线粒体解偶联和寿命的昼夜节律调节

Circadian regulation of mitochondrial uncoupling and lifespan

Keywords：Lifespan,Drosophila,Circadian regulation, cold shock,mitochondrial,uncoupling protein (UCP) UCP4C

关键词：寿命，果蝇，昼夜调节，冷休克，解偶联蛋白

模式生物：果蝇
作者：Ulgherait Matt, Chen Anna, McAllister Sophie F, Kim Han X, Delventhal Rebecca, Wayne Charlotte R, Garcia Christian J, Recinos Yocelyn, Oliva Miles, Canman Julie C, Picard Martin, Owusu-Ansah Edward, Shirasu-Hiza Mimi
出版期刊：《Nature Communications》（2022/4/21）

Abstract：

Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, upregulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents overproliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target.

文章摘要：

由于衰老与昼夜节律缺陷有关，因此昼夜节律失常被认为是致病因素并导致死亡。与之相反，我们证明雄性果蝇中特定生物钟组件周期 (Per) 和永恒 (Tim) 的丢失反而显著延长了寿命。这种寿命延长不是由典型的饮食限制（DR）长寿途径介导的，而是由于通过增加线粒体解偶联来改变细胞呼吸。每个突变体的寿命延长取决于肠道中的线粒体解偶联。此外，在肠道干细胞和肠母细胞中，通过上调解偶联蛋白 UCP4C 就足以延长寿命并维持肠道内伴随年龄增长的增殖性稳态。与诱导防止过度增殖的代谢状态一致，线粒体解偶联药物还可以延长寿命并抑制由于衰老甚至肿瘤发生引起的肠道干细胞过度增殖。这些结果表明，昼夜节律通过调节果蝇肠道线粒体的解偶联来控制其寿命，而这也暗示着一个新的潜在抗衰老治疗靶点。

点击链接即可查看和下载文章：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174288/pdf/41467_2020_Article_15617.pdf

文章题目、关键词与摘要译文仅用于参考。