Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1 alpha-mediated glycolytic adaptation

Ripoli, Maria and D'Aprile, Annamaria and Quarato, Giovanni and Sarasin-Filipowicz, Magdalena and Gouttenoire, Jérôme and Scrima, Rosella and Cela, Olga and Boffoli, Domenico and Heim, Markus H. and Moradpour, Darius and Capitanio, Nazzareno and Piccoli, Claudia. (2010) Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1 alpha-mediated glycolytic adaptation. Journal of virology, Vol. 84, H. 1. pp. 647-660.

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Official URL: http://edoc.unibas.ch/dok/A6003919

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Hepatitis C virus (HCV) infection induces a state of oxidative stress by affecting mitochondrial-respiratory-chain activity. By using cell lines inducibly expressing different HCV constructs, we showed previously that viral-protein expression leads to severe impairment of mitochondrial oxidative phosphorylation and to major reliance on nonoxidative glucose metabolism. However, the bioenergetic competence of the induced cells was not compromised, indicating an efficient prosurvival adaptive response. Here, we show that HCV protein expression activates hypoxia-inducible factor 1 (HIF-1) by normoxic stabilization of its alpha subunit. In consequence, expression of HIF-controlled genes, including those coding for glycolytic enzymes, was significantly upregulated. Similar expression of HIF-controlled genes was observed in cell lines inducibly expressing subgenomic HCV constructs encoding either structural or nonstructural viral proteins. Stabilization and transcriptional activation of HIF-1alpha was confirmed in Huh-7.5 cells harboring cell culture-derived infectious HCV and in liver biopsy specimens from patients with chronic hepatitis C. The HCV-related HIF-1alpha stabilization was insensitive to antioxidant treatment. Mimicking an impairment of mitochondrial oxidative phosphorylation by treatment of inducible cell lines with oligomycin resulted in stabilization of HIF-1alpha. Similar results were obtained by treatment with pyruvate, indicating that accumulation of intermediate metabolites is sufficient to stabilize HIF-1alpha. These observations provide new insights into the pathogenesis of chronic hepatitis C and, possibly, the HCV-related development of hepatocellular carcinoma.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Hepatology Laboratory (Heim)
UniBasel Contributors:Heim, Markus H.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Feb 2013 08:46
Deposited On:01 Feb 2013 08:43

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