牛津大学Gero Miesenböck小组取得一项新突破。他们研究出睡眠压力的线粒体起源。2025年7月16日出版的《自然》杂志发表了这项成果。

为了全面、公正地了解大脑中可能导致睡眠需求的分子变化，研究组对从休息和睡眠不足的果蝇中分离出来的单细胞的转录组进行了表征。

在这里，研究组报道了睡眠剥夺后，睡眠控制神经元中投射到背侧扇形体（dFBNs）的转录本上调，但在大脑中并不普遍，几乎只编码与线粒体呼吸和ATP合成有关的蛋白质。这些基因表达变化伴随着线粒体断裂、线粒体自噬增强以及线粒体和内质网之间接触数量的增加，从而为过氧化脂质的补充创造了管道。这种形态变化在恢复性睡眠后是可逆的，并因在呼吸链中安装电子溢出物而变得迟钝。诱导或阻止dFBNs中的线粒体分裂或融合会从相反的方向改变睡眠和睡眠控制细胞的电特性：超主题线粒体增加，而碎片化线粒体减少，神经元兴奋性和睡眠。在强制清醒后，dFBNs中的ATP浓度升高，因为在芳香介导的神经元抑制过程中，这些神经元的ATP消耗减少，从而增加了它们的线粒体电子泄漏。与这一观点一致的是，ATP合成过程中不耦合的电子通量减轻了睡眠压力，同时加剧了电子供应和ATP需求之间的不匹配（通过用光驱动质子泵为ATP合成提供动力），从而导致睡眠。睡眠，就像衰老一样，可能是有氧代谢不可避免的结果。

附：英文原文

Title: Mitochondrial origins of the pressure to sleep

Author: Sarnataro, Raffaele, Velasco, Cecilia D., Monaco, Nicholas, Kempf, Anissa, Miesenbck, Gero

Issue&Volume: 2025-07-16

Abstract: To gain a comprehensive, unbiased perspective on molecular changes in the brain that may underlie the need for sleep, we have characterized the transcriptomes of single cells isolated from rested and sleep-deprived flies. Here we report that transcripts upregulated after sleep deprivation, in sleep-control neurons projecting to the dorsal fan-shaped body1,2 (dFBNs) but not ubiquitously in the brain, encode almost exclusively proteins with roles in mitochondrial respiration and ATP synthesis. These gene expression changes are accompanied by mitochondrial fragmentation, enhanced mitophagy and an increase in the number of contacts between mitochondria and the endoplasmic reticulum, creating conduits3,4 for the replenishment of peroxidized lipids5. The morphological changes are reversible after recovery sleep and blunted by the installation of an electron overflow6,7 in the respiratory chain. Inducing or preventing mitochondrial fission or fusion8,9,10,11,12,13 in dFBNs alters sleep and the electrical properties of sleep-control cells in opposite directions: hyperfused mitochondria increase, whereas fragmented mitochondria decrease, neuronal excitability and sleep. ATP concentrations in dFBNs rise after enforced waking because of diminished ATP consumption during the arousal-mediated inhibition of these neurons14, which augments their mitochondrial electron leak7. Consistent with this view, uncoupling electron flux from ATP synthesis15 relieves the pressure to sleep, while exacerbating mismatches between electron supply and ATP demand (by powering ATP synthesis with a light-driven proton pump16) precipitates sleep. Sleep, like ageing17,18, may be an inescapable consequence of aerobic metabolism.

DOI: 10.1038/s41586-025-09261-y

Source: https://www.nature.com/articles/s41586-025-09261-y