Non-alcoholic steatohepatitis is associated with liver mitochondrial DNA damage and genome instability of cytochrome b, a component of the cellular respirasome supercomplex

FLICHMAN DIEGO; CARLOS J PIROLA; CASTAÑO GUSTAVO; GARAYCOECHEA MARTIN; SOOKOIAN SILVIA

LONDRES

Congreso; The International Liver Congress of the European Association for the Study of Liver; 2020

European Association for the Study of Liver

Background and Aims: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms is paralleled by the occurrence of complex molecular processes. Damaged liver mitochondria and mitochondrial respiratory chain dysfunction are hallmark features of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB) ?a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). Method: We included 252 liver specimens of NAFLD patients?from mild to severe histological disease, which were linked to clinical and biochemical information. We sequenced the MT-CYB gene and we used a semi-long run real-time PCR method to detect damaged mtDNA. HPLC?mass spectrometry was used to explore circulating level of Krebs cycle metabolites in a sub-sample of patients. Results: Compared to simple steatosis, the liver of patients with nonalcoholic steatohepatitis (NASH) exhibits a high level of MT-CYB sequence variation, from 12.1 to 15.6 substitutions per 103 bp, respectively (p = 5.5e − 10). The burden of liver MT-CYB variants was associated with changes in the level of metabolites, including alpha-ketoglutarate, branched-chain amino acids, glutamate, and hydroxyglutaric acid (Figure). Liver mtDNA damage at the cytochrome b region occurred more often in patients with advanced disease (p = 1e − 3) and high scores of lobular inflammation (p = 6.5e − 3). Nevertheless, the increase of damage level was a distinctive feature of patients with severe obesity (p = 7.9e − 5).Conclusion: NASH is associated with liver mtDNA damage, in particular, genetic alterations of cytochrome b, an important component of the cellular respirasome.