2. Academic Validation
  3. ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3

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

  • Nat Commun. 2025 Feb 6;16(1):1406. doi: 10.1038/s41467-025-56444-2.
Shiyang Wang # 1,  Xi Wu # 1,  Wenxin Bi 1,  Jiuzhi Xu 2,  Liyuan Hou 2,  Guilin Li 1,  Yuwei Pan 1,  Hanfu Zhang 1,  Mengzhen Li 1,  Sujuan Du 1,  Mingxin Zhang 1,  Di Liu 1,  Shuiling Jin 3,  Xiaojing Shi 4,  Yuhua Tian 4,  Jianwei Shuai 5 6,  Maksim V Plikus 7,  Moshi Song 8 9,  Zhaocai Zhou 10,  Lu Yu 11,  Cong Lv 12,  Zhengquan Yu 13 14 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China.
  • 2 Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, China.
  • 3 Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 4 Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
  • 5 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China.
  • 6 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, China.
  • 7 Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA.
  • 8 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 9 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
  • 10 State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 11 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China. yulu@cau.edu.cn.
  • 12 Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, China. lvc@cau.edu.cn.
  • 13 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China. zyu@cau.edu.cn.
  • 14 Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. zyu@cau.edu.cn.
  • 15 The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. zyu@cau.edu.cn.
  • # Contributed equally.
PMID: 39915446 DOI: 10.1038/s41467-025-56444-2
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.

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