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首页> 外文期刊>Cell metabolism >Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness
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Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness

机译：肝Bmal1调节节律性线粒体动力学并促进代谢适应性。

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摘要

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 homolog 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.
机译：线粒体响应代谢输入而发生结构/功能变化。尚不清楚如何在生理喂养/禁食状态下调节该过程。在这里，我们显示线粒体动力学（尤其是裂变和线粒体吞噬）和生物发生是昼夜节律调节器Bmal1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。 Bmal1功能丧失导致线粒体肿胀，无法适应不同的营养条件，并伴有呼吸减少和氧化应激增加。因此，肝脏特异性Bmal1基因敲除（LBmal1KO）小鼠积累氧化损伤并发展为肝胰岛素抵抗。恢复高脂饮食小鼠的肝Bmal1活性可改善代谢结果，而Fis1（一种促进质量控制的裂变蛋白）的表达可挽救LBmal1KO线粒体的形态/代谢缺陷。有趣的是，尽管缺乏昼夜节律，线虫中的Bmal1同系物AHA-1仍具有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上保守的能量调节剂。

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