title: Mitochondrial dysfunction in rabies virus infection of neurons.
abstract: Infection with the challenge virus standard-11 (CVS) strain of fixed rabies virus induces neuronal process degeneration in adult mice after hindlimb footpad inoculation. CVS-induced axonal swellings of primary rodent dorsal root ganglion neurons are associated with 4-hydroxy-2-nonenal protein adduct staining, indicating a critical role of oxidative stress. Mitochondrial dysfunction is the major cause of oxidative stress. We hypothesized that CVS infection induces mitochondrial dysfunction leading to oxidative stress. We investigated the effects of CVS infection on several mitochondrial parameters in different cell types. CVS infection significantly increased maximal uncoupled respiration and complex IV respiration and complex I and complex IV activities, but did not affect complex II-III or citrate synthase activities. Increases in complex I activity, but not complex IV activity, correlated with susceptibility of the cells to CVS infection. CVS infection maintained coupled respiration and rate of proton leak, indicating a tight mitochondrial coupling. Possibly as a result of enhanced complex activity and efficient coupling, a high mitochondrial membrane potential was generated. CVS infection reduced the intracellular ATP level and altered the cellular redox state as indicated by a high NADH/NAD+ ratio. The basal production of reactive oxygen species (ROS) was not affected in CVS-infected neurons. However, a higher rate of ROS generation occurred in CVS-infected neurons in the presence of mitochondrial substrates and inhibitors. We conclude that CVS infection induces mitochondrial dysfunction leading to ROS overgeneration and oxidative stress.
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada.
authors.forename: Thamir
authors.initials: T
authors.lastname: Alandijany
authors.forename: Wafa
authors.initials: W
authors.lastname: Kammouni
authors.forename: Subir K
authors.initials: SK
authors.lastname: Roy Chowdhury
authors.forename: Paul
authors.initials: P
authors.lastname: Fernyhough
authors.forename: Alan C
authors.initials: AC
authors.lastname: Jackson
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D005727:Ganglia, Spinal / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology / Q000821:virology; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011818:Rabies / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D011820:Rabies virus / Q000472:pathogenicity / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000447:Aldehydes; D017382:Reactive Oxygen Species; D009243:NAD; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D001275:ATP Citrate (pro-S)-Lyase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; C027576:4-hydroxy-2-nonenal