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SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and
Binbin Yan1, Qiang Liu2, Xiaobao Ding1
1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
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.
Insights
Sirtuin3 (SIRT3) deficiency worsens neuropathic pain by increasing mitochondrial dysfunction. Restoring SIRT3 levels protects against pain by deacetylating cyclophilin D, preventing mitochondrial permeability transition pore opening.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pain Research
Background:
- Mitochondrial dysfunction, including increased mPTP opening and ROS, is crucial in neuropathic pain.
- Sirtuin3 (SIRT3) deacetylase inhibits mitochondrial oxidative stress, but its role in neuropathic pain is unknown.
Purpose of the Study:
- To investigate the role of SIRT3 in neuropathic pain development.
- To elucidate the underlying mechanisms of SIRT3's action on mitochondrial function and pain.
Main Methods:
- Used spared nerve injury (SNI) model in mice to induce neuropathic pain.
- Assessed SIRT3 expression, mitochondrial parameters (mPTP, ROS, MMP, MnSOD), and CypD acetylation.
- Utilized point mutation (CypD-K166R) and pharmacological inhibition (CsA) to validate findings.
Main Results:
- SIRT3 levels were downregulated in SNI mice; SIRT3 overexpression alleviated pain hypersensitivity.
- SIRT3 reduced CypD K166 acetylation, inhibited mPTP opening, decreased ROS/MDA, and increased MMP/MnSOD.
- CypD-K166R mutation or CsA treatment ameliorated SNI-induced mitochondrial dysfunction and pain.
Conclusions:
- SIRT3 prevents neuropathic pain by deacetylating CypD at K166, thereby mitigating mitochondrial dysfunction.
- SIRT3 represents a potential therapeutic target for treating neuropathic pain.
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