Ripoli 2009 J Virol

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Ripoli Maria, D'Aprile Annamaria, Quarato Giovanni, Sarasin-Filipowicz Magdalena, Gouttenoire Jérôme, Scrima Rosella, Cela Olga, Boffoli Domenico, Heim Markus H, Moradpour Darius, Capitanio Nazzareno, Piccoli Claudia (2009) Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1α-mediated glycolytic adaptation. J Virol 84:647-60.

» PMID: 19846525 Open Access »O2k-brief

Ripoli Maria, D'Aprile Annamaria, Quarato Giovanni, Sarasin-Filipowicz Magdalena, Gouttenoire Jérôme, Scrima Rosella, Cela Olga, Boffoli Domenico, Heim Markus H, Moradpour Darius, Capitanio Nazzareno, Piccoli Claudia (2009) J Virol

Abstract: 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 α 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-1α 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-1α 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-1α. Similar results were obtained by treatment with pyruvate, indicating that accumulation of intermediate metabolites is sufficient to stabilize HIF-1α. These observations provide new insights into the pathogenesis of chronic hepatitis C and, possibly, the HCV-related development of hepatocellular carcinoma.

Keywords: Hepatitis C virus (HCV), HIF

O2k-Network Lab: IT Foggia Capitanio N


Labels: MiParea: Respiration, mt-Medicine  Pathology: Infectious  Stress:Oxidative stress;RONS  Organism: Human  Tissue;cell: Liver, Other cell lines  Preparation: Intact cells 

Regulation: Aerobic glycolysis  Coupling state: LEAK, ROUTINE 

HRR: Oxygraph-2k 

hypoxia-inducible factor, HIF, hepatitis, HCV, O2k-brief