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

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.