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Mitophagy Activation Targeting PINK1 Is an Effective Treatment to Inhibit Zika Virus Replication
Yike Huang1, Qingyuan Li2, Lan Kang1
1Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory for Transfusion-transmitted Infectious Diseases of the Health Commission of Sichuan Province, Chengdu 610052, Sichuan, China.
Abstract:
Mitophagy is a selective degradation mechanism that maintains mitochondrial homeostasis by eliminating damaged mitochondria. Many viruses manipulate mitophagy to promote their infection, but its role in Zika virus (ZIKV) is unclear. In this study, we investigated the effect of mitophagy activation on ZIKV replication by the mitochondrial uncoupling agent niclosamide. Our results demonstrate that niclosamide-induced mitophagy inhibits ZIKV replication by eliminating fragmented mitochondria, both in vitro and in a mouse model of ZIKV-induced necrosis. Niclosamide induces autophosphorylation of PTEN-induced putative kinase 1 (PINK1), leading to the recruitment of PRKN/Parkin to the outer mitochondrial membrane and subsequent phosphorylation of ubiquitin. Knockdown of PINK1 promotes ZIKV infection and rescues the anti-ZIKV effect of mitophagy activation, confirming the role of ubiquitin-dependent mitophagy in limiting ZIKV replication. These findings demonstrate the role of mitophagy in the host response in limiting ZIKV replication and identify PINK1 as a potential therapeutic target in ZIKV infection.
Insights
Mitophagy activation, triggered by niclosamide, inhibits Zika virus (ZIKV) replication by clearing damaged mitochondria. This process involves PINK1 and Parkin, highlighting mitophagy as a host defense against ZIKV.
Area of Science:
- Cellular Biology
- Virology
- Immunology
Background:
- Mitophagy is crucial for mitochondrial quality control.
- Viruses often exploit mitophagy, but its role in Zika virus (ZIKV) infection is unknown.
- Understanding mitophagy's role in ZIKV is vital for developing antiviral strategies.
Purpose of the Study:
- To investigate how mitophagy activation affects ZIKV replication.
- To explore niclosamide as a mitophagy inducer against ZIKV.
- To elucidate the molecular mechanisms underlying mitophagy's impact on ZIKV.
Main Methods:
- Utilized niclosamide to induce mitophagy in vitro and in vivo.
- Assessed ZIKV replication and mitochondrial fragmentation.
- Examined the roles of PTEN-induced putative kinase 1 (PINK1) and PRKN/Parkin in mitophagy-dependent antiviral response.
- Performed PINK1 knockdown experiments.
Main Results:
- Niclosamide-induced mitophagy significantly inhibited ZIKV replication.
- Fragmented mitochondria were eliminated, reducing viral load both in vitro and in a mouse model.
- Niclosamide activated the PINK1/Parkin pathway, essential for ubiquitin-dependent mitophagy.
- PINK1 knockdown impaired mitophagy's anti-ZIKV effect and increased viral replication.
Conclusions:
- Mitophagy acts as a host defense mechanism against ZIKV infection.
- The PINK1/Parkin pathway is critical for mitophagy-mediated inhibition of ZIKV.
- PINK1 is a potential therapeutic target for ZIKV infections.
