Respiratory Syncytial Virus Matrix Protein Is Sufficient and Necessary to Remodel Host Mitochondria in Infection

MengJie Hu1,2, Marie A Bogoyevitch2, David A Jans1

  • 1Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.

Cells
|May 13, 2023
PubMed

Insights

The respiratory syncytial virus (RSV) matrix protein (M) alone disrupts host cell mitochondria, impairing respiration and increasing oxidative stress. This M protein is crucial for RSV infection, offering a new target for antiviral therapies.

Area of Science:

  • Virology
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Respiratory syncytial virus (RSV) is a major cause of respiratory illness globally, yet lacks effective vaccines or treatments.
  • Previous studies indicated RSV infection alters mitochondrial function, increasing reactive oxygen species (ROS).

Purpose of the Study:

  • To identify the specific RSV component responsible for mitochondrial dysfunction.
  • To elucidate the role of the RSV matrix (M) protein in modulating host cell mitochondria.

Main Methods:

  • Ectopic expression of individual RSV proteins to assess mitochondrial effects.
  • Site-directed mutagenesis and truncation analysis of the RSV M protein.
  • Generation and characterization of recombinant RSV with M protein mutations.
  • Analysis of mitochondrial respiration, membrane potential, ROS generation, and gene expression.

Main Results:

  • The RSV M protein, but not other viral proteins, induced mitochondrial perinuclear clustering, impaired respiration, reduced membrane potential, and increased mitochondrial ROS (mtROS).
  • The central nucleic acid-binding domain of M, particularly arginine/lysine residues 170/172, is essential for these mitochondrial effects.
  • Recombinant RSV with mutations in these M protein residues failed to induce mitochondrial changes and showed impaired virus production.
  • Wild-type RSV, but not the M mutant, inhibited mRNA expression of genes encoding mitochondrial proteins, including Complex I subunits.

Conclusions:

  • The RSV M protein is sufficient and necessary to induce significant mitochondrial dysfunction, including mtROS generation and impaired respiration.
  • Mitochondrial remodeling by the M protein is critical for efficient RSV replication.
  • The RSV M protein represents a promising novel target for developing anti-RSV therapeutic strategies.

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