SIRT3 attenuates chronic pain-induced depressive-like behaviors by deacetylating CypD at lysine 166 in central amygdala.

Abstract

Chronic pain often acts as a trigger of depression. Mitochondrial dysfunction is increasingly recognized as a key player in the pathogenesis of depression and pain. Sirtuin 3 (SIRT3), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, has been found to ameliorate mitochondrial function. However, the role of SIRT3 in the development of chronic pain-induced depression remains unclear. In this study, it was observed that the expression of SIRT3 in the central amygdala (CeA) was downregulated in spared nerve injury (SNI) male mice with comorbid pain and depression. However, the overexpression of SIRT3 in CeA γ-aminobutyric acid-ergic (GABAergic) neurons mitigated the sensory pain and depressive-like behaviors induced by SNI. Further study demonstrated that the overexpression of SIRT3 in CeA GABAergic neurons decreased the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), inhibited the opening of mitochondrial permeability transition pore (mPTP) and the production of reactive oxygen species (ROS), and increased mitochondrial membrane potential (MMP) and manganese superoxide dismutase (MnSOD) levels in SNI mice. Nevertheless, CypD-K166R mutant mice that mimic deacetylation were protected from mitochondrial dysfunction and depressive-like behaviors caused by SNI. Furthermore, blocking mPTP opening using cyclosporin A (CsA) improved mitochondrial function and alleviated neuropathic pain and its comorbid depression in SNI mice. Taken together, our findings suggest that SIRT3 in CeA GABAergic neurons attenuates chronic pain and its comorbid depression by deacetylating CypD-K166 and subsequently ameliorating mitochondrial dysfunction. This study provides a potential therapeutic target for both the sensory and emotional dimensions of chronic pain.