Zika virus inhibits mitophagy to facilitate its replication

Abstract Zika virus (ZIKV) infection can lead to severe neurological and reproductive pathologies, posing a persistent threat to global public health. As the cellular energy hub and pivotal innate immune platform, mitochondria not only defend against pathogen invasion but also provide essential sites and materials for viral replication. This study revealed a significant increase in mitochondrial mass and membrane potential in ZIKV-infected cells, along with increased expression of genes associated with electron transport chain ATP synthesis and oxidative phosphorylation. Furthermore, we demonstrated that ZIKV inhibits mitophagy in host cells, as evidenced by transmission electron microscopy and confocal microscopy. This inhibition was found to benefit ZIKV replication during the assembly and release stages. Notably, the natural compound ginsenoside Rh2, an effective mitophagy inducer, attenuated clinical outcomes and delayed mortality in ZIKV-infected mice. In summary, this research reveals that ZIKV inhibits mitophagy to facilitate its replication in host cells and offers potential therapeutic strategies that target the induction of mitophagy for ZIKV infection.