The morphological structure and metabolic activity of mitochondria are coordinately regulated by circadian mechanisms. However, the mechanistic interplay between circadian mechanisms and mitochondrial architecture remains poorly understood. Here, we demonstrate circadian rhythmicity of Rheb protein in liver, in line with that of Per2. Using genetic mouse models, we show that Rheb, a small GTPase that binds mTOR, is critical for circadian oscillation of mTORC1 activity in liver. Disruption of Rheb oscillation in hepatocytes by persistent expression of Rheb transgene interrupted mTORC1 oscillation. We further show that Rheb-regulated mTORC1 altered mitochondrial fission factor DRP1 in liver, leading to altered mitochondrial dynamics. Our results suggest that Rheb/mTORC1 regulated DRP1 oscillation involves ubiquitin-mediated proteolysis. This study identifies Rheb as a nodal point that couples circadian clock and mitochondrial architecture for optimal mitochondrial metabolism.

中文翻译：

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昼夜节律性 Rheb 振荡改变肝脏 mTORC1 活性和线粒体形态的动力学

线粒体的形态结构和代谢活动受昼夜节律机制的协调调节。然而，昼夜节律机制和线粒体结构之间的相互作用机制仍然知之甚少。在这里，我们证明了肝脏中 Rheb 蛋白的昼夜节律性，与 Per2 一致。使用遗传小鼠模型，我们表明 Rheb（一种结合 mTOR 的小 GTPase）对于肝脏中 mTORC1 活性的昼夜节律振荡至关重要。通过持续表达 Rheb 转基因破坏肝细胞中的 Rheb 振荡，从而中断了 mTORC1 振荡。我们进一步表明，Rheb 调节的 mTORC1 改变了肝脏中的线粒体裂变因子 DRP1，导致线粒体动力学改变。我们的结果表明，Rheb/mTORC1 调节的 DRP1 振荡涉及泛素介导的蛋白水解。