The hepatitis C virus (HCV) infection produces several pathological effects in host organism through a wide number of molecular/metabolic pathways. Today it is worldwide accepted that oxidative stress actively participates in HCV pathology, even if the antioxidant therapies adopted until now were scarcely effective. HCV causes oxidative stress by a variety of processes, such as activation of prooxidant enzymes, weakening of antioxidant defenses, organelle damage, and metals unbalance. A focal point, in HCV-related oxidative stress onset, is the mitochondrial failure. These organelles, known to be the “power plants” of cells, have a central role in energy production, metabolism, and metals homeostasis, mainly copper and iron. Furthermore, mitochondria are direct viral targets, because many HCV proteins associate with them. They are the main intracellular free radicals producers and targets. Mitochondrial dysfunctions play a key role in the metal imbalance. This event, today overlooked, is involved in oxidative stress exacerbation and may play a role in HCV life cycle. In this review, we summarize the role of mitochondria and metals in HCV-related oxidative stress, highlighting the need to consider their deregulation in the HCV-related liver damage and in the antiviral management of patients. 1. Introduction Hepatitis C virus (HCV) is a human pathogen affecting about 4 million new subjects every year [1]. Approximately 3% of the world’s population is estimated to be chronically infected by HCV [2]. Differently from the other hepatitis viruses (A, B, and E), more than 80% of HCV patients become chronic [3]. HCV is a member of the genus Hepacivirus of Flaviviridae family. It is a single-stranded RNA virus with positive polarity. The genome of HCV encodes a polyprotein of about 3000 amino acids that is expressed from a single long open reading frame (ORF). This polyprotein is cleaved into ten different products: the core protein (Core) and the envelope glycoproteins 1 and 2 (E1 and E2, resp.), which are constituents of the HCV particles, p7 and nonstructural protein 2 (NS2), primarily involved in HCV assembly, NS3, NS4A, NS4B, NS5A, and NS5B nonstructural proteins with important roles in the polyprotein processing and HCV replication [4]. HCV infection frequently leads to severe liver diseases, including liver cirrhosis and HCC [5]. Chronic HCV infected patients are commonly characterized by metabolic derangements, such as steatosis, insulin resistance (IR), and altered homeostasis of trace metals [6–8]. Many works suggest that oxidative stress (OS) plays a
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