Cited by 62Sleep and Wakefulness ResearchNeurobiology and Insect Physiology ResearchCircadian rhythm and melatonin

Mitochondrial origins of the pressure to sleep

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Sarnataro, Raffaele, Velasco, Cecilia D., Monaco, Nicholas, Kempf, Anissa, Miesenböck, Gero·2025·Nature

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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 body 1,2 (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 conduits 3,4 for the replenishment of peroxidized lipids 5 . The morphological changes are reversible after recovery sleep and blunted by the installation of an electron overflow 6,7 in the respiratory chain. Inducing or preventing mitochondrial fission or fusion 8–13 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 neurons 14 , which augments their mitochondrial electron leak 7 . Consistent with this view, uncoupling electron flux from ATP synthesis 15 relieves the pressure to sleep, while exacerbating mismatches between electron supply and ATP demand (by powering ATP synthesis with a light-driven proton pump 16 ) precipitates sleep. Sleep, like ageing 17,18 , may be an inescapable consequence of aerobic metabolism.

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  • Reactive oxygen species impair mitochondrial ATP synthesis, and their suppression is essential for sustaining neuronal activity.

    “Such protection is crucial, as ROS impair mitochondrial ATP synthesis and their suppression is essential for sustaining neuronal activity67,68.”

    From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [68]

    In “Sleep alters mitochondrial dynamics” (page not provided), the paper says ROS generation triggers mitochondrial fission and that reducing electron diversion into ROS preserves mitochondrial morphology in Drosophila sleep-promoting neurons. It does not establish that ROS impair mitochondrial ATP synthesis or that suppressing ROS is essential to sustain neuronal activity. (LLM, conf=0.83)

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Research works printed but not linked: 2

  1. [29]von Economo, C. in Handbuch der normalen und pathologischen Physiologie Vol. 17 (eds Adler, L. et al.) 591–610 (Springer, 1926).
  2. [114]Agresti, A. Categorical Data Analysis (Wiley, 2013).

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Authors
Sarnataro, R., Velasco, C. D., Monaco, N., Kempf, A., & Miesenböck, G.
Affiliations
  • University of Oxford (GB)
  • University of Basel (CH)
Corresponding author
Miesenböck, Gero
Venue
Nature
Published
2025-07-16
Volume
645
Issue
8081
Pages
722-728
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W4412479105
Cited by
62
References
113
Citations by year
2026: 38 · 2025: 21 · 2024: 3
FWCI
33.47
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
Wellcome Trust (107457/Z/15/Z, 203141/A/16/Z, 091911/B/10/Z)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Keywords
sleep pressure, sleep deprivation, mitochondrial respiration, ATP production, mitochondrial fragmentation, mitophagy, electron transport chain, ATP consumption, neuronal excitability, lipid hydroperoxides, electron leak, uncoupling, mitochondrial fusion, mitochondrial fission, Drosophila
MeSH terms
Adenosine Triphosphate, Animals, Brain, Drosophila melanogaster, Endoplasmic Reticulum, Female, Male, Mitochondria, Neurons, Sleep, Sleep Deprivation, Wakefulness, Single-Cell Analysis, Transcriptome, Mitochondrial Dynamics, Mitophagy

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