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Peer-reviewedCC BY 4.0Advanced Science

CKMT1 Counteracts VDAC1 Oligomerization‐Induced Neuronal Pyroptosis Through Steric Hindrance in Ischemic Stroke

  • Xiaoyu Wang1
  • Sai Shi2
  • Jianghui Wu1
  • Jingge Zhang1,3
  • Shuqin Li1,3
  • Yuyan Hu1,3,4
  • Haifeng Yin1
  • Chenguang Zhao5
  • Dong Ma6
  • Xiaohui Xian1,3,4
  • Lizhe Liu1,3,4
  • Ling Zhao7
6 more authors
  • Xiyun Liu8
  • Zhikai Yu9
  • Lihua Dong6
  • Wenbin Li1,3,4
  • Lingyan Zhang1,3,4
  • Min Zhang1,3,4,10
10 affiliations
  1. 1Department of Pathophysiology Hebei Medical University Shijiazhuang People's Republic of China
  2. 2Department of Medical and Pharmaceutical Informatics Hebei Medical University Shijiazhuang People's Republic of China
  3. 3Hebei Key Laboratory of Critical Disease Mechanism and Intervention Shijiazhuang People's Republic of China
  4. 4The Key Laboratory of Neural and Vascular Biology Hebei Medical University Shijiazhuang People's Republic of China
  5. 5Foreign Languages Department Hebei Medical University Shijiazhuang People's Republic of China
  6. 6Department of Biochemistry and Molecular Biology Hebei Medical University Shijiazhuang People's Republic of China
  7. 7Department of Obstetrics The Fourth Hospital of Hebei Medical University Shijiazhuang People's Republic of China
  8. 8Transformation Center for Scientific and Technological Achievements Hebei University of Chinese Medicine Shijiazhuang People's Republic of China
  9. 9Undergraduate Student in Pediatrics Hebei Medical University Shijiazhuang People's Republic of China
  10. 10Hebei Key Laboratory of Forensic Medicine Hebei Medical University Shijiazhuang People's Republic of China
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Abstract

Ischemic stroke is one of the leading causes of death and disability worldwide; yet effective therapeutic options remain limited. Cytosolic leakage of mitochondrial DNA (mtDNA) is a critical driver of ischemic brain injury. Voltage‐dependent anion channel 1 (VDAC1), embedded in the mitochondrial outer membrane, promotes mtDNA leakage through oligomerization. However, the regulatory mechanisms underlying VDAC1 oligomerization in ischemic stroke remain poorly understood. This study demonstrates that ischemic stroke promotes VDAC1 oligomerization, leading to mtDNA leakage, activating the absent in melanoma 2 (AIM2) inflammasome, and subsequent neuronal pyroptosis. Pharmacological inhibition of VDAC1 oligomerization using VBIT‐4 effectively disrupts this cascade. Creatine kinase mitochondrial 1 (CKMT1) is identified as a novel endogenous inhibitor of VDAC1 oligomerization. CKMT1 inhibits VDAC1 oligomerization through a dual‐region synergistic mechanism. Specifically, the N‐terminal domain of CKMT1 (residues R75 and E121) forms a stable interface with the C‐terminal domain of VDAC1 (residues R218 and E189), whereas the CKMT1 signal peptide (residues 1–39) sterically hinders VDAC1 dimerization, thereby blocking oligomerization. Moreover, neuronal overexpression of CKMT1 significantly attenuates neuronal apoptosis, whereas CKMT1 knockdown aggravates neuronal injury. Collectively, these findings demonstrate that CKMT1 protects against cerebral ischemic injury by suppressing the VDAC1–mtDNA–AIM2 axis and identify CKMT1 as a novel therapeutic target for ischemic stroke.

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Cite

BibTeXRIS
BibTeX
@article{wang2026ckmt1,
  title = {{CKMT1 Counteracts VDAC1 Oligomerization‐Induced Neuronal Pyroptosis Through Steric Hindrance in Ischemic Stroke}},
  author = {Xiaoyu Wang and Sai Shi and Jianghui Wu and Jingge Zhang and Shuqin Li and Yuyan Hu and Haifeng Yin and Chenguang Zhao and Dong Ma and Xiaohui Xian and Lizhe Liu and Ling Zhao and Xiyun Liu and Zhikai Yu and Lihua Dong and Wenbin Li and Lingyan Zhang and Min Zhang},
  journal = {Advanced Science},
  year = {2026},
  month = nov,
  doi = {10.1002/advs.78611},
  url = {https://doi.org/10.1002/advs.78611},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - CKMT1 Counteracts VDAC1 Oligomerization‐Induced Neuronal Pyroptosis Through Steric Hindrance in Ischemic Stroke
AU  - Xiaoyu Wang
AU  - Sai Shi
AU  - Jianghui Wu
AU  - Jingge Zhang
AU  - Shuqin Li
AU  - Yuyan Hu
AU  - Haifeng Yin
AU  - Chenguang Zhao
AU  - Dong Ma
AU  - Xiaohui Xian
AU  - Lizhe Liu
AU  - Ling Zhao
AU  - Xiyun Liu
AU  - Zhikai Yu
AU  - Lihua Dong
AU  - Wenbin Li
AU  - Lingyan Zhang
AU  - Min Zhang
PY  - 2026
DA  - 2026/11/05
JO  - Advanced Science
DO  - 10.1002/advs.78611
UR  - https://doi.org/10.1002/advs.78611
AB  - Ischemic stroke is one of the leading causes of death and disability worldwide; yet effective therapeutic options remain limited. Cytosolic leakage of mitochondrial DNA (mtDNA) is a critical driver of ischemic brain injury. Voltage‐dependent anion channel 1 (VDAC1), embedded in the mitochondrial outer membrane, promotes mtDNA leakage through oligomerization. However, the regulatory mechanisms underlying VDAC1 oligomerization in ischemic stroke remain poorly understood. This study demonstrates that ischemic stroke promotes VDAC1 oligomerization, leading to mtDNA leakage, activating the absent in melanoma 2 (AIM2) inflammasome, and subsequent neuronal pyroptosis. Pharmacological inhibition of VDAC1 oligomerization using VBIT‐4 effectively disrupts this cascade. Creatine kinase mitochondrial 1 (CKMT1) is identified as a novel endogenous inhibitor of VDAC1 oligomerization. CKMT1 inhibits VDAC1 oligomerization through a dual‐region synergistic mechanism. Specifically, the N‐terminal domain of CKMT1 (residues R75 and E121) forms a stable interface with the C‐terminal domain of VDAC1 (residues R218 and E189), whereas the CKMT1 signal peptide (residues 1–39) sterically hinders VDAC1 dimerization, thereby blocking oligomerization. Moreover, neuronal overexpression of CKMT1 significantly attenuates neuronal apoptosis, whereas CKMT1 knockdown aggravates neuronal injury. Collectively, these findings demonstrate that CKMT1 protects against cerebral ischemic injury by suppressing the VDAC1–mtDNA–AIM2 axis and identify CKMT1 as a novel therapeutic target for ischemic stroke.
SN  - 2198-3844
ER  -