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.