Neurobiology Lab for Brain Aging and Mental Health, Molecular & Cognitive Neuroscience, Transfaculty Research Platform, University of Basel, 4002 Basel, Switzerland.
Psychiatric University Clinics Basel, Medical Faculty, University of Basel, 4002 Basel, Switzerland.
Cells. 2020 Oct 19;9(10):2323. doi: 10.3390/cells9102323.
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.
神经甾体是在神经系统中合成的甾体，类固醇生成的第一步发生在线粒体中，伴随着 pregnenolone 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，具有重要的大脑特异性功能。在这里，我们首次表明线粒体神经甾体生成遵循昼夜节律，并且与线粒体形态的节律性变化相关。我们使用同步化的人 A172 神经胶质瘤细胞，这是一种具有功能性核心分子钟的甾体生成细胞，表明 pregnenolone 水平和转位蛋白 (TSPO) 受到时钟的控制，可能是通过线粒体融合/裂变的昼夜节律调节。在小鼠大脑中重现了关键发现。我们还表明，融合/裂变活性的遗传或药理学阻断以及扰乱核心分子钟，会消除 pregnenolone 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）和昼夜节律之间的串扰提供了新的见解。
