HCV induced oxidative stress, mitochondrial damage, and autophagy in human hepatoma cells

Hepatitis C virus (HCV)‐induced oxidative stress is strongly implicated in HCV‐mediated liver disorders and the development of hepatocellular carcinoma. However, the underlying mechanisms remain elusive. To better define the HCV‐mediated effects at the cellular level, we carried out in vitro studies using Huh7 cells expressing the full‐length HCV polyprotein, non‐structural (NS) proteins, or the core protein. Expression of both HCV structural and NS proteins results in increased oxidative stress and damage in mitochondria with enhanced Mitosox staining, decreased mitochondrial numbers, and enlarged mitochondria with disrupted cristae. Increased lipid accumulation is also evident. Despite these defects, only cells expressing the full‐length HCV polyprotein show a marked increase in cell doubling time and a decrease in cyclin D1 levels. Cells with NS proteins show reduced cell volume and a significant up‐regulation of antioxidant enzymes, Prxn 1 & 3. Constitutive expression of NS proteins also leads to increased autophagosome formation and enhanced LC3 staining. In contrast, cells expressing only the core protein show a modest increase in autophagy. Taken together, our data show that HCV‐mediated damage is not limited to mitochondria, and different components of HCV polyproteins may cause various degrees of damage in different cellular compartments thus eliciting different cellular responses.