2. Academic Validation
  3. Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis

Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis

  • J Adv Res. 2024 Aug 3:S2090-1232(24)00326-6. doi: 10.1016/j.jare.2024.08.003.
Xiaowei Song 1,  Yiliang Wang 2,  Weixiangmin Zou 3,  Zexu Wang 3,  Wenyan Cao 3,  Minting Liang 3,  Feng Li 4,  Qiongzhen Zeng 3,  Zhe Ren 3,  Yifei Wang 5,  Kai Zheng 6
Affiliations

Affiliations

  • 1 Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou 510632, China; Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China.
  • 2 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510440, China.
  • 3 Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou 510632, China.
  • 4 Infectious Diseases Institute, Guangzhou Eighth People's Hospital, Guangzhou 510440, China.
  • 5 Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou 510632, China. Electronic address: twang-yf@163.com.
  • 6 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: zhengk@szu.edu.cn.
PMID: 39103048 DOI: 10.1016/j.jare.2024.08.003
Abstract

Introduction: Mitophagy, a selective form of Autophagy responsible for maintaining mitochondrial homeostasis, regulates the Antiviral immune response and acts as viral replication platforms to facilitate Infection with various viruses. However, its precise role in herpes simplex virus 1 (HSV-1) Infection and herpes simplex encephalitis (HSE) remains largely unknown.

Objectives: We aimed to investigate the regulation of Mitophagy by HSV-1 neurotropic Infection and its role in viral encephalitis, and to identify small compounds that regulate Mitophagy to affect HSV-1 Infection.

Methods: The Antiviral effects of compounds were investigated by Western blot, RT-PCR and plaque assay. The changes of Parkin (PRKN)-mediated Mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation were examined by TEM, RT-qPCR, Western blot and ELISA. The therapeutic effect of taurine or PRKN-overexpression was confirmed in the HSE mouse model by evaluating survival rate, eye damage, neurodegenerative symptoms, immunohistochemistry analysis and histopathology.

Results: HSV-1 Infection caused the accumulation of damaged mitochondria in neuronal cells and in the brain tissue of HSE mice. Early HSV-1 Infection led to Mitophagy activation, followed by inhibition in the later viral Infection. The HSV-1 proteins ICP34.5 or US11 deregulated the EIF2S1-ATF4 axis to suppress PRKN/Parkin mRNA expression, thereby impeding PRKN-dependent Mitophagy. Consequently, inhibition of Mitophagy by specific inhibitor midiv-1 promoted HSV-1 Infection, whereas Mitophagy activation by PRKN overexpression or agonists (CCCP and rotenone) attenuated HSV-1 Infection and reduced the NF-κB-mediated neuroinflammation. Moreover, PRKN-overexpressing mice showed enhanced resistance to HSV-1 Infection and ameliorated HSE pathogenesis. Furthermore, taurine, a differentially regulated gut microbial metabolite upon HSV-1 Infection, acted as a Mitophagy Activator that transcriptionally promotes PRKN expression to stimulate Mitophagy and to limit HSV-1 Infection both in vitro and in vivo.

Conclusion: These results reveal the protective function of Mitophagy in HSE pathogenesis and highlight Mitophagy activation as a potential Antiviral therapeutic strategy for HSV-1-related diseases.

Keywords

EIF2S1-ATF4; Herpes simplex virus; Neuroinflammation; PRKN-dependent mitophagy; Taurine.

Figures
Products