Moreover, preliminary reports have hinted that some NRTIs also have

the ability to directly inhibit mitochondria,28 thereby implying that specific combinations of the drugs used in highly CAL-101 cost active antiretroviral therapy have a particularly profound impact on mitochondrial function. In our study, clinically relevant concentrations of ABC, but not of 3TC, significantly inhibited respiration and ATP levels without interfering with the production of ROS. Their combined use with EFV did not result in further synergistic reduction of respiration or ATP levels but did potentiate the effects of EFV on ROS production. The interpretation and clinical implications of these initial results, including the mitochondrial targets involved, is a complex issue that demands further evaluation. Cells maintain ATP levels within narrow limits, and the AMPK cascade is emerging as one important sensor of energy status. Its activation switches off ATP-consuming processes whereas

switching on catabolic pathways that facilitate the generation of ATP, including processes related to lipid and glucose metabolism.29 The fact that EFV produces rapid increases in the expression of P-AMPK in human cells and tissue can be interpreted as a response to mitochondrial dysfunction and reduction of ATP. Furthermore, there is previous evidence that EFV modifies http://www.selleckchem.com/products/iwr-1-endo.html selleck products the metabolism of glucose and lipogenic pathways in a way that is compatible with the activation of AMPK.30 The ability to switch on glycolysis is an important factor in the capacity of cells to survive the metabolic stress caused by intense mitochondrial malfunction.25 However, in the current study, the analysis of glucose uptake and expression of the glucose transporter GLUT-1 suggest that there was no such increase in anaerobic glycolysis after 4 hours’ incubation with EFV. This is somewhat paradoxical but could

be a consequence of the highly glycolytic nature of Hep3B, which leaves little room for an improvement in this pathway.31 Mitochondria also use fatty acids as fuel to generate ATP. Indeed, an AMPK-mediated increase in fatty acid uptake and beta-oxidation has been described after energy deprivation, whereas activation of AMPK has been related to a decrease in hepatic steatosis.32 Nevertheless, given the oxidative capacity of the mitochondria inhibited by EFV, it is possible that lipids entering the cell accumulate over time within the cytoplasm. This is supported by our finding that 24-hour exposure to EFV produced an increase in the levels of neutral lipids, which are present in lipid droplets.