Piccoli Claudia, Scrima Rosella, Quarato Giovanni, D'Aprile Annamaria, Ripoli Maria, Lecce Lucia, Boffoli Domenico, Moradpour Darius, Capitanio Nazzareno
Department of Biomedical Sciences, University of Foggia, Foggia, Italy.
Hepatology. 2007 Jul;46(1):58-65. doi: 10.1002/hep.21679.
Hepatitis C virus (HCV) infection induces a state of oxidative stress that is more pronounced than that in many other inflammatory diseases. In this study we used well-characterized cell lines inducibly expressing the entire HCV open-reading frame to investigate the impact of viral protein expression on cell bioenergetics. It was shown that HCV protein expression has a profound effect on cell oxidative metabolism, with specific inhibition of complex I activity, depression of mitochondrial membrane potential and oxidative phosphorylation coupling efficiency, increased production of reactive oxygen and nitrogen species, as well as loss of the Pasteur effect. Importantly, all these effects were causally related to mitochondrial calcium overload, as inhibition of mitochondrial calcium uptake completely reversed the observed bioenergetic alterations.
Expression of HCV proteins causes deregulation of mitochondrial calcium homeostasis. This event occurs upstream of further mitochondrial dysfunction, leading to alterations in the bioenergetic balance and nitro-oxidative stress. These observations provide new insights into the pathogenesis of hepatitis C and may offer new opportunities for therapeutic intervention.
丙型肝炎病毒（HCV）感染会引发一种氧化应激状态，这种状态比许多其他炎症性疾病中的更为明显。在本研究中，我们使用了可诱导表达整个HCV开放阅读框的特征明确的细胞系，以研究病毒蛋白表达对细胞生物能量学的影响。结果表明，HCV蛋白表达对细胞氧化代谢有深远影响，具体表现为对复合体I活性的特异性抑制、线粒体膜电位降低以及氧化磷酸化偶联效率下降，活性氧和氮物种生成增加，同时巴斯德效应丧失。重要的是，所有这些效应都与线粒体钙超载存在因果关系，因为抑制线粒体钙摄取完全逆转了所观察到的生物能量学改变。
HCV蛋白的表达导致线粒体钙稳态失调。这一事件发生在进一步的线粒体功能障碍之前，导致生物能量平衡和硝基氧化应激的改变。这些观察结果为丙型肝炎的发病机制提供了新的见解，并可能为治疗干预提供新的机会。
