Recently, a study has been published by the group of John Lemasters, showing that high acute doses of ethanol in mice cause a widespread but reversible depolarization of mitochondria (Zhong et al. 2014). In their study, Zhong and colleagues used a two-photon imaging with vital dyes to visualize mitochondrial potential. This technique allows generating videos of the living organ with a spatial resolution of approximately 200 nm. Living mice received injections of Rhodamine 123, a cationic fluorophore that is taken up by polarized mitochondria and by its green fluorescence indicates mitochondrial activity (Zhong et al. 2014). Loss of green fluorescence signal indicates mitochondrial depolarization. The authors administered 6 g/kg ethanol, a very high dose, corresponding to extreme ‘binge drinking.’ As a consequence, a transient mitochondrial depolarization of almost all hepatocytes was observed. More than 24 h were required until mitochondria returned to the control situation (Zhong et al. 2014). Mitochondrial depolarization depends on ethanol metabolism, since deficiency of CYP2E1 as well as alcohol dehydrogenase antagonized the effect (Zhong et al. 2014).

The paper of Zhong and colleagues describes a novel and amazing phenomenon. It may seem surprising that depolarization occurs as an all-or-nothing phenomenon. This suggests that ethanol acts by a so far unknown threshold mechanism. It is of interest to learn whether transient mitochondrial depolarization and consequently compromised energy metabolism disturb further hepatocellular functions, such as drug metabolism. In the past decade, numerous projects focused on organotypical in vitro systems with human and rodent hepatocytes (Hewitt et al. 2007; Schug et al. 2013; Reif 2014a, b; Reif et al. 2015; Godoy et al. 2013, 2015). In case it is possible to mimic this transient depolarization in vitro, one can use human hepatocytes to determine whether similar mechanisms are active also in human. Recently, mitochondrial dysregulation has been described as a key mechanism of numerous chemicals (Bonifacio et al. 2014; Yang et al. 2014; McGill et al. 2014; Monteiro et al. 2013), oxidative stress-induced adverse effects (Toledo et al. 2014; Sinha et al. 2013) but also in adaptive responses (Nair et al. 2014; Lu et al. 2013). Moreover, mitochondria represent one of the most frequent targets in drug-induced liver injury (Lancaster et al. 2015; Schyschka et al. 2013). In future, it will be interesting to learn how ethanol-induced mitochondrial depolarization influences liver physiology and susceptibility of the hepatocytes to chemicals.