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ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3

Author

Listed:
  • Shiyang Wang

    (China Agricultural University)

  • Xi Wu

    (China Agricultural University)

  • Wenxin Bi

    (China Agricultural University)

  • Jiuzhi Xu

    (China Agricultural University)

  • Liyuan Hou

    (China Agricultural University)

  • Guilin Li

    (China Agricultural University)

  • Yuwei Pan

    (China Agricultural University)

  • Hanfu Zhang

    (China Agricultural University)

  • Mengzhen Li

    (China Agricultural University)

  • Sujuan Du

    (China Agricultural University)

  • Mingxin Zhang

    (China Agricultural University)

  • Di Liu

    (China Agricultural University)

  • Shuiling Jin

    (the First Affiliated Hospital of Zhengzhou University)

  • Xiaojing Shi

    (Zhengzhou University)

  • Yuhua Tian

    (Zhengzhou University)

  • Jianwei Shuai

    (University of Chinese Academy of Sciences
    Vision and Brain Health))

  • Maksim V. Plikus

    (Irvine)

  • Moshi Song

    (Chinese Academy of Sciences
    Beijing Institute for Stem Cell and Regenerative Medicine)

  • Zhaocai Zhou

    (Fudan University)

  • Lu Yu

    (China Agricultural University)

  • Cong Lv

    (China Agricultural University)

  • Zhengquan Yu

    (China Agricultural University
    Zhengzhou University
    The First Affiliated Hospital of Zhengzhou University)

Abstract

Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.

Suggested Citation

  • Shiyang Wang & Xi Wu & Wenxin Bi & Jiuzhi Xu & Liyuan Hou & Guilin Li & Yuwei Pan & Hanfu Zhang & Mengzhen Li & Sujuan Du & Mingxin Zhang & Di Liu & Shuiling Jin & Xiaojing Shi & Yuhua Tian & Jianwei , 2025. "ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56444-2
    DOI: 10.1038/s41467-025-56444-2
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    References listed on IDEAS

    as
    1. Derek C. Radisky & Dinah D. Levy & Laurie E. Littlepage & Hong Liu & Celeste M. Nelson & Jimmie E. Fata & Devin Leake & Elizabeth L. Godden & Donna G. Albertson & M. Angela Nieto & Zena Werb & Mina J., 2005. "Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability," Nature, Nature, vol. 436(7047), pages 123-127, July.
    2. Sanghee Lim & Nicole Hermance & Tenny Mudianto & Hatim M. Mustaly & Ian Paolo Morelos Mauricio & Marc A. Vittoria & Ryan J. Quinton & Brian W. Howell & Hauke Cornils & Amity L. Manning & Neil J. Ganem, 2019. "Identification of the kinase STK25 as an upstream activator of LATS signaling," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
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