Citation

  • Yi Wang & Hao-Yuan Yu & Zi-Juan Yi & Lian-Yu Qi & Jing-Song Yang & Hai-Xin Xie & Min Zhao & Na-Hui Liu & Jia-Qi Chen & Tian-Jiao Zhou & Lei Xing & Xian-Wu Cheng & Hu-Lin Jiang, 2025. "Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64486-9
    DOI: 10.1038/s41467-025-64486-9
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    References listed on IDEAS

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