2. Academic Validation
  3. CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis

CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis

  • Cell Death Dis. 2025 Mar 15;16(1):177. doi: 10.1038/s41419-025-07504-4.
Zhijie Wang # 1 2 3 4,  Haicong Wu # 1 3 5,  Xin Chang # 1 3 4,  Yihang Song # 1 3 4,  Yan Chen # 3 4,  Ziwei Yan 1 3 4,  Lun Gu 1 4,  Ruxi Pang 1 4,  Tian Xia 1 3 4,  Zixuan He 1 4,  Zhaoshen Li 6 7 8 9,  Shuling Wang 10 11 12 13,  Yu Bai 14 15 16
Affiliations

Affiliations

  • 1 National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.
  • 2 Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
  • 3 National Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, China.
  • 4 Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China.
  • 5 Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan, China.
  • 6 National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China. lizhaoshen0708@sina.com.
  • 7 National Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, China. lizhaoshen0708@sina.com.
  • 8 Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China. lizhaoshen0708@sina.com.
  • 9 Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan, China. lizhaoshen0708@sina.com.
  • 10 National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China. wangshuling0000@126.com.
  • 11 National Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, China. wangshuling0000@126.com.
  • 12 Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China. wangshuling0000@126.com.
  • 13 Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. wangshuling0000@126.com.
  • 14 National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China. baiyu1998@hotmail.com.
  • 15 National Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, China. baiyu1998@hotmail.com.
  • 16 Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China. baiyu1998@hotmail.com.
  • # Contributed equally.
PMID: 40089459 DOI: 10.1038/s41419-025-07504-4
Abstract

Mitochondrial dysfunction contributes to the pathogenesis of ulcerative colitis (UC). As a mitochondrial isozyme of creatine kinases, which control energy metabolism, CKMT1 is thought to be a critical molecule in biological processes. However, the specific role of CKMT1 in intestinal inflammation remains largely unknown. Here, we observed markedly decreased CKMT1 expression in the colon tissues of UC patients and dextran sodium sulfate (DSS)-induced colitis mice. We generated intestinal epithelial-specific CKMT1 knockout mice and demonstrated the key role of CKMT1 in mitochondrial homeostasis, intestinal epithelial barrier function, oxidative stress, and Apoptosis. In the in vitro experiments, CKMT1 expression limited the activation of the intrinsic and extrinsic apoptotic pathways in IECs. Mechanistically, the loss of CKMT1 expression in IECs increased TNF-α-induced mitochondrial Reactive Oxygen Species (ROS) generation via reverse electron transfer (RET). RET-ROS promoted mitochondrial permeability transition pore (mPTP) opening, ultimately resulting in cell Apoptosis during intestinal inflammation. In conclusion, our data demonstrated that CKMT1 is important in maintaining intestinal homeostasis and mitochondrial function. This study provides a promising basis for future research and a potential therapeutic target for inflammatory bowel disease (IBD).

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