SARS‐CoV‐2 nucleocapsid protein enhances the level of mitochondrial reactive oxygen species

Abstract Coronavirus disease 2019 (COVID‐19) pathogenesis is influenced by reactive oxygen species (ROS). Nevertheless, the precise mechanisms implicated remain poorly understood. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the main driver for this condition, is a structural protein indispensable for viral replication and assembly, and its role in ROS production has not been reported. This study shows that SARS‐CoV‐2 N protein expression enhances mitochondrial ROS level. Bulk RNA‐sequencing suggests of aberrant redox state of the electron transport chain. Accordingly, this protein hinders ATP production but simultaneously augments the activity of complexes I and III, and most mitochondrially encoded complex I and III proteins are upregulated by it. Mechanistically, N protein of SARS‐CoV‐2 shows significant mitochondrial localization. It interacts with mitochondrial transcription components and stabilizes them. Moreover, it also impairs the activity of antioxidant enzymes with or without detectable interaction.