Mitochondrial calcium overload contributes to mechanical allodynia in neuropathic pain via inducing mitochondrial dynamic imbalance.

Abstract

Neuropathic pain is a chronic and devastating clinical problem with few effective treatments. Mitochondrial dysfunction plays a critical role in the pathological process of neuropathic pain. Recently, mitochondrial calcium overload has been identified as the initial part of mitochondrial dysfunction, such as dynamic imbalance and excessive superoxide. Mitochondrial Cauniporter (MCU) serves as the primary channel for mitochondrial Cauptake, and Na/Caexchanger (NCLX) is the dominant mechanism for mitochondrial calcium ion excretion. Herein, we investigated the role of mitochondrial calcium overload and its regulated channels in a rat model of neuropathic pain. Our results showed significant mitochondrial calcium overload in the spinal dorsal horn of SNI rats, accompanied by the upregulation of MCU and downregulation of NCLX. MCU inhibition or NCLX overexpression remarkably relieved mechanical allodynia and mitochondrial high calcium levels in SNI rats. Conversely, upregulation of MCU or downregulation of NCLX induced mitochondrial calcium overload and mechanical allodynia in naïve rats. We also observed excessive mitochondrial fission and reduced fusion in the spinal cord of SNI rats, which could be mitigated by MCU inhibition and NCLX overexpression, respectively. Notably, mitochondrial fission inhibitor or mitochondrial fusion promoter effectively reversed the MCU overexpression or NCLX knockdown-induced mechanical allodynia. Collectively, our data indicate that the MCU/NCLX-mediated mitochondrial calcium overload drives excessive mitochondrial fission, which promotes the progression of SNI.