Cytoplasmic Escape of Mitochondrial DNA Mediated by Mfn2 Downregulation Promotes Microglial Activation via cGas-Sting Axis in Spinal Cord Injury

Spinal cord injury (SCI) often leads to inflammation, which worsens patient outcomes. This study found that a protein called Sting, which triggers inflammation, increases in microglia (immune cells in the brain and spinal cord) after SCI. The researchers discovered that Sting activation in microglia can worsen nerve damage after SCI. They also found that a protein called Mfn2, which is involved in mitochondrial function, is reduced in microglia after SCI. This reduction leads to the release of mitochondrial DNA (mtDNA), which then activates the Sting pathway. The scientists developed a nanoparticle to deliver a drug (MASM7) that increases Mfn2 levels. This treatment reduced inflammation and improved nerve function in mice with SCI, suggesting that targeting the Mfn2-mtDNA-Sting pathway could be a new way to treat SCI.

• 1
  Sting expression is increased in activated microglia after SCI, and knockout of Sting in microglia improves neurological function recovery after SCI.
• 2
  Downregulation of Mfn2 in microglial cells leads to mtDNA release, which mediates the activation of the cGas-Sting signaling pathway and aggravates inflammatory response damage after SCI.
• 3
  A biomimetic microglial nanoparticle strategy to deliver MASM7 (MSNs-MASM7@MI) improves nerve function after SCI, suggesting a potential therapeutic approach.