Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1 alpha-mediated glycolytic adaptation.
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.
Department of Biomedical Sciences, University of Foggia, Foggia, Italy.
Maria
M
Ripoli
Annamaria
A
D'Aprile
Giovanni
G
Quarato
Magdalena
M
Sarasin-Filipowicz
Jérôme
J
Gouttenoire
Rosella
R
Scrima
Olga
O
Cela
Domenico
D
Boffoli
Markus H
MH
Heim
Darius
D
Moradpour
Nazzareno
N
Capitanio
Claudia
C
Piccoli
D000222:Adaptation, Physiological; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D006019:Glycolysis; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000821:virology*; D010085:Oxidative Phosphorylation; D055550:Protein Stability; D014764:Viral Proteins
D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014764:Viral Proteins