title: Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection.
abstract: Mitochondria are sentinel organelles that are impacted by various forms of cellular stress, including viral infections. While signaling events associated with mitochondria, including those activated by pathogen associated molecular patterns (PAMPs), are widely studied, alterations in mitochondrial distribution and changes in mitochondrial dynamics are also beginning to be associated with cellular insult. Cells of neuronal origin have been demonstrated to display remarkable alterations in several instances, including neurodegenerative disorders. Venezuelan Equine Encephalitis Virus (VEEV) is a New World alphavirus that infects neuronal cells and contributes to an encephalitic phenotype. We demonstrate that upon infection by the vaccine strain of VEEV (TC-83), astrocytoma cells experience a robust drop in mitochondrial activity, which corresponds with an increased accumulation of reactive oxygen species (ROS) in an infection-dependent manner. Infection status also corresponds with a prominent perinuclear accumulation of mitochondria. Cellular enzymatic machinery, including PINK1 and Parkin, appears to be enriched in mitochondrial fractions as compared with uninfected cells, which is indicative of mitochondrial damage. Dynamin related protein 1 (Drp1), a protein that is associated with mitochondrial fission, demonstrated a modest enrichment in mitochondrial fractions of infected cells. Treatment with an inhibitor of mitochondrial fission, Mdivi-1, led to a decrease in caspase cleavage, suggesting that mitochondrial fission was likely to contribute to apoptosis of infected cells. Finally, our data demonstrate that mitophagy ensues in infected cells. In combination, our data suggest that VEEV infection results in significant changes in the mitochondrial landscape that may influence pathological outcomes in the infected cell.
authors.affiliation: a National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University , Manassas , VA , USA.
authors.forename: Forrest
authors.initials: F
authors.lastname: Keck
authors.affiliation: a National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University , Manassas , VA , USA.
authors.forename: Taryn
authors.initials: T
authors.lastname: Brooks-Faulconer
authors.affiliation: a National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University , Manassas , VA , USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Lark
authors.affiliation: b University of California , Davis, Davis , CA , USA.
authors.forename: Pavitra
authors.initials: P
authors.lastname: Ravishankar
authors.affiliation: a National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University , Manassas , VA , USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.affiliation: c Bioengineering Department , George Mason University , Fairfax , VA , USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Salvador-Morales
authors.affiliation: a National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University , Manassas , VA , USA.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D017209:Apoptosis; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics / Q000502:physiology*; D004685:Encephalomyelitis, Venezuelan Equine / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D006736:Horses; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species
keywords: Venezuelan equine encephalitis; membrane depolarization; mitochondrial dynamics; mitophagy; reactive oxygen species