2. Academic Validation
  3. Inhibition of mitoNEET ameliorates traumatic brain injury-induced ferroptosis and cognitive dysfunction by stabilizing dihydroorotate dehydrogenase

Inhibition of mitoNEET ameliorates traumatic brain injury-induced ferroptosis and cognitive dysfunction by stabilizing dihydroorotate dehydrogenase

  • Exp Neurol. 2025 Jul:389:115235. doi: 10.1016/j.expneurol.2025.115235.
Jing Li 1,  Bowen Jia 2,  Yejia Xu 2,  Yang Zhao 3,  Shangwen Wang 3,  Rui Yang 3,  Li Su 4,  Xiaofeng Zeng 3,  Qianqian Li 5,  Chengliang Luo 6
Affiliations

Affiliations

  • 1 Department of Forensic Medicine, School of Forensic Medicine, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming 650500, China; Hebei Key Laboratory of Forensic Medicine, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China; Department of Forensic Medicine, School of Basic Medicine, Soochow University, Suzhou 215123, China.
  • 2 Department of Forensic Medicine, School of Basic Medicine, Soochow University, Suzhou 215123, China.
  • 3 Department of Forensic Medicine, School of Forensic Medicine, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming 650500, China.
  • 4 School of Forensic Medicine, Wannan Medical College, Wuhu 241002, China.
  • 5 Department of Forensic Medicine, School of Forensic Medicine, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming 650500, China. Electronic address: bzliqian@126.com.
  • 6 Department of Forensic Medicine, School of Forensic Medicine, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming 650500, China; Hebei Key Laboratory of Forensic Medicine, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China; Department of Forensic Medicine, School of Basic Medicine, Soochow University, Suzhou 215123, China. Electronic address: luochengliang@kmmu.edu.cn.
PMID: 40189124 DOI: 10.1016/j.expneurol.2025.115235
Abstract

Background: Due to the complexity of the causes and mechanisms of traumatic brain injury (TBI), there is still a lack of effective clinical treatments. Ferroptosis is an iron-dependent mode of cell death characterized by lipid peroxidation, which is involved in the pathophysiology of TBI. The process of Ferroptosis involves mitochondria, and mitochondrial alterations are important biomarkers for the detection of Ferroptosis. As an iron‑sulfur [2Fe-2S] cluster protein, mitoNEET (gene: CISD1) is located on the outer surface of mitochondria, and plays a key role in regulating cellular energy use, lipid metabolism, and mitochondrial iron content. However, whether mitoNEET is involved in regulating Ferroptosis and cognitive decline caused by TBI is unclear.

Results: In the present study, we observed that a mitoNEET ligand or inhibitor, NL-1 intervention significantly inhibited the occurrence of Ferroptosis and alleviated neuronal injury after TBI. The gain and loss-function models of mitoNEET were then used to confirm the role of mitoNEET in Ferroptosis and cognitive dysfunction after TBI. Knockdown of mitoNEET alleviated cognitive dysfunction and exhibited significant anti-ferroptosis effects in a mouse model of TBI, whereas mitoNEET overexpression exerted the opposite effects. Furthermore, silencing of DHODH blocked the anti-ferroptosis and neuroprotective effects of NL-1.

Conclusions: Taken together, these data demonstrated that NL-1 reversed TBI-induced Ferroptosis and neurodegeneration, at least in part through the activation of mitoNEET/DHODH signaling axis. Pharmacological and gene inhibition of mitoNEET ameliorated TBI-induced Ferroptosis and cognitive dysfunction. Mechanically, NL-1 may be through targeting mitoNEET to potentiate DHODH-mediated Ferroptosis defense.

Keywords

Dihydroorotate dehydrogenase (DHODH); Ferroptosis; Neurodegeneration; Traumatic brain injury; mitoNEET.

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