FIS1 alleviates neuropathic pain by inhibiting mitochondrial fragmentation

Although neuropathic pain leads to abnormal mitochondrial fission in neurons, it remains unclear whether inhibiting abnormal mitochondrial fission has analgesic effects. This study focused on mitochondrial fission protein 1 (FIS1) to investigate its role in spared nerve injury (SNI)-induced neuropathic pain and the underlying mitochondrial mechanisms. Using MiNA analysis, electron microscopy, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and adenosine triphosphate (ATP) detection, we observed that mitochondrial networks in both excitatory and inhibitory neurons of the spinal dorsal horn (SDH) were disrupted in SNI mice, as demonstrated through the use of specifically constructed GAD2-MITO and vGluT2-MITO transgenic mouse models. Furthermore, down-regulating FIS1 specifically in excitatory neurons, but not inhibitory neurons, of spinal dorsal horn could exert analgesic effects, as demonstrated using vGluT2-Cre mice and GAD2-Cre mice. Third, epigallocatechin gallate (EGCG), which was capable of down-regulating FIS1 in the spinal dorsal horn, concurrently inhibited SNI-induced neuropathic pain. The above results indicate that down-regulating FIS1 in SDH can alleviate neuropathic pain by reducing mitochondrial fragmentation. In addition, down-regulating of FIS1 in excitatory neurons of the SDH can alleviate neuropathic pain by improving mitochondrial dysfunction. Our research findings suggest that FIS1 may represent a novel molecular target for the treatment of pain.