Effect of Hepatitis B and C Viruses on Mitochondrial Function

Abstract

HCV and HBV infections are leading causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma and can induce metabolic dysfunction, which may offer a selective advantage for liver cancer proliferation and survival. The liver is enriched with numerous mitochondria, providing a continuous supply of ATP for a range of cellular activities. The hypothesis of this thesis is that HBV and HCV induce mitochondrial dysfunction and metabolic disorders. A range of cell culture models and in vitro techniques were used to test this hypothesis, including the Seahorse analyser to measure mitochondrial function in real time. Mitochondrial function and membrane potential during HCV and HBV infection were decreased, which were independent of mitochondrial biogenesis. HCV infection promotes steatosis due to a combination of viral and host metabolic factors, whereas steatosis during HBV is more variable. Therefore, potential changes in lipid metabolism were investigated in our HCV and HBV models. Impaired lipid oxidation was observed during HCV infection, but not during HBV expression. Perturbation of pyruvate metabolism was proposed as a possible mechanism for mitochondrial dysfunction during HBV expression. No significant change in pyruvate but an increase in lactate concentrations was observed, due to elevated lactate dehydrogenase A, which converts pyruvate to lactate. Proteomics analysis revealed other key proteins involved in pyruvate metabolism to be differentially regulated, including increased levels of pyruvate dehydrogenase kinase. In summary, HCV infection causes mitochondrial dysfunction and reduced lipid oxidation, resulting in intracellular accumulation of lipids. In contrast, HBV expression does not affect lipids but alters pyruvate metabolism, causing lactate accumulation and promoting the “Warburg effect”. Thus, although HBV does not cause steatosis, the lactate accumulation and altered cell metabolism may promote the development and progression of liver cancer.