Mitochondrial oxidative function in NAFLD: friend or foe?

Abstract Background Mitochondrial oxidative function plays a key role in the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance (IR). Recent studies support that fatty liver might not be a result of decreased mitochondrial fat oxidation caused by mitochondrial damage. Rather, NAFLD and IR cause an elevation in mitochondrial function, which covers the increased demand for carbon intermediates and ATP caused by elevated lipogenesis and gluconeogenesis. Furthermore, mitochondria play a role regulating hepatic insulin sensitivity and lipogenesis by modulating redox-sensitive signaling pathways. Scope of review We review the contradictory studies indicating that NAFLD and hyperglycemia can either increase or decrease mitochondrial oxidative capacity in liver. We summarize mechanisms regulating mitochondrial heterogeneity inside the same cell and discuss how these mechanisms may determine the role of mitochondria in NAFLD. We further discuss the role of endogenous antioxidants in the control of mitochondrial H2O2 release and redox-mediated signaling. Finally, we describe the emerging concept that the subcellular location of cellular antioxidants is a key determinant of their effects on NAFLD. Major Conclusions. The balance of fat oxidation versus accumulation is dependent on mitochondrial fuel preference, rather than ATP-synthesizing respiration. As such, therapies targeting fuel preference might be more suitable to treat NAFLD. Similarly, suppressing maladaptive antioxidants, rather than interfering with physiological mitochondrial H2O2-mediated signaling, may allow for the maintenance of intact hepatic insulin signaling in NAFLD. Exploration of sub-cellular compartmentalization of different antioxidant systems and the unique functions of specific mitochondrial sub-populations may offer new points of intervention to treat NAFLD.