Hepatitis B Virus X Protein Colocalizes to Mitochondria with a Human Voltage-Dependent Anion Channel, HVDAC3, and Alters Its Transmembrane Potential

Rahmani, Zohra; Huh, Kyung-Won; Lasher, Robert S.; Siddiqui, Aleem

doi:10.1128/jvi.74.6.2840-2846.2000

Cited by 286 publications

(286 citation statements)

References 38 publications

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“…In addition to this accepted marker of mitochondrial stress, maintenance of the mitochondrial membrane potential (MMP) is also utilized as a marker of mitochondrial function [17,18,24,38]. We have shown that these two events correlate with increased mitochondrial fission and mitophagy, contributing to cell death in an infection dependent manner [24].…”

Section: Resultsmentioning

confidence: 99%

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

et al. 2018

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Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that eventually contributes to neurodegenerative phenotypes. In this study, we utilize the TC-83 strain of VEEV, which is known to induce the expression of IL-6, IL-8, and other pro-inflammatory cytokines. We had previously demonstrated that TC-83 infection resulted in changes in mitochondrial function, eventually resulting in mitophagy. In this manuscript, we provide data that links upstream mitochondrial dysfunction with downstream pro-inflammatory cytokine production in the context of microglia and astrocytoma cells. We also provide data on the role of bystander cells, which significantly contribute to the overall inflammatory load. Use of a mitochondrial-targeted antioxidant, mitoquinone mesylate, greatly reduced the inflammatory cytokine load and ameliorated bystander cell inflammatory responses more significantly than a broad-spectrum anti-inflammatory compound (BAY 11–7082). Our data suggest that the inflammatory mediators, especially IL-1β, may prime naïve cells to infection and lead to increased infection rates in microglial and astrocytoma cells. Cumulatively, our data suggest that the interplay between mitochondrial dysfunction and inflammatory events elicited in a neuronal microenvironment during a TC-83 infection may contribute to the spread of infection.

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Section: Resultsmentioning

confidence: 99%

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

et al. 2018

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“…HBx exerts powerful effects on mitochondria either directly owing to their channel-forming activity or indirectly through interactions with endogenous channels (Takada et al, 1999;Henkler et al, 2001;Lee et al, 2004). HBx reportedly interacts with at least two mitochondrial proteins, namely heat-shock protein 60 and 70 (Tanaka et al, 2004;Zhang et al, 2005b) and the VDAC isoform VDAC3 (Rahmani et al, 2000;Kim, 2005).…”

Section: Hbxmentioning

confidence: 99%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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As discussed in detail in other chapters of this review, chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated with the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarize the current knowledge on the mechanisms involved in HBVrelated liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus, as well as between viral infections and other environmental factors, such as alcohol.

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“…HBx acts as a transcriptional co-activator in the nucleus and stimulates various signal transduction pathways in the cytoplasm. In addition, HBx is often found localized at the mitochondria [6][7][8]. HBx targeting to mitochondria causes a loss of mitochondrial membrane potential that has been linked to cell death [9] and oxidative liver injury [10].…”

Section: Introductionmentioning

confidence: 99%

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBx Δ68-117 ) neither increased intracellular ROS levels nor induced COX-2 expression. HBx 68-117 , which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calciumdependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.

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Hepatitis B Virus X Protein Colocalizes to Mitochondria with a Human Voltage-Dependent Anion Channel, HVDAC3, and Alters Its Transmembrane Potential

Abstract: Understanding the mechanism(s) of action of the hepatitis B virus (HBV)-encoded protein

Cited by 286 publications

References 38 publications

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

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