SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress

Abstract

Numerous studies have shown that mitochondrial dysfunction manifested by increased mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) level, and decreased mitochondrial membrane potential (MMP) plays an important role in the development of neuropathic pain. Sirtuin3 (SIRT3), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, has been shown to inhibit mitochondrial oxidative stress. However, the role of SIRT3 in neuropathic pain is unclear. In this study, we found that the protein and mRNA levels of SIRT3 were significantly downregulated in the spinal cords of spared nerve injury- (SNI-) induced neuropathic pain mice, while overexpression of spinal SIRT3 reversed SNI-induced pain hypersensitivity. Further study showed that SIRT3 overexpression reduced the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), the regulatory component of the mPTP, inhibited the mPTP opening, decreased ROS and malondialdehyde (MDA) levels, and increased MMP and manganese superoxide dismutase (MnSOD) in SNI mice. Point mutation of K166 to arginine on CypD (CypD-K166R) abrogated SNI-induced mitochondrial dysfunction and neuropathic pain in mice. Moreover, inhibiting mPTP opening by cyclosporin A (CsA) improved mitochondrial function and neuropathic pain in SNI mice. Together, these data show that SIRT3 is necessary to prevent neuropathic pain by deacetylating CypD-K166 and further improving mitochondrial dysfunction. This study may shed light on a potential drug target for the treatment of neuropathic pain.

The deubiquitinase USP11 ameliorates intervertebral disc degeneration by regulating oxidative stress-induced ferroptosis via deubiquitinating and stabilizing Sirt3

“…Gain and loss of function was used to prove USP11 could ameliorate ferroptosis and mitigate IVDD by increasing Sirt3 in vitro. Previous studies have showed that Sirt3 relives neuropathic pain [ 82 , 83 ], thus the in vivo experiments were further performed in the current study. Notably, we confirmed that USP11 depletion promotes oxidative stress-induced ferroptosis by degrading Sirt3, leading to more severe IVDD and poor pain-related behavioral scores.…”

Soluble Epoxide Hydrolase Inhibitor TPPU Alleviates Nab-Paclitaxel-Induced Peripheral Neuropathic Pain via Suppressing NF-κB Signalling in the Spinal Cord of a Rat

“…Similar to our findings, a study found that TIPE2 reduced the expression of TAK1, thereby inhibiting the activated pathway of NF- κ B and further improving sciatic nerve injury-induced neuropathic pain [ 19 ]. A growing number of studies suggest that the development and maintenance of neuropathic pain were related to mitochondrial dysfunction and abnormal oxidative stress [ 21 , 22 ]. In this study, the levels and activities of SOD, CAT, MDA, and GSH were tested, and the results showed that nab-paclitaxel treatment could downregulate antioxidant levels and upregulate oxidative stress.…”

Sirtuin-3: A potential target for treating several types of brain injury

“…Animal experiments have shown that abnormal opening of the MPTP after ischaemic stroke leads to mitochondrial calcium overload, changes in mitochondrial membrane potential, the release of cytochrome C, and disruption of the electron respiratory chain, which leads to rapid apoptosis and irreversible brain damage ( Yang Y. et al, 2021 ). Current research shows that three main molecules are involved in MPTP opening, CypD, VDAC1, and ANT1, which are all downstream molecules of SIRT3 ( Yan et al, 2022 ). In particular, OPA1, acetylated by SIRT3 at K926 and K931, regulates mitochondrial dynamics, mitochondrial respiration, and mitochondrial membrane fusion and renewal ( Samant et al, 2014 ; Chan, 2020 ).…”