HBV Infection Induces Changes in Mitochondrial Architecture and Remodeling of Mitochondria–ER Interactions

Mitochondria are central hubs of cellular metabolism, playing essential roles in energy production, lipid metabolism, calcium homeostasis, and redox signaling. Findings show that many of these activities are regulated by contact sites between mitochondria and the endoplasmic reticulum (ER) (mitochondria–ER contacts, MERCs). Several studies suggest that Hepatitis B Virus (HBV) can affect mitochondrial functions, inducing metabolic alterations and oxidative stress. This work aimed to investigate, at an ultrastructural level, whether HBV infection causes changes in mitochondrial architecture and MERC modulation. Using HepG2-NTCP cells as an in vitro model system, we analyzed mitochondrial modifications after HBV infection at 2, 5, and 10 days. Electron and confocal microscopy analyses highlighted changes in mitochondrial morphology with a progressive enlargement of mitochondrial size and a remodeling of the mitochondrial network, together with an increase in MERC establishment. Moreover, functional assays showed decreased ATP production, despite increased mitochondrial membrane potential and tight regulation of mitochondrial reactive oxygen species (mtROS) levels. These findings suggest that HBV does not cause irreversible mitochondrial damage but drives a dynamic and coordinated adaptation involving metabolism, ultrastructure, ER interaction, and network organization.