Human cytomegalovirus infection increases mitochondrial biogenesis

Kaarbø, Mari; Ager-Wick, Eirill; Osenbroch, Pia Ø.; Kilander, Anette; Skinnes, Ragnhild; Müller, Fredrik; Eide, Lars

doi:10.1016/j.mito.2011.08.008

Cited by 55 publications

(80 citation statements)

References 60 publications

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“…Mitochondria-related terms were observed in the upregulated cluster 2 and the downregulated cluster 4, suggesting differential regulation of mitochondria proteins during infection. However, an overall increase in mitochondria proteins was observed late in infection, supporting previous reports on increased mitochondria; biogenesis and selective upregulation of the electron transport chain complex IV (Kaarbo et al, 2011) during HCMV infection. Furthermore, the localization of mitochondria around the Assembly Complex (Fig.…”

Section: Resultssupporting

confidence: 88%

“…Something to consider is that, within each organelle, proteins can have distinct functions that may be differentially regulated during infection. Indeed, some organelles had a larger spread in protein fold changes (e.g., plasma membrane) likely due to multiple functions, while others showed clear trends supported by previous studies (e.g., mitochondria) (Kaarbo et al, 2011). In general, the spread of protein fold changes within organelles increased as infection progressed, suggesting that different proteins within the same organelle are differentially regulated late in infection.…”

Section: Resultssupporting

confidence: 74%

“…HCMV infection causes mitochondrial fission, triggering anti-apoptotic effects (McCormick et al, 2003) and augmented respiration (Kaarbo et al, 2011). In agreement, mitochondria network fragmentation was observed at 48 hpi, increasing by 120 hpi.…”

Section: Resultsmentioning

confidence: 99%

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A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection

2016

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SUMMARY The organelles within a eukaryotic host are manipulated by viruses to support successful virus replication and spread of infection, yet the global impact of viral infection on host organelles is poorly understood. Integrating microscopy, sub-cellular fractionation, mass spectrometry, and functional analyses, we conducted a cell-wide study of organelles in primary fibroblasts throughout the timecourse of human cytomegalovirus (HCMV) infection. We used label-free and isobaric-labeling proteomics to characterize nearly 4,000 host and 100 viral proteins, then classified their specific subcellular locations over time using machine learning. We observed a global reorganization of proteins across the secretory pathway, plasma membrane, and mitochondria, including reorganization and processing of lysosomal proteins into distinct subpopulations and translocations of individual proteins between organelles at specific timepoints. We also demonstrate that MYO18A, an unconventional myosin that translocates from the plasma membrane to the viral assembly complex, is necessary for efficient HCMV replication. This study provides a comprehensive resource for understanding host and virus biology during HCMV pathogenesis.

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Section: Resultssupporting

confidence: 88%

Section: Resultssupporting

confidence: 74%

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A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection

2016

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“…For example, mouse embryonic fibroblasts contain fewer mitochondria in the absence of Rb (10), whereas adipocytes contain more (17). HCMV infection increases mitochondrial biogenesis, which supports efficient viral replication (42). We therefore sought to determine whether HCMV replicated less efficiently in Rb knockdown cells because it could no longer induce mitochondrial biogenesis.…”

Section: Resultsmentioning

confidence: 99%

Deficiencies in Cellular Processes Modulated by the Retinoblastoma Protein Do Not Account for Reduced Human Cytomegalovirus Replication in Its Absence

VanDeusen

Kalejta

2015

J Virol

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Despite encoding multiple viral proteins that modulate the retinoblastoma (Rb) protein in a manner classically defined as inactivation, human cytomegalovirus (HCMV) requires the presence of the Rb protein to replicate efficiently. In uninfected cells, Rb controls numerous pathways that the virus also commandeers during infection. These include cell cycle progression, senescence, mitochondrial biogenesis, apoptosis, and glutaminolysis. We investigated whether a potential inability of HCMV to regulate these Rb-controlled pathways in the absence of the Rb protein was the reason for reduced viral productive replication in Rb knockdown cells. We found that HCMV was equally able to modulate these pathways in the parental Rb-expressing and Rb-depleted cells. Our results suggest that Rb may be required to enhance a specific viral process during HCMV productive replication. R etinoblastoma (Rb) protein function is modified by multiple viruses (1-3). Through transcriptional repression of the E2F-responsive genes required for DNA replication, hypophosphorylated (active) Rb impedes cell cycle transit through G 1 and into S phase (4). Rb can also induce the formation of heterochromatin at E2F responsive genes, leading to permanent transcriptional silencing and replicative senescence (5, 6), providing a tumor suppressive function. As the role of Rb as a mediator of senescence and restrictor of cell cycle progression has long been acknowledged, the prevailing model in the field of DNA virology has associated viral targeting of Rb with maintaining a cell cycle state conducive to viral replication (7). Specifically, it was proposed that viruses alter the function of Rb to provide an S-phase-like environment where the enzymes and small molecule precursors necessary for DNA synthesis would be readily available for viral DNA replication. Indeed, the ability of the E7 protein of the high-risk human papillomavirus strain 16 to bind Rb is necessary for viral DNA replication (8).However, we recently reported that transient and stable Rb knockdown reduces the efficiency of human cytomegalovirus (HCMV) DNA synthesis and productive replication (9). This result was unexpected as HCMV encodes at least four viral proteins reported to modify several biological functions of Rb (2). Therefore, the relationship between viruses and Rb appears more complicated than the current paradigm allows.In recent years Rb has been shown to affect many facets of mitochondrial function in addition to its critical role in controlling the cell cycle. These include mitochondrial biogenesis, apoptosis, and the utilization of glutamine for the tricarboxylic acid (TCA) cycle and the production of glutathione. In the absence of Rb, cells have lower ratios of mitochondrial to cellular DNA, and this has been ascribed to defects in mitochondrial biogenesis (10,11). Rb regulates apoptosis directly at the mitochondria by binding to Bax (12,13). Interestingly, it is a phosphorylated form of Rb that interacts with Bax, and loss of this form can trigger apoptosis (12...

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“…HCMV infection results in a number of effects on host mitochondria including increased mitochondrial biogenesis and an increase in mitochondrial activity [180]. Cellular invasion by the virus leads to significant changes to the proteins mediating contact between the endoplasmic reticulum and mitochondria, coupled with increased calcium signaling to the organelle with the aim of up-regulating bioenergetics performance to maximize the production of progeny [181].…”

Section: Cytomegalovirusmentioning

confidence: 99%

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

Morris¹,

Berk

Walder

et al. 2015

Mol Neurobiol

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Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms. More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

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Human cytomegalovirus infection increases mitochondrial biogenesis

Cited by 55 publications

References 60 publications

A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection

A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection

Deficiencies in Cellular Processes Modulated by the Retinoblastoma Protein Do Not Account for Reduced Human Cytomegalovirus Replication in Its Absence

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

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