DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB.

Neuroinflammation is a major pathogenic mechanism underlying neurodegenerative diseases. Understanding how neuroinflammation is regulated is critical to therapeutic development. Here, we report that dynaminrelated protein 1 (DRP1), well-recognized for its role in mitochondrial fission, also functions as a transcription factor that regulates neuroinflammation. Using multiple inflammatory models, we demonstrate that upon stimulation with pro-inflammatory lipopolysaccharides (LPS), DRP1 translocates from the cytosol to the nucleus, where it binds to the promoter region of Rela (encoding NF-κB p65) to activate its gene products and other downstream inflammatory cytokines. Our data further reveal a significant role of the proinflammatory lipocalin-2 in the brain. In combination, this study identifies a previously unrecognized function of DRP1 in mediating neuroinflammation via the NF-κB-lipocalin-2 axis and highlights DRP1-mediated pathways as potential therapeutic targets for neurodegenerative and other inflammation-related diseases.