Mitochondrial Bioenergetic Alterations in Mouse Neuroblastoma Cells Infected with Sindbis Virus: Implications to Viral Replication and Neuronal Death

Costa, Leandro Silva da; Silva, Ana Paula Pereira da; Poian, Andrea T. Da; El‐Bacha, Tatiana

doi:10.1371/journal.pone.0033871

Cited by 41 publications

(44 citation statements)

References 65 publications

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“…Also, for hepatitis C virus (HCV)-infected cells, massive generation of ROS and a decreased ⌬ m were described (2). Mitochondrial dysfunction and ROS generation were observed 24 h after infection of a mouse neuroblastoma cell line by Sindbis virus, the prototype member of the alphavirus genus within the family Togaviridae (26). In contrast to these observations, we found that the metabolic activities of mitochondria are maintained through the entire RV replication cycle.…”

Section: Discussioncontrasting

confidence: 86%

“…HCV-infected cells show an impairment of OXPHOS, which appears to be mainly due to a reduction in the activity of RC complex I of up to 50% (30). The respiratory capacities of complexes I and II decrease when Sindbis virus infection of a mouse neuroblastoma cell line proceeds (26). An increase in the activities of both the respiratory complex IV and the ATP synthase has been described to occur after HIV-1 infection (31).…”

Section: Discussionmentioning

confidence: 99%

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Activity Increase in Respiratory Chain Complexes by Rubella Virus with Marginal Induction of Oxidative Stress

Claus

Schönefeld

Hübner

et al. 2013

J Virol

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bMitochondria are important for the viral life cycle, mainly by providing the energy required for viral replication and assembly. A highly complex interaction with mitochondria is exerted by rubella virus (RV), which includes an increase in the mitochondrial membrane potential as a general marker for mitochondrial activity. We aimed in this study to provide a more comprehensive picture of the activity of mitochondrial respiratory chain complexes I to IV. Their activities were compared among three different cell lines. A strong and significant increase in the activity of mitochondrial respiratory enzyme succinate:ubiquinone oxidoreductase (complex II) and a moderate increase of ubiquinol:cytochrome c oxidoreductase (complex III) were detected in all cell lines. In contrast, the activity of mitochondrial respiratory enzyme cytochrome c oxidase (complex IV) was significantly decreased. The effects on mitochondrial functions appear to be RV specific, as they were absent in control infections with measles virus. Additionally, these alterations of the respiratory chain activity were not associated with an elevated transcription of oxidative stress proteins, and reactive oxygen species (ROS) were induced only marginally. Moreover, protein and/or mRNA levels of markers for mitochondrial biogenesis and structure were elevated, such as nuclear respiratory factors (NRFs) and mitofusin 2 (Mfn2). Together, these results establish a novel view on the regulation of mitochondrial functions by viruses. Mitochondria are required for the maintenance of cell function and integrity. Their most important role lies in energy production, but they are also at the intersection of regulatory pathways that coordinate metabolic processes (e.g., calcium homeostasis and cellular proliferation), cellular fate (apoptosis and necrosis), and antiviral defense (1, 2). Even a participation of mitochondria in the innate immune response was identified (2). There are a number of viruses that interfere with the important role of mitochondria in cellular antiviral response pathways, mainly with the regulation of apoptosis (1). Additionally, as the powerhouses of the cell, mitochondria provide most of the energy for viral replication and assembly. Up to 90% of the cellular ATP is produced in the inner mitochondrial membrane (IMM) by oxidative phosphorylation (OXPHOS), (3). OXPHOS comprises a series of redox reactions carried out by four multisubunit enzyme complexes (complexes I to IV) of the electron transport chain (ETC). Electrons are transferred in a stepwise manner through this series of electron carriers from NADH (and FADH 2 ) as reducing equivalents to the final acceptor molecular oxygen. A small percentage of electrons that are transported through the respiratory complexes leaks out, which results in generation of reactive oxygen species (ROS). The main ROS species is hydrogen peroxide, which is converted to water by enzymes such as catalase, peroxiredoxin, or glutathione peroxidase as components of the cellular antioxidant system. Respiratory c...

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Section: Discussioncontrasting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Activity Increase in Respiratory Chain Complexes by Rubella Virus with Marginal Induction of Oxidative Stress

Claus

Schönefeld

Hübner

et al. 2013

J Virol

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“…The increase in macromolecular synthesis for the generation of viral components also trigger synthesis of host factors that promote cell sustenance and survival resulting in an overall increase in the host cell biosynthetic activity [22]. Earlier studies in Sindbis virus infection, the prototype Alphavirus, have identified modulation of mitochondrial bioenergetics to favor ATP synthesis that is required to support active viral replication [23]. Similarly, in our study we see that the mitochondrial proteins are regulated during CHIKV infection in the HEK293 cell line.…”

Section: Changes In Cellular Energy Metabolismsupporting

confidence: 76%

High throughput proteomic analysis and a comparative review identify the nuclear chaperone, Nucleophosmin among the common set of proteins modulated in Chikungunya virus infection

Abraham

Mudaliar

Jaleel

et al. 2015

Journal of Proteomics

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Chikungunya remained as a neglected tropical disease till its re-emergence in 2005 in the La RéUnion islands and subsequently, in India and many parts of South East Asia. These and the epidemics that followed in subsequent years ran an explosive course leading to extreme morbidity and attributed mortality to this originally benign virus infection. Apart from classical symptoms of acute fever and debilitating polyarthralgia lasting for several weeks, a number of complications were documented. These included aphthous-like ulcers and vesiculo-bullous eruptions on the skin, hepatic involvement, central nervous system complications such as encephalopathy and encephalitis, and transplacental transmission. The disease has recently spread to the Americas with its initial documentation in the Caribbean islands. The Asian genotype of this positive-stranded RNA virus of the Alphavirus genus has been attributed in these outbreaks. However, the disease ran a similar course as the one caused by the East, Central and South African (ECSA) genotype in the other parts of the world. Studies have documented a number of mutations in the re-emerging strains of the virus that enhances mosquito adaptability and modulates virus infectivity. This might support the occurrence of fiery outbreaks in the absence of herd immunity in affected population. Several research groups work to understand the pathogenesis of chikungunya and the mechanisms of complications using cellular and animal models. A few proteomics approaches have been employed earlier to understand the protein level changes in the infected cells. Our present study, which couples a high throughput proteomic analysis and a comparative review of these earlier studies, identifies a few critical molecules as hypothetical candidates that might be important in this infection and for future study.

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“…As infection progresses, cellular stress increases, however, host cells have developed strategies to compensate metabolic shift as an attempt to maintain energy homeostasis and cell viability. Mitochondrial bioenergetics’ and metabolic balance are among the fundamental mechanisms used by cells to become tolerant to the stress caused by viral [10] or bacterial [11] infection. However, the extent to which parasites such as N. caninum alter host cell metabolism for their own replication, and the consequence of this disruption, remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Effects of Neospora caninum infection on brain microvascular endothelial cells bioenergetics

et al. 2013

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BackgroundThe brain is the most commonly affected organ during Neospora caninum infection but the mechanisms utilized by this protozoan parasite for traversal of the blood–brain barrier (BBB) are not yet understood. Herein, we investigate the cellular pathogenicity of N. caninum infection on bioenergetics of human brain microvascular endothelial cells (HBMECs), a fundamental component of the BBB.MethodsWe tracked the growth kinetics of N. caninum in HBMECs. Focusing on cell bioenergetics, oxygen consumption rate (OCR) was determined using Clark electrode system and mitochondrial membrane potential (ΔΨm) was evaluated using DePsipher staining by fluorescence microscopy in the presence and absence of infection.ResultsHBMECs provided a receptive environment for parasite proliferation. N. caninum tachyzoites were able to invade and replicate within HBMECs without significantly altering cell proliferation rate, as measured with the MTT assay, up to 24 hr post infection (pi). The oxygen consumption rate (OCR) was significantly inhibited (p < 0.001) by 10 mM glucose [from −2.26±0.23 to −0.6±0.21 nmol 106 cell min-1 and from −0.29±0.09 to −0.16±0.1 nmol 106 cell min-1 for uninfected HBMECs and free N. Caninum tachyzoites, respectively]. After normalization for DNA content the basal OCR did not differ between two host cell types: HBMECs and K562. The OCR of HBMECs was significantly elevated 24 hr pi in the absence of substrate, in 10 mM glucose and in the presence of a tetramethyl-p-phenylenediamine (TMPD)/ascorbate redox shuttle. Although quantitatively similar results were observed for uninfected K562 cells, there was no effect on their OCR 24 hr pi with N. caninum under any of the above substrate conditions. 6mM azide abolished OCR in all situations. Mitochondrial staining with DePsipher indicated no change in their membrane potential (Δψm) up to 24 hr pi.ConclusionsN. caninum is able to grow in HBMECs without markedly disrupting their normal proliferation or mitochondrial integrity. However, it is associated with an increase in infected cell respiration. Whether this increase reflects numeric addition of the parasites own respiration or results from an additional energy demand upon the host cell remains to be elucidated.

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Mitochondrial Bioenergetic Alterations in Mouse Neuroblastoma Cells Infected with Sindbis Virus: Implications to Viral Replication and Neuronal Death

Cited by 41 publications

References 65 publications

Activity Increase in Respiratory Chain Complexes by Rubella Virus with Marginal Induction of Oxidative Stress

Activity Increase in Respiratory Chain Complexes by Rubella Virus with Marginal Induction of Oxidative Stress

High throughput proteomic analysis and a comparative review identify the nuclear chaperone, Nucleophosmin among the common set of proteins modulated in Chikungunya virus infection

Effects of Neospora caninum infection on brain microvascular endothelial cells bioenergetics

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