Abstract Background Traumatic brain injury (TBI) can cause neuroinflammation and neuronal death. The role of mitochondrial dysfunction in regulating inflammasome activation during TBI remains unclear. Methods We used a mouse TBI model and in vitro scratch-injured HT22 cells and primary neurons to examine changes in mitochondrial dynamics and NLRP3 inflammasome activation. Metformin treatment, Mfn1 knockdown and regulation of the Mfn1 pathway were applied to evaluate the therapeutic effects and mechanisms. Results TBI triggered NLRP3 inflammasome activation and neuronal pyroptosis, along with impaired mitochondrial function and oxidative stress. Metformin reduced inflammasome activation, improved mitochondrial homeostasis, and alleviated neuronal injury. These effects were lost when Mfn1 was silenced, highlighting its essential role. Furthermore, we determined that the AMPK pathway modulates these observed effects. Conclusion Metformin protects against TBI-induced neuronal damage by restoring Mfn1-dependent mitochondrial dynamics and suppressing inflammasome activation. Mfn1 is a key mediator linking mitochondrial health to neuroinflammatory responses in TBI.
Liu et al. (Fri,) studied this question.