Defining PISD mislocalization as a novel mechanism of mitochondrial damage in Coxsackievirus B3 infection.

Over 1 million cases of myocarditis occur annually, and viral infections have been recognized as the most prevalent cause. Despite its prevalence, the interaction between the virus and cardiomyocytes is not completely understood. Coxsackievirus B3 (CVB3) was used as a model to study the mechanisms of viral-host interactions. Due to the energy demands of the heart, cardiomyocytes are abundant in mitochondria but the direct mechanistic interactions between CVB3 and mitochondria are not well known. Using in-vitro cell-based studies as well as imaging techniques to visualize mitochondrial morphology and protein localization, our study identified the mislocalization of the inner mitochondrial membrane protein PISD that converts lipid species PS to PE. Upon infection, PISD mislocalization was associated with increase in CVB3-induced LC3 lipidation, indicative of disrupted autophagy. Further, we identified that CVB3 viral proteins 3A and 3D can synergistically damage the mitochondria but are unable to induce the same PISD mislocalization. Together, we show a novel mechanism of mitochondrial injury during CVB3 infection.