Dengue virus non-structural protein 3 inhibits mitochondrial respiration by impairing complex I function

• DOI: 10.1128/msphere.00406-24
• Publication Date: 2024-07-09T13:00:58Z
• Authors: Bruna G. Sousa; Nathane C. Mebus-...; Lorena O. Fernand...; Marjolly B. Caruso; Georgia N. Saraiva; Clara F. Carvalho; Thais C. Neves-Ma...; Antonio Galina; Russolina B. Zingali; Julianna D. Zeidler; Andrea T. Da Poian
• Keywords: NS3; Bioenergetics

Dengue virus (DENV) infection is known to affect host cell metabolism, but the molecular players involved are still poorly known. Using a proteomics approach, we identified six DENV proteins associated with mitochondria isolated from infected hepatocytes, and most of peptides were NS3. We also found an at least twofold decrease several electron transport system (ETS) proteins. Thus, investigated whether NS3 could modulate ETS function by incubating recombinant constructs in mouse liver. that NS3pro (NS3 protease domain), not correspondent catalytically inactive mutant (NS3proS135A), impairs complex I (CI)-dependent NADH:ubiquinone oxidoreductase activity, activities complexes II, III, IV, or V. Accordingly, using high-resolution respirometry, both full-length respiratory rates malate/pyruvate oxidation mitochondria. The NS3-induced impairment mitochondrial respiration occurs without altering either leak mitochondria's capacity maintain membrane potential, suggesting does deeply integrity. Remarkably, CI activity inhibited DENV-infected cells, supporting effects observed may be relevant context infection. Finally,