Mitochondrial stress in advanced fibrosis and cirrhosis associated with chronic hepatitis B, chronic hepatitis C, or nonalcoholic steatohepatitis

Abstract

Background & aims: Hepatitis B virus infection causes oxidative stress and alters mitochondria in experimental models. We postulated that HBV might alter liver mitochondria also in human, and the resulting mitochondrial stress might account for the progression of fibrosis in chronic hepatitis B (CHB). Approach & results:The study included 146 treatment-naïve CHB mono-infected patients. Patients with CHB and advanced fibrosis or cirrhosis (F3-F4) were compared to patients with no-mild-moderate fibrosis (F0-F2). Patients with CHB were further compared to patients with chronic hepatitis C (CHC) (n=33), nonalcoholic steatohepatitis (NASH) (n=12) and healthy controls (n=24). We detected oxidative damage to mtDNA including mtDNA strand beaks, and identified multiple mtDNA deletions in patients with F3-F4 as compared to patients with F0-F2. Alterations in mitochondrial function, mitochondrial unfolded protein response, biogenesis, mitophagy and liver inflammation were observed in patients with advanced fibrosis or cirrhosis associated with CHB, CHC and NASH.In vitro, significant increases of the mitochondrial formation of superoxide and peroxynitrite as well as mtDNA damage, nitration of the mitochondrial respiratory chain complexes and impairment of complex I occurred in HepG2 cells replicating HBV or transiently expressing Hepatitits B virus X protein. mtDNA damage and complex I impairment were prevented with the superoxide scavenging Mito-Tempo or with iNOS specific inhibitor 1400W. Conclusion: Our results emphasized the importance of mitochondrial oxidative stress, mtDNA damage and associated alterations in mitochondrial function and dynamics in the advanced fibrosis or cirrhosis in CHB and NASH. Mitochondria might be a target in drug development to stop fibrosis progression.

Human cytomegalovirus infection activates NLRP3 inflammasome by releasing mtDNA into the cytosol in human THP‐1 cells

“…Mitochondria are the target of viral attacks, and viral infections have a varying degree of effects on mitochondria 25,26 . To examine the impact of HCMV infection on mitochondrial function, we measured ROS levels 48 h after infection and found that HCMV infection significantly induced ROS production in THP‐1 cells (Figure 1c).…”

“…Mitochondria are the target of viral attacks, and viral infections have a varying degree of effects on mitochondria. 25,26 To examine the impact of HCMV infection on mitochondrial function, we measured ROS levels 48 h after infection and found that HCMV infection significantly induced ROS production in THP-1 cells (Figure 1c). At the same time, mitochondrial membrane potential (ΔΨm), which is important for mitochondrial homeostasis, was decreased after HCMV infection (Figure 1d).…”

Hepatocellular organellar abnormalities following elimination of hepatitis C virus

“…Recent report has also shown that ROS and lipotoxic intermediates damage mitochondrial DNA, and severe mitochondrial dysfunction further increases ROS production and activates HSC proliferation and dedifferentiation. Therefore, inflammatory cytokines by immune cells may maintain mitochondrial stress and promote fibrosis progression 26 . Hepatocytes are exposed to a high‐oxygen environment due to structural changes in the microvascular system, which is an irreversible lesion of liver fibrosis 23,24 .…”

HBV, mitochondrial stress, and liver fibrosis: chicken or the egg

“…In this issue of Hepatology, [9] Loureiro and co-workers present the first comprehensive study that correlates mitochondrial oxidative stress and fibrosis progression in liver samples from a large cohort of 146 treatment-naive chronic hepatitis B (CHB) mono-infected patients, compared with patients with chronic hepatitis C (n = 33), NASH-related cirrhosis (n = 12), and healthy controls (n = 24). A comprehensive study of mtDNA damage and several parameters of mitochondrial dysfunctions was performed and patients with F3-F4 advanced fibrosis (AF) were compared with patients with no/mild (F0-F1) to moderate (F2) fibrosis in each group and between the groups.…”

“…Leakage of mtDNA and other mito-DAMPs induces both autocrine and paracrine inflammatory responses in neighboring hepatocytes, macrophages, and Kupffer cells and activates HSC to favor the progression of fibrosis. A direct measurement of circulating mtDNA [9] might be informative. The role of these different cell types and inflammatory cells infiltrating the liver should be addressed in patients with different etiologies.…”