Inhibition of mitoNEET ameliorates traumatic brain injury-induced ferroptosis and cognitive dysfunction by...

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.

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.

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.