The emergence of neuropathic pain is significantly influenced by the impairment of mitochondrial processes. Ensuring the stability of mitochondrial activity requires a delicate equilibrium between the processes of mitochondrial fission and fusion. However, the specific alterations in mitochondrial activity across different models of neuropathic pain and the underlying mechanisms remain largely unclear. We developed a persistent compression injury (CCI) model targeting the sciatic nerve in mice. CCI induced pain like behaviors in mice, which were associated with increased levels of dynamin related protein 1 (Drp1) and decreased expression of the fusion protein OPA1 and an increase in the percentage of DRG nerve cell mitochondria in the fission form, and a decrease in percentage in the fusion form. Ultrastructural analysis showed that mitochondria in CCI mice were smaller in perimeter and area, adopting a more circular shape. Overexpression of OPA1 mediated by AAV attenuated pain hypersensitivity, lowered oxidative stress, and expanded mitochondrial circumference and area. Mdivi-1 treatment reduced pain, whereas blocking fusion with MYLS22 augmented pain and oxidative stress and further led to increased mitochondrial fragmentation. Our results illustrate that Mitochondria in DRG nerve cell are highly sensitive to neuropathic pain. Modulating mitochondrial fission and fusion through targeted gene overexpression and pharmacological inhibitors restores mitochondrial dynamics, reduces oxidative stress, and alleviates neuropathic pain in mice. These findings position mitochondrial dynamics as promising therapeutic targets for pain management.
© 2025. The Author(s).