Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our findings provide new insights into the crosstalk between mitochondrial function (here, neurosteroidogenesis) and circadian cycles.

中文翻译：

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时钟控制的线粒体动力学与环状孕烯醇酮合成相关。

神经类固醇是在神经系统中合成的类固醇，类固醇生成的第一步是在线粒体内发生孕烯醇酮的合成。它们通过在神经传递，学习和记忆过程以及神经保护中发挥作用来发挥重要的大脑特定功能。在这里，我们首次显示线粒体神经甾体生成遵循昼夜节律，并与线粒体形态的节奏变化相关。我们使用同步化的人类A172胶质瘤细胞（这是具有功能性核心分子时钟的类固醇生成细胞）来显示孕烯醇酮的水平和易位蛋白（TSPO）受时钟控制，可能是通过昼夜节律对线粒体融合/裂变进行调控。在小鼠大脑中概括了主要发现。我们还表明，融合/裂变活性的遗传或药理学废除，以及干扰核心分子钟，都消除了孕烯醇酮和TSPO的昼夜节律。我们的发现为线粒体功能（此处为神经甾体生成）与昼夜节律周期之间的串扰提供了新的见解。