Hepatitis C Virus-Linked Mitochondrial Dysfunction Promotes Hypoxia-Inducible Factor 1α-Mediated Glycolytic Adaptation
Hepatitis C Virus-Linked Mitochondrial Dysfunction Promotes Hypoxia-Inducible Factor 1α-Mediated Glycolytic Adaptation
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DOI：
10.1128/jvi.00769-09
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发表时间：
2010-01-01
影响因子：
5.4
通讯作者：
Piccoli, Claudia
中科院分区：
文献类型：
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作者：
Ripoli, Maria;D'Aprile, Annamaria;Piccoli, Claudia
丙型肝炎病毒（HCV）感染通过影响线粒体-补体链的活性而诱导氧化应激状态。通过使用诱导表达不同HCV构建体的细胞系，我们先前表明病毒蛋白表达导致线粒体氧化磷酸化严重受损，并主要依赖于非氧化葡萄糖代谢。然而，诱导的细胞的生物能量能力没有受到损害，表明有效的促生存适应性反应。在这里，我们表明，HCV蛋白表达激活缺氧诱导因子1（HIF-1）的常氧稳定的α亚基。因此，HIF控制的基因，包括那些编码糖酵解酶的基因的表达显著上调。在诱导表达编码结构或非结构病毒蛋白的亚基因组HCV构建体的细胞系中观察到类似的HIF控制基因表达。HIF-1 α的稳定和转录激活在携带细胞培养衍生的感染性HCV的Huh-7.5细胞和慢性丙型肝炎患者的肝活检标本中得到证实。HCV相关的HIF-1 α稳定化对抗氧化剂治疗不敏感。通过用寡霉素处理诱导型细胞系来模拟线粒体氧化磷酸化的损伤，导致HIF-1 α的稳定。用丙酮酸处理获得了类似的结果，表明中间代谢物的积累足以稳定HIF-1 α。这些观察结果提供了新的见解慢性丙型肝炎的发病机制，并可能，HCV相关的肝细胞癌的发展。
Hepatitis C virus (HCV) infection induces a state of oxidative stress by affecting mitochondrial-respiratorychain 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-1 alpha 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-1 alpha 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-1 alpha. Similar results were obtained by treatment with pyruvate, indicating that accumulation of intermediate metabolites is sufficient to stabilize HIF-1 alpha. These observations provide new insights into the pathogenesis of chronic hepatitis C and, possibly, the HCV-related development of hepatocellular carcinoma.