TDP-43 mediated oxidative stress induced mitochondrial dysfunction in neurons and hyperalgesia in sciatic nerve...

Neuropathic pain (NP) is a chronic pain with a highly complex pathogenesis, in which oxidative stress and mitochondrial dysfunction play significant roles in its progression, but its underlying mechanism is still unclear. TAR DNA-binding protein 43 (TDP-43) is one of the DNA-binding protein contributing to the homeostasis of mitochondria. This study is to explore the role of TDP-43 in mitochondrial dysfunction and pain formation in a mouse model. Therefore, in the mouse sciatic nerve chronic constriction injury (CCI) model and the H₂O₂-induced oxidative stress damage model in N2a cells, we examined the expression of TDP-43, and assessed whether inhibiting TDP-43 alleviated oxidative stress induced mitochondrial dysfunction. Additionally, we examined whether knockdown of TDP-43 could alleviate nociceptive behavior in CCI mice. Our results revealed a time-dependent upregulation of TDP-43 expression in the lumbar spinal dorsal horn neurons of CCI mice. In both in vivo and in vitro experiments, inhibiting TDP-43 attenuates oxidative stress-induced alterations in mitochondrial membrane potential (ΔΨm) and optic atrophy 1 (opa1) expression-a key regulator of mitochondrial fission. Furthermore, intrathecal injection of siRNA to knock down TDP-43 alleviated hyperalgesia and allodynia in CCI mice. These data indicate that TDP-43 in spinal neurons may contribute to NP by impairing mitochondrial function induced by oxidative stress, which may provide a new potential target for the treatment of NP.