Targeting mitofusin 1-mediated mitochondrial dynamics to suppress neuroinflammation and pyroptosis after traumatic brain injury

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. This study aims to explore mitochondrial regulation of neuroinflammation and pyroptosis after TBI. Methods: We used a mouse TBI model and in vitro scratch-injured HT22 cells and primary neurons to examine changes in mitochondrial dynamics and nucleotide-binding oligomerization domain-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome activation. Metformin treatment, mitofusin 1 (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.

Keywords

Traumatic brain injury / NLRP3 inflammasome / Pyroptosis / Mitochondrial dynamics / Metformin / Mitofusin 1

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