TSPO, a Mitochondrial Outer Membrane Protein, Controls Ethanol-Related Behaviors in Drosophila
TSPO, a Mitochondrial Outer Membrane Protein, Controls Ethanol-Related Behaviors in Drosophila
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DOI：
10.1371/journal.pgen.1005366
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发表时间：
2015-08-01
期刊：
影响因子：
4.5
通讯作者：
Wallace, Douglas C.
中科院分区：
文献类型：
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作者：
Lin, Ran;Rittenhouse, Danielle;Wallace, Douglas C.
酒精的大量消耗会导致酒精使用障碍（AUDs），影响患者，他们的家庭和社会。然而，使人类易患AUDs的遗传和生理因素仍不清楚。一种假设是线粒体功能的改变调节神经元对乙醇暴露的敏感性。使用果蝇遗传学，我们报告说，线粒体外膜转运蛋白18kDa（TSPO），也被称为外周苯二氮卓受体的失活，影响乙醇镇静和耐受性的雄性苍蝇。成年雄性神经元中dTSPO的敲低导致对乙醇镇静的敏感性增加，并且这种效应需要dTSPO消耗介导的活性氧（ROS）产生的增加和蝇头中半胱天冬酶活性的抑制。雄性果蝇中dTSPO的系统性丢失阻断了对重复乙醇暴露的耐受性的发展，当dTSPO仅在神经元中失活时未观察到这种效应。雌性果蝇对乙醇的敏感性高于雄性果蝇，雌性果蝇头部的dTSPO mRNA水平明显低于雄性果蝇。因此，线粒体TSPO功能在乙醇敏感性和耐受性中起重要作用。由于已经开发了大量与外周苯二氮卓类受体相互作用的苯二氮卓类类似物，线粒体TSPO可能为治疗AUDs提供重要的新靶点。
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.