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

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 Shuai, Maksim V. Plikus, Moshi Song, Zhaocai Zhou, Lu Yu (), Cong Lv () and Zhengquan Yu ()
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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
Maksim V. Plikus: Irvine
Moshi Song: Chinese Academy of Sciences
Zhaocai Zhou: Fudan University
Lu Yu: China Agricultural University
Cong Lv: China Agricultural University
Zhengquan Yu: China Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56444-2

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