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

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

  • J Mol Neurosci. 2024 Mar 13;74(1):30. doi: 10.1007/s12031-024-02192-9.
Ruonan Dang # 1 2,  Xuyang Hou # 1 3,  Xinglan Huang # 2 4,  Caifeng Huang 2 5,  Xiaoqing Zhao 2 6,  Xingrong Wang 2 5,  Ning Zhang 2 5,  Yuqi Yang 2 6,  Nan Li 2 7,  Sheng Liu 2 5,  Peng Yan 2 8,  Ping Fan 1 3,  Xinghua Song 1 3,  Suiying Zhang 2 9,  Yuqiong Deng 2 10,  Xiping Cheng 11 12,  Xinhua Xia 13 14
Affiliations

Affiliations

  • 1 Department of Chinese Medicine, School of First Clinical Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China.
  • 2 State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 510182, China.
  • 3 Institute of Integration of Traditional and Western Medicine, Guangzhou Medical University, Guangzhou, 510182, China.
  • 4 Department of Dermatology, Guangzhou Twelfth People's Hospital, Guangzhou, 510620, China.
  • 5 Department of Dermatology, School of First Clinical Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China.
  • 6 Department of Endocrinology, The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510130, China.
  • 7 Department of Dermatology, Haizhu Maternal and Child Health Hospital, Guangzhou, 510240, China.
  • 8 Department of Critical Care Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China.
  • 9 Department of Dermatology, SSL Central Hospital, Southern Medical University, Dongguan, 523888, China.
  • 10 Department of Dermatology, Panyu Maternal and Child Care Service Centre of Guangzhou, Guangzhou, 511400, China.
  • 11 State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 510182, China. cxplunwenyx@163.com.
  • 12 Department of Dermatology, School of First Clinical Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China. cxplunwenyx@163.com.
  • 13 Department of Chinese Medicine, School of First Clinical Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China. star1124@163.com.
  • 14 Institute of Integration of Traditional and Western Medicine, Guangzhou Medical University, Guangzhou, 510182, China. star1124@163.com.
  • # Contributed equally.
PMID: 38478195 DOI: 10.1007/s12031-024-02192-9
Abstract

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.

Keywords

Glucocorticoid; Glucocorticoid receptor; Microglia; Mitochondria oxidative stress; Neurodegenerative diseases; Pyroptosis.

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