Seneca Valley virus induces mitochondrial apoptosis by activating ER stress or the PERK pathway based on Ca ²⁺ transfer from ER to mitochondria

Viruses have developed multiple mechanisms to facilitate their proliferation or persistence through manipulating various organelles in cells. Seneca Valley virus (SVV), as a novel emerging pathogen associated with vesicular disease, is clinically and economically important infections that affect farm animals. Previously, we had confirmed that SVV-induced endoplasmic reticulum (ER) stress benefited for viral replication. Ca²⁺, as an intracellular signaling messenger mainly stored in the ER, is regulated by ER stress and then involved in apoptosis. However, the precise mechanism that Ca²⁺ transfer induced by SVV infection triggered apoptosis remained unclear. Here, we found that SVV infection triggered the Ca²⁺ transform from ER to mitochondria, resulting in mitochondrial dysfunction, and finally induced mitochondrial apoptosis. Our study shed light on a novel mechanism revealing how ER stress manipulates Ca²⁺ homeostasis to induce mitochondrial apoptosis and regulate viral proliferation.