Abstract

White spot syndrome virus (WSSV), a major pathogen causing severe losses in global crustacean aquaculture, ranks among the largest known animal enveloped DNA viruses. While some features of WSSV–host interactions are known, the mechanisms by which the virus exploits host mitochondrial functions to promote its replication remain unclear. Here, using the red claw crayfish (Cherax quadricarinatus) model, we demonstrate that WSSV infection activates host mitophagy. This process is orchestrated by the mitochondria-targeting viral protein wsv156, which acts as a key effector that triggers the formation of mitochondrial aggregates (mito-aggresomes) and initiates mitophagy. Mechanistically, wsv156 recruits and activates dynamin-related protein 1 (CqDrp1) to drive mitochondrial fission and aggregation. Concurrently, wsv156 facilitates the recruitment of the E3 ubiquitin ligase Parkin (CqParkin) to mitochondria, engaging the canonical PTEN-induced putative kinase 1 (CqPINK1)–Parkin pathway to initiate mitophagy. Intriguingly, the viral envelope protein VP26 blocks the final step of autophagic degradation, arresting the process in an incomplete state. We further show that this incomplete mitophagy benefits viral replication through a dual mechanism: it enhances glycolysis to meet the heightened energy and biosynthetic demands of infection while suppressing cell apoptosis to preserve cellular viability. Collectively, our findings uncover how a large DNA virus exploits and precisely modulates host mitophagy, specifically by initiating and then arresting it to craft a supportive intracellular niche for replication. This study not only advances the understanding of WSSV pathogenesis but also provides evolutionary insights into conserved viral strategies for manipulating mitochondrial quality control across diverse hosts, from crustaceans to mammals.