FW: Mitochondrial dysfunction as a consequence of viral infection

[Guest guest]

Very interesting description/discussion of host mitochondria being deployed

to provide energy for virus morphogenetic processes ­ Viral assembly and

budding occuring on mitochondrial membrane. pdf attached, also through

http://jvi.asm.org/cgi/content/full/79/15/9991?view=long & pmid=16014959

<http://jvi.asm.org/cgi/content/full/79/15/9991?view=long & amp;pmid=16014959>

Access of viral proteins to mitochondria via mitochondria-associated

membranes

http://www3.interscience.wiley.com/cgi-bin/fulltext/122322250/PDFSTART (free

access)

By exploiting host cell machineries, viruses provide powerful tools for

gaining insight into cellular pathways. Proteins from two unrelated viruses,

human CMV (HCMV) and HCV, are documented to traffic sequentially from the ER

into mitochondria, probably through the mitochondria-associated membrane

(MAM) compartment. The MAM are sites of ER-mitochondrial contact enabling

the direct transfer of membrane bound lipids and the generation of high

calcium (Ca2+) microdomains for mitochondria signalling and responses to

cellular stress. Both HCV core protein and HCMV UL37 proteins are associated

with Ca2+ regulation and apoptotic signals. Trafficking of viral proteins to

the MAM may allow viruses to manipulate a variety of fundamental cellular

processes, which converge at the MAM, including Ca2+ signalling, lipid

synthesis and transfer, bioenergetics, metabolic flow, and apoptosis.

Because of their distinct topologies and targeted MAM sub-domains,

mitochondrial trafficking (albeit it through the MAM) of the HCMV and HCV

proteins predictably involves alternative pathways and, hence, distinct

targeting signals. Indeed, we found that multiple cellular and viral

proteins, which target the MAM, showed no apparent consensus primary

targeting sequences. Nonetheless, these viral proteins provide us with

valuable tools to access the poorly characterised MAM compartment, to define

its cellular constituents and describe how virus infection alters these to

its own end. Furthermore, because proper trafficking of viral proteins is

necessary for their function, discovering the requirements for MAM to

mitochondrial trafficking of essential viral proteins may provide novel

targets for the rational design of anti-viral drugs. PMID: 19367604

Effect of [Ca2+]i and neuronal mitochondria transmembrane potentials in

hippocampus of murine cytomegalovirus infected mice.

To explore the effect of [Ca2+]i and neuronal mitochondria transmembrane

potentials in hippocampus of murine cytomegalovirus (MCMV) infected mice,

newborn Balb/c mice were randomly divided into two groups: a virus

inoculated group and a control group. After 56 days, single cell of

hippocampus was isolated, and mitochondria transmembrane potentials and the

intracellular free calcium level [Ca2+]i in hippocampus were measured by

means of flow cytometry (FCM). Compared with the control group, the

mitochondria transmembrane potentials was decreased (P<0.01) and the

intracellular free calcium level [Ca2+]i was increased (P<0.01) in

inoculated group. The dysfunction of [Ca2+]i and mitochondria transmembrane

potentials in hippocampus may play an important role in the functional

disorders in CMV-infected CNS.

Hepatitis C virus protein expression causes calcium-mediated mitochondrial

bioenergetic dysfunction and nitro-oxidative stress.

http://www3.interscience.wiley.com/journal/114278640/abstract

Hepatitis C virus (HCV) infection induces a state of oxidative stress that

is more pronounced than that in many other inflammatory diseases. In this

study we used well-characterized cell lines inducibly expressing the entire

HCV open-reading frame to investigate the impact of viral protein expression

on cell bioenergetics. It was shown that HCV protein expression has a

profound effect on cell oxidative metabolism, with specific inhibition of

complex I activity, depression of mitochondrial membrane potential and

oxidative phosphorylation coupling efficiency, increased production of

reactive oxygen and nitrogen species, as well as loss of the Pasteur effect.

Importantly, all these effects were causally related to mitochondrial

calcium overload, as inhibition of mitochondrial calcium uptake completely

reversed the observed bioenergetic alterations. CONCLUSION: Expression of

HCV proteins causes deregulation of mitochondrial calcium homeostasis. This

event occurs upstream of further mitochondrial dysfunction, leading to

alterations in the bioenergetic balance and nitro-oxidative stress. These

observations provide new insights into the pathogenesis of hepatitis C and

may offer new opportunities for therapeutic intervention. PMID: 17567832

Human cytomegalovirus pUL37x1 induces the release of endoplasmic reticulum

calcium stores.

http://www.pnas.org/content/103/50/19117.long

The human CMV UL37x1-encoded protein, also known as the viral

mitochondria-localized inhibitor of apoptosis, traffics to the endoplasmic

reticulum and mitochondria of infected cells. It induces the fragmentation

of mitochondria and blocks apoptosis. We demonstrate that UL37x1 protein

mobilizes Ca(2+) from the endoplasmic reticulum into the cytosol. This

release is accompanied by cell rounding, cell swelling, and reorganization

of the actin cytoskeleton, and these morphological changes can be

substantially blocked by a Ca(2+) chelating agent. The UL37x1-mediated

release of Ca(2+) from the endoplasmic reticulum likely has multiple

consequences, including induction of the unfolded protein response,

modulation of mitochondrial function, induction of mitochondrial fission,

and protection against apoptotic stimuli.PMID: 17135350

Hepatitis B virus replication is associated with an HBx-dependent

mitochondrion-regulated increase in cytosolic calcium levels.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & pubmedid=176

99583

<http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & amp;pubmedi

d=17699583>

The nonstructural hepatitis B virus (HBV) protein HBx has an important role

in HBV replication and in HBV-associated liver disease. Many activities have

been linked to HBx expression; however, the molecular mechanisms underlying

many of these activities are unknown. One proposed HBx function is the

regulation of cytosolic calcium. We analyzed calcium levels in HepG2 cells

that expressed HBx or replicating HBV, and we demonstrated that HBx,

expressed in the absence of other HBV proteins or in the context of HBV

replication, elevates cytosolic calcium. We linked this elevation of

cytosolic calcium to the association of HBx with the mitochondrial

permeability transition pore.MID: 17699583

Mitochondrial dysfunction in hepatitis C virus infection.

The mechanisms of liver injury in chronic hepatitis C virus (HCV) infection

are poorly understood though HCV induces a state of hepatic oxidative stress

that is more pronounced than that present in many other inflammatory

diseases. This mini-review will focus on recent findings revealing an

unexpected role of mitochondria in providing a central role in the innate

immunity and in addition will illustrate the application of stably

transfected human-derived cell lines, inducibly expressing the entire HCV

open reading frame for in vitro studies on mitochondria. Results obtained by

a comparative analysis of the respiratory chain complexes activities along

with mitochondrial morpho-functional confocal microscopy imaging show a

detrimental effect of HCV proteins on the cell oxidative metabolism with

specific inhibition of complex I activity, decrease of mtDeltaPsi, increased

production of reactive oxygen species. A possible de-regulation of calcium

recycling between the endoplasmic reticulum and the mitochondrial network is

discussed to provide new insights in the pathogenesis of hepatitis C. pMID:

16814246

HIV-1 Tat Activates Neuronal odine Receptors with Rapid Induction of the

Unfolded Protein Response and Mitochondrial Hyperpolarization

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & pubmedid=190

09018

<http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & amp;pubmedi

d=19009018>

Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is

ultimately refractory to highly active antiretroviral therapy (HAART)

because of failure of complete virus eradication in the central nervous

system (CNS), and disruption of normal neural signaling events by virally

induced chronic neuroinflammation. We have previously reported that HIV-1

Tat can induce mitochondrial hyperpolarization in cortical neurons, thus

compromising the ability of the neuron to buffer calcium and sustain energy

production for normal synaptic communication. In this report, we demonstrate

that Tat induces rapid loss of ER calcium mediated by the ryanodine receptor

(RyR), followed by the unfolded protein response (UPR) and pathologic

dilatation of the ER in cortical neurons in vitro. RyR antagonism attenuated

both Tat-mediated mitochondrial hyperpolarization and UPR induction.

Delivery of Tat to murine CNS in vivo also leads to long-lasting pathologic

ER dilatation and mitochondrial morphologic abnormalities. Finally, we

performed ultrastructural studies that demonstrated mitochondria with

abnormal morphology and dilated endoplasmic reticulum (ER) in brain tissue

of patients with HIV-1 inflammation and neurodegeneration. Collectively,

these data suggest that abnormal RyR signaling mediates the neuronal UPR

with failure of mitochondrial energy metabolism, and is a critical locus for

the neuropathogenesis of HIV-1 in the CNS. PMID: 19009018

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