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Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression

Author

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  • Bingjie Guan

    (Shanghai Jiao Tong University School of Medicine)

  • Youdong Liu

    (Shanghai Jiao Tong University School of Medicine)

  • Bowen Xie

    (Shanghai Jiao Tong University School of Medicine)

  • Senlin Zhao

    (Fudan University Shanghai Cancer Center
    Fudan University)

  • Abudushalamu Yalikun

    (Shanghai Jiao Tong University School of Medicine)

  • Weiwei Chen

    (Shanghai Jiao Tong University School of Medicine)

  • Menghua Zhou

    (Shanghai Jiao Tong University School of Medicine)

  • Qi Gu

    (Shanghai Jiao Tong University School of Medicine)

  • Dongwang Yan

    (Shanghai Jiao Tong University School of Medicine)

Abstract

Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFβ1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFβ1 expression and promoting tumor progression via the TGFβ/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.

Suggested Citation

  • Bingjie Guan & Youdong Liu & Bowen Xie & Senlin Zhao & Abudushalamu Yalikun & Weiwei Chen & Menghua Zhou & Qi Gu & Dongwang Yan, 2024. "Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48100-y
    DOI: 10.1038/s41467-024-48100-y
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