Hepatitis B Virus and Hepatitis C Virus Affect Mitochondrial Function Through Different Metabolic Pathways, Explaining Virus-Specific Clinical Features of Chronic Hepatitis

Abstract Background Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesized these differences may be due to virus-specific effects on mitochondrial function. Methods Seahorse technology was used to investigate effects of virus infection on mitochondrial function. Cell-based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV-expressing, HCV-infected, and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real-time polymerase chain reaction (PCR) and western blot. Results Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impaired glycolysis and fatty acid oxidation, promoting lipid accumulation whereas HBV caused lactate accumulation. In HBV-expressing cells enrichment of pyruvate dehydrogenase kinase inhibited pyruvate to acetyl-CoA conversion thereby reducing its availability for mitochondrial oxidative phosphorylation. Conclusions HBV and HCV impair mitochondrial function. HCV infection reduces lipid oxidation causing its accumulation and fatty liver disease. HBV infection affects pyruvate processing causing lactate accumulation, cellular stress, and increased risk of liver disease and cancer. HBV and HCV impair mitochondrial function. HCV infection reduces breakdown of fat, causing lipid accumulation and fatty liver disease. HBV infection affects pyruvate processing resulting in lactate accumulation, causing cellular stress and increasing the risk of liver disease and cancer. Graphical abstract Graphical abstract Summary of mitochondrial metabolic regulation by HCV and HBV. This schematic figure summarizes the altered regulation of mitochondrial metabolic pathways during HCV infection and HBV expression. The image was created with BioRender.com.