SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption

Area of Science:

• Virology
• Cell Biology
• Biochemistry

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structural proteins, like the envelope (E) protein, are implicated in viral assembly, egress, host cell dysfunction, and disease severity.
• The precise mechanisms by which SARS-CoV-2 E protein contributes to pathogenesis are not fully understood, particularly its interactions with host cellular machinery.

Purpose of the Study:

• To investigate the subcellular localization and functional impact of the SARS-CoV-2 E protein on host cell mitochondria.
• To elucidate how SARS-CoV-2 E protein expression affects mitochondrial structure, metabolism, redox homeostasis, and cell viability.

Main Methods:

• Fluorescence microscopy to observe E protein localization and colocalization with mitochondria and lipid domains.
• Lipidomic and metabolomic profiling to analyze changes in cellular lipids and metabolites.
• Mitochondrial stress testing using Seahorse to assess mitochondrial function and electron transport chain (ETC) activity.
• Measurement of mitochondrial membrane potential and reactive oxygen species (ROS) production.

Main Results:

• SARS-CoV-2 E protein localizes to host cell mitochondria, forming tubular structures and altering mitochondrial morphology.
• E protein expression led to significant reductions in key phospholipids (cardiolipin, phosphatidylcholine) and altered lipid metabolism.
• Mitochondrial membrane potential decreased, indicating disrupted ETC activity, accompanied by increased mitochondrial ROS production.
• Despite oxidative stress, E protein did not induce apoptosis, and significant metabolic shifts were observed, including altered glycolysis, TCA cycle, and glutathione metabolism.

Conclusions:

• SARS-CoV-2 E protein directly interacts with and dysregulates host cell mitochondria, affecting lipid and metabolic homeostasis.
• Mitochondrial dysfunction induced by E protein may involve ROS containment within the organelle and promote aerobic glycolysis, potentially supporting viral replication.
• These findings reveal a novel role for the SARS-CoV-2 E protein in modulating host cell metabolism and highlight mitochondria as a key target in SARS-CoV-2 pathogenesis.