Abstract
Background and Aims: Hepatitis B virus (HBV) infection causes oxidative stress (OS) and alters mitochondria in experimental models. Our goal was to investigate whether HBV might alter liver mitochondria also in humans, and the resulting mitochondrial stress might account for the progression of fibro-sis in chronic hepatitis B (CHB).
Approach and Results: The study included 146 treatment-naïve CHB mono-infected patients. Patients with CHB and advanced fibrosis (AF) 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 mitochondrial DNA (mtDNA), including mtDNA strand beaks, and identified multiple mtDNA dele-tions 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 AF 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 hepatitis B virus X protein. mtDNA damage and complex I impairment were prevented with the superoxide-scavenging Mito-Tempo or with inducible nitric oxide synthase (iNOS)–specific inhibitor 1400 W.
Conclusions: Our results emphasized the importance of mitochondrial OS, mtDNA damage, and associated alterations in mitochondrial function and dynamics in AF or cirrhosis in CHB and NASH. Mitochondria might be a target in drug development to stop fibrosis progression.
Proposed mechanisms:
The authors proposed that mtDNA damage resulted in the disturbance of mitochondrial homeostasis, function, and dynamics in patients with CHB and patients with NASH. Suppressed mtUPR in combination with altered mitophagy leads to an overall significant mtDNA damage accumulation that subsequently increases mitophagic burden, leading to mDAMP release, and subsequent expression of inflammatory and profibrogenic mediators . All these mitochondrial alterations likely play important roles in triggering/exacerbating inflammatory and profibrotic responses that promote the development and progression of fibrosis. The observation that HBV- and HBx- induced mtDNA damage and mitochondrial dysfunction is preventable in vitro raises the hope that the dire prognosis of advanced fibrosis or cirrhosis could be therapeutically improved or slowed in vivo. Further investigations of the modulation of these potential mitochondrial biomarkers in large cohorts of patients with other liver diseases are urgently needed to confirm the feasibility of these markers for therapeutic and diagnosis purposes.
