13 How this is related to the autophagic stress that we describe herein is not fully known, but we can speculate that both phenomena are associated. Importantly, pharmacological inhibition of autophagy enhances the proapoptotic action of EFV. A complex relationship between autophagy and apoptosis has been suggested for several xenobiotics that induced both processes (imiquimod in basal cell carcinoma31 or oridonin in HeLa cells32) and, of note, in both cases the inhibition of autophagy promoted apoptosis which is in keeping with our results. Our understanding

of the role of autophagy in liver pathophysiology, especially regarding drug-induced hepatotoxicity, is limited.33, 34 However, sequestration of several subcellular compartments has been documented in hepatocytes under check details different conditions. Autophagy may play a role in three important aspects of hepatic physiopathology: organelle turnover, balance of nutrients and energy, and removal of misfolded/damaged proteins,33 and has been recently implicated in conditions such as liver ischemia-reperfusion injury, alcohol-related liver damage, hepatitis B/C infection, hepatocellular carcinoma, and nonalcoholic

liver disease.33, 34 Interestingly, hepatocytes were an early model for mitophagy following MPT and loss of ΔΨm. Recent data suggest that autophagy facilitates cell survival in various conditions of liver injury, including drug toxicity34; mitophagy was found to reduce hepatotoxicity and steatosis associated with

buy BMS-354825 acute ethanol exposure,35 confer resistance to injury from menadione-induced oxidative stress,36 and promote survival of HepG2 cells against ginsenoside Rk1-induced apoptosis.37 Failure of this adaptive mechanism may lead to autophagic cell death. Our results add weight to this hypothesis, because Ponatinib ic50 the mitochondrial degradation detected in our model occurs as a rescue mechanism that promotes hepatic cell survival, as shown by the fact that its pharmacological inhibition leads to increased EFV-induced cell damage. Nevertheless, when a massive autophagic response is induced the degradation capacity of the cell is exceeded, and “autophagic stress” is produced. Finally, there is growing evidence of a complex role of autophagy in viral infections including HIV38 and HBV/HCV,34 which is of special relevance in the light of our results. Hepatitis coinfections are very common among HIV patients and greatly enhance the hepatic toxicity of EFV.1, 2 In addition, there is evidence of autophagy induced by several protease inhibitors.39, 40, 41 Moreover, HIV patients usually receive concurrent medications that may be potentially hepatotoxic.1 All of this provides a picture of autophagic signaling/induction in which complex interactions take place between EFV and concomitant conditions which may ultimately influence liver function.