Mitochondrial fusion orchestrated by hepatitis E virus couples pro-viral autophagy and innate immune evasion for efficient replication.

Hepatitis E virus (HEV) is a major cause of acute hepatitis globally, yet the mechanisms underlying its replication and pathogenesis remain poorly understood. While mitochondrial dynamics are increasingly recognized as central to antiviral responses, their role in HEV infection has not been defined. Here, we demonstrate that HEV induces profound mitochondrial structural remodeling-characterized by elongated morphology in patient liver biopsies and active mitochondrial fusion in cell culture models, a process essential for viral replication. Mechanistically, this remodeling is driven by a biphasic regulatory program: acute infection preferentially upregulates inner membrane fusion protein OPA1, whereas chronic infection shifts dependence to outer membrane mediator MFN1. Genetic ablation of OPA1 or MFN1 not only reversed mitochondrial elongation but also significantly suppressed HEV replication. Integrated transcriptomic and functional analyses revealed that this virus-induced fusion licenses a pro-viral autophagic response while concurrently dampening interferon-stimulated gene expression. Furthermore, we identified that HEV orchestrates a G0/G1 cell cycle arrest to actively enforce and maintain this pro-fusion mitochondrial state. Clinically, the presence of elongated mitochondrial profiles in patient livers correlated with disease severity, and HEV ORF2 protein levels positively correlated with OPA1/MFN1 expression. Our study establishes mitochondrial fusion as a critical host pathway co-opted by HEV, revealing a previously unrecognized viral strategy that integrates organelle dynamics, autophagy, cell cycle control, and immune evasion to promote replication. These findings position mitochondrial fusion machinery as a promising target for therapeutic intervention against hepatitis E.