Mitochondrial dysfunctions and altered metals homeostasis: new weapons to counteract HCV-related oxidative stress

Abstract

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.

Figure 1

Molecular mechanisms through which HCV induces mitochondrial damage and the consequent increased ROS production. Several HCV proteins associate with both endoplasmic reticulum (ER) and mitochondria. In particular, Core localizes also on MAMs and may play a role in the increase of mitochondrial Ca⁺⁺ pool, which in turn is involved in mitochondrial permeability transition pore (mPTP) opening, release of cytochrome c (Cyt C), and consequent mitochondrial depolarization. Organelle depolarization may be responsible for electron transport chain (ETC) failure and reactive oxygen species (ROS) overproduction. Enhanced ROS, in turn, may cause a further mPTP opening (dashed line), worsening the mitochondrial depolarization, thus leading to the onset of a vicious deleterious circle that aggravates the mitochondrial damage. Furthermore, some reports indicate that Complexes I and IV (CI and CIV, resp.) of the ETC are main targets of HCV actions. The fall of their activities plays key role in ETC failure and increased ROS production.