Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis

Sakthi Priya Selvamani; Anis Khan; Enoch S E Tay; Matthew Garvey; Harout Ajoyan; Eve Diefenbach; Brian S Gloss; Thomas Tu; Jacob George; Mark W Douglas

doi:10.1093/infdis/jiae210

Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis

J Infect Dis. 2024 Apr 24:jiae210. doi: 10.1093/infdis/jiae210. Online ahead of print.

Authors

Affiliations

¹ Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
² Protein Core Facility, The Westmead Institute for Medical Research, Westmead, NSW, Australia.
³ Westmead Research Hub, The Westmead Institute for Medical Research, Westmead, NSW, Australia.
⁴ Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Westmead, NSW, Australia.

PMID: 38655824
DOI: 10.1093/infdis/jiae210

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 hypothesised these differences may be due to virus-specific effects on mitochondrial function.

Methods: Seahorse technology was utilised 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 PCR and western blot.

Results: Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation.

Conclusions: HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.

Keywords: hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; liver cancer; metabolism; mitochondria; steatosis.