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.