Effects of the Glucocorticoid-Mediated Mitochondrial Translocation of Glucocorticoid Receptors on Oxidative Stress and Pyroptosis in BV-2 Microglia

• Published in: Journal of molecular neuroscience 2024-03, Vol.74 (1), p.30-30, Article 30
• Main Authors: Dang, Ruonan, Hou, Xuyang, Huang, Xinglan, Huang, Caifeng, Zhao, Xiaoqing, Wang, Xingrong, Zhang, Ning, Yang, Yuqi, Li, Nan, Liu, Sheng, Yan, Peng, Fan, Ping, Song, Xinghua, Zhang, Suiying, Deng, Yuqiong, Cheng, Xiping, Xia, Xinhua
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Apoptosis; ATP; Biomedical and Life Sciences; Biomedicine; Brain damage; Brain injury; Caspase-1; Cell Biology; Central nervous system; Coding; Cytochrome; Cytochrome-c oxidase; Cytochromes; Dexamethasone; Electron transport; Emergency response; Gene expression; Glucocorticoid receptors; Glucocorticoids; Inflammation; Macrophages; Membrane permeability; Microglia; Mitochondria; Mitochondrial permeability transition pore; Neurochemistry; Neurology; Neurosciences; Oxidase; Oxidative stress; Proteins; Proteomics; Pyroptosis; Receptors; Translocation
• ISSN: 1559-1166; 0895-8696; 1559-1166
• DOI: 10.1007/s12031-024-02192-9

Microglia are resident macrophages within the central nervous system, serving as the first responders to neuroinflammation. Glucocorticoids (GCs) may cause damage to brain tissue, but the specific mechanism remains unclear. This study was divided into two parts: a glucocorticoid receptor (GR) mitochondrial translocation intervention experiment and a mitochondrial oxidative stress inhibition experiment. BV-2 microglia were stimulated with dexamethasone (DEX) and treated with either tubastatin-A or mitoquinone (MitoQ) for 24 h. Our results showed that DEX increased the translocation of GRs to mitochondria, and this effect was accompanied by decreases in the expression of mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) and mitochondrially encoded cytochrome c oxidase 3 (MT-CO3) and increases in the expression of NOD-like receptor thermal protein domain–associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD). The level of mitochondrial respiratory chain complex IV (MRCC IV) and adenosine triphosphate (ATP) was decreased. An elevation in the level of mitochondrial oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP) was also observed. Mechanistically, tubastatin-A significantly suppressed the mitochondrial translocation of GRs, improved the expression of mitochondrial genes, promoted the restoration of mitochondrial function, and inhibited pyroptosis. MitoQ significantly prevented mitochondrial oxidative stress, improved mitochondrial function, and reduced apoptosis and pyroptosis. Both tubastatin-A and MitoQ suppressed DEX-induced pyroptosis. This study substantiates that the increase in the mitochondrial translocation of GRs mediated by GCs exacerbates oxidative stress and pyroptosis in microglia, which indicates that the regulation of mitochondrial pathways by GCs is pathogenic to microglia. Graphical Abstract The increase in mitochondrial translocation of GRs mediated by GCs aggravates mitochondrial dysfunction and oxidative stress, leading to pyroptosis in BV-2 microglia. Tubastatin-A and MitoQ can inhibit GR translocation and oxidative stress in mitochondria, respectively, and these effects can inhibit pyroptosis and other damage induced by GCs to microglia.