2. Academic Validation
  3. Tk2 deficiency-mediated mitochondrial dysfunction drives neuroinflammation and seizure frequency in epilepsy

Tk2 deficiency-mediated mitochondrial dysfunction drives neuroinflammation and seizure frequency in epilepsy

  • Neuroscience. 2026 Feb 16:595:171-186. doi: 10.1016/j.neuroscience.2026.01.001.
Xi Zhang 1,  Jiahao Lian 1,  Yongbin Pang 2,  Haohao Cui 1,  Xiaobo Ye 1,  Qiang Meng 1,  Yong Liu 1,  Huanfa Li 1,  Yutao Ren 1,  Ying Zhang 3,  Hua Zhang 4,  Hao Wu 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Neurosurgery, Cardiovascular and Cerebrovascular Disease Hospital, Yan'an University, Yan'an, China.
  • 3 Instrument Analysis Center, Xi'an Jiaotong University, Xi'an, China.
  • 4 Department of Neurosurgery, Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
  • 5 Department of Neurosurgery, Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
PMID: 41500441 DOI: 10.1016/j.neuroscience.2026.01.001
Abstract

Seizure frequency is a key indicator of disease severity and treatment response in epilepsy, yet its molecular determinants remain unclear. We performed proteomic profiling of resected epileptogenic brain tissue from patients, stratified by seizure frequency and by temporal versus extratemporal origin, and functionally validated candidate differentially expressed proteins (DEPs). Seizure foci of high and low frequencies in distinct brain regions displayed region-specific proteomic profiles. However, bioinformatic analyses of both temporal and extratemporal cohorts consistently showed that the down-regulated proteins converge on mitochondrial localization and function. Among these, mitochondrial thymidine kinase 2 (Tk2) exhibited a robust inverse correlation with seizure frequency, a finding confirmed in patient tissues across different frequency groups. Consistently, Tk2 expression was reduced across multiple brain regions in two seizure models induced by pilocarpine or ferric chloride. Mechanistically, loss of Tk2 activated the cGAS-STING pathway, upregulated inflammatory genes, and then increased seizure susceptibility. These findings identify Tk2 as a mitochondrial kinase that couples energetic failure to neuroinflammation, and provide a mechanistic basis for targeting the Tk2-mitochondria-inflammation axis in epilepsy.

Keywords

Epilepsy; Metabolism inflammation; Molecular biomarkers; Proteomics.

Figures
Products
Inhibitors & Agonists
Other Products