Background Obesity and type 2 diabetes feature higher prevalence of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). In obesity-related insulin resistance, the liver may adapt its oxidative capacity, but the role of mitochondrial turnover in progressive NAFL/NASH remains uncertain.
Methods This cross-sectional study compared individuals with class III obesity (n=8/group) and with NAFL (OBE NAFL, NAFLD activity score: 2.3±0.4), NASH (OBE NASH, 5.3±0.3, p<0.05 vs. both other groups) or without fatty liver (control, OBE CON; 0.4±0.1). Hepatic mitochondrial ultrastructure was assessed by transmission electron microscopy, mitochondrial respiration by high-resolution respirometry and biomarkers of mitochondrial quality control by protein expression.
Results Mitochondrial oxidative capacity was 31% higher in OBE NAFL, but 25% lower in OBE NASH (both p<0.05 vs. OBE CON). Conversely, OBE NASH showed ~1.5fold lower mitochondrial number, but ~1.2-1.5fold higher mitochondrial diameter and area (p<0.001 vs. both other groups). Biomarkers of autophagy (p62), mitophagy (PINK1, PARKIN), fission (DRP-1, FIS1) and fusion (MFN1/2, OPA1) were reduced in OBE NASH (p<0.05 vs. OBE NAFL). Selected biomarkers (p62, p-PARKIN/PARKIN, p-DRP-1) were lower in OBE NAFL (p<0.05 vs. OBE CON). Mitochondrial diameter associated inversely with fusion and fission biomarkers and with oxidative capacity, but positively with H2O2.
Conclusion Humans with NAFL exhibit impaired mitochondrial turnover, despite upregulated oxidative capacity. In NASH, oxidative stress likely mediates the progressive decline of mitochondrial turnover along with impaired mitochondrial ultrastructure and respiration. Thus, mitochondrial quality control is key for hepatic energy metabolism and may have potential for targeting obesity-related NASH.