**4. Future perspectives**

**Figure 1** summarizes the mitochondrial alterations described after the different patterns of ethanol consumption (**Figure 1**). Acute ethanol exposure triggers mitochondrial toxicity, increasing ROS production and decreasing antioxidant defenses [38]. In turn, this leads to reduced ATP production [41] and finally to the opening of mPTP [26]. All these events could eventually lead to apoptotic neuronal death [32, 39] (**Figure 1.1**). After ethanol consumption, a hangover condition can be produced [58]. In this state, the mitochondrial alterations described in acute ethanol conditions are also accompanied by a period of reduced activity of the electron respiratory chain complexes [69] and a loss of mitochondrial membrane potential

When ethanol consumption implicates the ingestion of a high amount of ethanol on repeated occasions and cannot be controlled, this is considered a pattern of chronic ethanol consumption [81–83]. This condition is pathological, and therefore the mitochondrial alterations are also more complex. In addition to redox imbalance [23, 94], deficiency in ATP generation and a loss of mitochondrial membrane potential can be detected by a reduction in the expression of respiratory complexes and increased levels of mitochondrial calcium [23, 94, 95]. Altogether, these events lead to severe loss of mitochondrial function (**Figure 1.3**). Chronic ethanol consumption implicates the development of addictive behaviors; therefore, in the absence of ethanol, those affected present ethanol withdrawal symptoms [87, 101]. In this state, the mitochondrial effects already described in chronic consumption are

**Figure 2.** Ethanol binge-drinking affects mitochondrial structure and function. Binge-like ethanol consumption during the adolescence induces changes in the structure and function of the mitochondria that persist on time until adulthood. One week after binge ethanol pretreatment (BEP), rat hippocampus has increased expression of fission proteins and protein oxidation, accompanied by reduced expression of Cyp-D. Three weeks after BEP, addition is possibly observed decreased ATP production and reduced expression of VDAC. Finally, at adulthood (7 weeks post BEP), the levels of both fission and fusion proteins suggest decreased mitochondrial dynamics, and the deficiency in ATP production is

more severe.

372 Mitochondrial Diseases

[69] that suggests a major state of mitochondrial dysfunction (**Figure 1.2**).

We propose that the mitochondrion is the main mediator of ethanol neurotoxicity where mitochondrial alterations reveal the severity of ethanol toxicity. The initial effect of ethanol exposure implicates an imbalance in the cellular redox state, followed by changes in the respiratory complexes from the electron transport chain that leads to the reduction in ATP production and the opening of mPTP. Persistent ethanol consumption also induced the loss of mitochondrial membrane potential and increased Ca+2 entries into the mitochondria that provoke the prolonged opening of mPTP and finally promote neurodegeneration. Interestingly, these mitochondrial alterations ethanol-associated may could occur mainly in glial cells, inducing inflammation and interfering with the glial-neuronal communication in specific brain areas [119]. The hippotalamus, important to ethanol dependence, and the hippocampus, associated to learning and memory, are particularly vulnerable; possibly due to the downregulation of melanocortin system induced by ethanol [119]. Therefore, the description of all these events highlights the importance of maintaining the function of the mitochondria to prevent the harmful effects of ethanol consumption and propose a new potential treatment for the pathological condition related to ethanol use and abuse.
