Mitochondrial dysfunction in rabies virus infection of neurons

Alandijany, Thamir A.; Kammouni, Wafa; Chowdhury, Subir; Fernyhough, Paul; Jackson, Alan C.

doi:10.1007/s13365-013-0214-6

Cited by 39 publications

(26 citation statements)

References 174 publications

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“…Mitochondrial dysfunction generally also involves the generation of excess reactive oxygen species (ROS; Alandijany et al, 2013). We detected the accumulation of extra ROS in the pollen grains of LWHY2-1 (Fig.…”

Section: High Mtdna Copy Number Causes Respiratory Abnormalitiesmentioning

confidence: 85%

Elevation of Pollen Mitochondrial DNA Copy Number by WHIRLY2: Altered Respiration and Pollen Tube Growth in Arabidopsis

et al. 2015

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In plants, the copy number of the mitochondrial DNA (mtDNA) can be much lower than the number of mitochondria. The biological significance and regulatory mechanisms of this phenomenon remain poorly understood. Here, using the pollen vegetative cell, we examined the role of the Arabidopsis (Arabidopsis thaliana) mtDNA-binding protein WHIRLY2 (AtWHY2). AtWHY2 decreases during pollen development, in parallel with the rapid degradation of mtDNA; to examine the importance of this decrease, we used the pollen vegetative cell-specific promoter Lat52 to express AtWHY2. The transgenic plants (LWHY2) had very high mtDNA levels in pollen, more than 10 times more than in the wild type (ecotype Columbia-0). LWHY2 plants were fertile, morphologically normal, and set seeds; however, reciprocal crosses with heterozygous plants showed reduced transmission of LWHY2-1 through the male and slower growth of LWHY2-1 pollen tubes. We found that LWHY2-1 pollen had significantly more reactive oxygen species and less ATP compared with the wild type, indicating an effect on mitochondrial respiration. These findings reveal that AtWHY2 affects mtDNA copy number in pollen and suggest that low mtDNA copy numbers might be the normal means by which plant cells maintain mitochondrial genetic information.

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Section: High Mtdna Copy Number Causes Respiratory Abnormalitiesmentioning

confidence: 85%

Elevation of Pollen Mitochondrial DNA Copy Number by WHIRLY2: Altered Respiration and Pollen Tube Growth in Arabidopsis

et al. 2015

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“…In fact, mitochondrial membrane potential is essential for cellular ATP production and increase ROS production (Englezou et al 2012;Schachtele et al 2010). Rabies virus, a neurotropic virus that infects human and animals, has been incriminated to induce neuronal death by ROS formation (Alandijany et al 2013). Previous studies revealed that mitochondrial membrane potential can be altered without affecting non-transformed cellular cycle after infected by BHV5 (Brenner et al 2012;Garcia et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Bovine herpesviruses induce different cell death forms in neuronal and glial-derived tumor cell cultures

et al. 2016

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Oncolytic viruses have the ability to infect tumor cells and leave healthy cells intact. In this study, bovine herpesvirus 1 (BHV1; Los Angeles, Cooper, and SV56/90 strains) and bovine herpesvirus 5 (BHV5; SV507/99 and GU9457818 strains) were used to infect two neuronal tumor cell lineages: neuro2a (mouse neuroblastoma cells) and C6 (rat glial cells). BHV1 and BHV5 strains infected both cell lines and positively correlated with viral antigen detection (p < 0.005). When neuro2a cells were infected by Los Angeles, SV507/99, and GU9457818 strains, 40 % of infected cells were under early apoptosis and necroptosis pathways. Infected C6 cells were >40 % in necroptosis phase when infected by BHV5 (GU9457818 strain). Blocking caspase activation did not interfere with cell death. However, when necroptosis was blocked, 60-80 % of both infected cells with either virus switched to early apoptosis pathway with no interference with virus replication. Moreover, reactive oxygen species production and mitochondrial membrane dysfunction were detected at high levels in both infected cell lines. In spite of apoptosis and necroptosis blockage, tumor necrosis factor alpha (TNFA) and virus transcription were positively correlated for all viral strains studied. Thus, these results contribute to the characterization of BHV1 and BHV5 as potential oncolytic viruses for non-human cells. Nonetheless, the mechanisms underlying their oncolytic activity in human cells are still to be determined.

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“…ROS are mainly generated in the electron transport chain (ETC), primarily at Complex I and Complex III (Murphy 2009). Since we found evidence of oxidative stress in cultured DRG neurons, we comprehensively evaluated CVS and mock infection in a variety of neuronal and non-neuronal cell types, including neurons with neurites (DRG neurons and PC12 cells), neurons without neurites (mouse neuroblastoma cells [MNA]), and nonneuronal cells (BHK cells) for abnormalities of mitochondrial function (Alandijany et al 2013). No changes were found in Krebs cycle enzyme activities (e.g., citrate synthase) in CVS versus mock infection.…”

Section: Bases For Neuronal Injury In Rabiesmentioning

confidence: 99%

“…Increased Complex IV activity was found in CVS-infected cells versus mock-infected cells, but this increase did not correlate with the susceptibility of the cells to CVS infection, suggesting that the increase in activity was unlikely due to a direct viral effect. A mitochondrial respiration assay was performed in which the rate of oxygen consumption was measured under different states (rate of proton leak, coupled respiration, maximal uncoupled respiration, and Complex IV respiration) (Alandijany et al 2013). In CVS infection, coupled respiration and the rate of proton leak were maintained, indicating a tight mitochondrial coupling.…”

Section: Bases For Neuronal Injury In Rabiesmentioning

confidence: 99%

“…Our studies of CVS infection in DRG neurons indicate evidence of oxidative stress resulting in axonal swellings and degeneration and impaired axonal growth. Studies of mitochondrial function indicate increased activity of mitochondrial respiratory chain Complex I, which correlates with the susceptibility of the cell type to RABV infection, a high mitochondrial membrane potential, increased NADH/NAD+ ratio, reduced ATP content, and normal coupled respiration and rate of proton leak (Alandijany et al 2013). This work strongly suggests that increased Complex I activity explains ROS overproduction, which was supported by Amplex Red assays for hydrogen peroxide production.…”

Section: Bases For Neuronal Injury In Rabiesmentioning

confidence: 99%

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Diabolical effects of rabies encephalitis

Jackson

2015

J. Neurovirol.

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Rabies is an acute encephalomyelitis in humans and animals caused by rabies virus (RABV) infection. Because the neuropathological changes are very mild in rabies, it has been assumed that neuronal dysfunction likely explains the severe clinical disease. Recently, degenerative changes have been observed in neuronal processes (dendrites and axons) in experimental rabies. In vitro studies have shown evidence of oxidative stress that is caused by mitochondrial dysfunction. Recent work has shown that the RABV phosphoprotein (P) interacts with mitochondrial Complex I leading to overproduction of reactive oxygen species, which results in injury to axons. Amino acids at positions 139 to 172 of the P are critical in this process. Rabies vectors frequently show behavioral changes. Aggressive behavior with biting is important for transmission of the virus to new hosts at a time when virus is secreted in the saliva. Aggression is associated with low serotonergic activity in the brain. Charlton and coworkers performed studies in experimentally infected striped skunks with skunk rabies virus and observed aggressive behavioral responses. Heavy accumulation of RABV antigen was found in the midbrain raphe nuclei, indicating that impaired serotonin neurotransmission from the brainstem may account for the aggressive behavior. We now have an improved understanding of how RABV causes neuronal injury and how the infection results in behavioral changes that promote viral transmission to new hosts.

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Mitochondrial dysfunction in rabies virus infection of neurons

Cited by 39 publications

References 174 publications

Elevation of Pollen Mitochondrial DNA Copy Number by WHIRLY2: Altered Respiration and Pollen Tube Growth in Arabidopsis

Elevation of Pollen Mitochondrial DNA Copy Number by WHIRLY2: Altered Respiration and Pollen Tube Growth in Arabidopsis

Bovine herpesviruses induce different cell death forms in neuronal and glial-derived tumor cell cultures

Diabolical effects of rabies encephalitis

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