Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness.
Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness.
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DOI：
10.1016/j.cmet.2015.08.006
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发表时间：
2015-10-06
期刊：
影响因子：
29
通讯作者：
Lee CH
中科院分区：
文献类型：
--
作者：
Jacobi D;Liu S;Burkewitz K;Kory N;Knudsen NH;Alexander RK;Unluturk U;Li X;Kong X;Hyde AL;Gangl MR;Mair WB;Lee CH
线粒体经历响应于代谢输入的结构/功能变化。这一过程在生理进食/禁食状态下是如何调节的尚不清楚。在这里，我们表明，线粒体动力学（特别是裂变和线粒体自噬）和生物合成的昼夜节律调节Bmal 1在小鼠肝脏中的转录目标，并表现出与昼夜生物能量需求同步的代谢节律。Bmal 1功能丧失导致肿胀的线粒体不能适应不同的营养条件，伴随着呼吸减少和氧化应激升高。因此，肝脏特异性Bmal 1敲除（LBmal 1 KO）小鼠积累氧化损伤并发展为肝脏胰岛素抵抗。在高脂喂养的小鼠中，肝脏Bmal 1活性的恢复改善了代谢结果，而促进质量控制的裂变蛋白Fis 1的表达挽救了LBmal 1 KO线粒体的形态/代谢缺陷。有趣的是，Bmal 1同源物AHA-1在C.尽管缺乏昼夜节律调节，但秀丽线虫保留了调节氧化代谢和寿命的能力。这些结果表明，时钟基因是进化保守的能量调节器。
Mitochondria undergo architectural/functional changes in response to metabolic inputs. How this process is regulated in physiological feeding/fasting states remains unclear. Here we show that mitochondrial dynamics (notably fission and mitophagy) and biogenesis are transcriptional targets of the circadian regulator Bmal1 in mouse liver and exhibit a metabolic rhythm in sync with diurnal bioenergetic demands. Bmal1 loss-of-function causes swollen mitochondria incapable of adapting to different nutrient conditions accompanied by diminished respiration and elevated oxidative stress. Consequently, liver-specific Bmal1 knockout (LBmal1KO) mice accumulate oxidative damage and develop hepatic insulin resistance. Restoration of hepatic Bmal1 activities in high fat fed mice improves metabolic outcomes, whereas expression of Fis1, a fission protein that promotes quality control rescues morphological/metabolic defects of LBmal1KO mitochondria. Interestingly, Bmal1 homologue AHA-1 in C. elegans retains the ability to modulate oxidative metabolism and lifespan despite lacking circadian regulation. These results suggest clock genes are evolutionarily conserved energetics regulators.