Abstract
The heavy consumption of ethanol can lead to alcohol use disorders (AUDs) which impact patients, their families, and societies. Yet the genetic and physiological factors that predispose humans to AUDs remain unclear. One hypothesis is that alterations in mitochondrial function modulate neuronal sensitivity to ethanol exposure. Using Drosophila genetics we report that inactivation of the mitochondrial outer membrane translocator protein 18kDa (TSPO), also known as the peripheral benzodiazepine receptor, affects ethanol sedation and tolerance in male flies. Knockdown of dTSPO in adult male neurons results in increased sensitivity to ethanol sedation, and this effect requires the dTSPO depletion-mediated increase in reactive oxygen species (ROS) production and inhibition of caspase activity in fly heads. Systemic loss of dTSPO in male flies blocks the development of tolerance to repeated ethanol exposures, an effect that is not seen when dTSPO is only inactivated in neurons. Female flies are naturally more sensitive to ethanol than males, and female fly heads have strikingly lower levels of dTSPO mRNA than males. Hence, mitochondrial TSPO function plays an important role in ethanol sensitivity and tolerance. Since a large array of benzodiazepine analogues have been developed that interact with the peripheral benzodiazepine receptor, the mitochondrial TSPO might provide an important new target for treating AUDs.
Highlights
Alcohol is one of the most widely used drugs worldwide, but long term consumption leads to its abuse and dependence
In previous studies we showed that the nuclear DNA coded Drosophila translocator protein 18kDa is localized in outer mitochondrial membrane (OMM) and important for regulating mitochondria bioenergetics, reactive oxygen species (ROS) production, caspase activity, and apoptotic function [20]
To determine what might be the physiological basis of the neuron-specific effects of dTSPO deficiency on male ethanol sedation, we examined the effects on ROS production, which we previously found was increased in dTSPO deficient mitochondria [20]
Summary
Alcohol is one of the most widely used drugs worldwide, but long term consumption leads to its abuse and dependence. An estimated 17.6 million adults in the United States have AUDs with associated health concerns of alcohol dependence, liver cirrhosis, cancer, and injuries. Neuronal function is highly dependent on mitochondrial bioenergetics [6,7]. In addition to the direct metabolizing of ethanol, the mitochondria are central to a wide range of essential neuronal cell functions including ATP synthesis, ROS production and REDOX homeostasis, Ca2+ buffering, and the metabolic regulation of apoptosis [8,9,10]. In humans mitochondrial DNA (mtDNA) alterations have been correlated with alcoholism, involving both acute ethanol responses and chronic damage [11,12,13,14,15,16]. Variation in the mtDNA genes have been shown to have profound effects of nuclear gene expression [19]
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