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

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Seneca Valley virus (SVV), also known as Senecavirus A, a porcine pathogen that causes vesicular diseases, is prevalent in pig herds worldwide. SVV infection induces endoplasmic reticulum (ER) stress in PK-15 and BHK-21 cells, accompanied by activation of the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) pathways, which in turn facilitates SVV replication. ER stress is associated with the regulation of Ca 2+ homeostasis and mitochondrial apoptosis. However, the precise role of Ca 2+ in SVV-induced apoptosis remains unclear. In this study, western blotting, flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) detection revealed that either ER stress or the PERK pathway is involved in the apoptosis of SVV-infected cells treated with specific inhibitors. Furthermore, SVV-mediated ER stress markedly contributed to the transfer of Ca 2+ from the ER to mitochondria. The subsequent increase in mitochondrial Ca 2+ content was accompanied by an increased number of ER membranes near the mitochondria. Finally, the inhibition of mitochondrial Ca 2+ overload, ER stress, and the PERK pathway substantially attenuated SVV-mediated mitochondrial dysfunction, as evidenced by analyzing mitochondrial membrane potential (MMP), mitochondrial permeability transition poremPTP, reactive oxygen speciesROS, and adenosine 5′-triphosphate ATP, and the levels of mitochondrial apoptosis. These findings demonstrate that SVV induces mitochondrial apoptosis, which is dependent on ER stress-mediated transmission of Ca 2+ from the ER to the mitochondria. IMPORTANCE 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. Ca 2+ , 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 Ca 2+ transfer induced by SVV infection triggered apoptosis remained unclear. Here, we found that SVV infection triggered the Ca 2+ 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 Ca 2+ homeostasis to induce mitochondrial apoptosis and regulate viral proliferation.