Neurobiology of mitochondrial dynamics in sleep

The cycling of sleep and wakefulness reshapes neuronal activity, gene expression, and cellular metabolism of the brain. Such reshuffling of brain metabolism implicates key mediation by mitochondria. Mitochondrial dynamics enable organelles to adapt their morphofunction to changing metabolic demands, and experimental evidence increasingly links these processes to sleep-wake regulation. Across species, sleep loss perturbs mitochondrial gene expression, increases oxidative stress, and disrupts organelle structure, particularly in energy-demanding brain regions. In Drosophila, sleep-control neurons projecting to the dorsal fan-shaped body (dFBNs) exhibit a homeostatic feedback mechanism coupling mitochondrial activity to behavioural state. As sleep pressure elevates, dopaminergic inhibition reduces dFBN excitability and ATP consumption, triggering mitochondrial fission and accumulation of reactive oxygen species (ROS) that biochemically prime the neurons for subsequent sleep induction. Upon relief of inhibition during recovery sleep, dFBNs elevate their activity, consume ATP, and undergo mitochondrial fusion to restore energy balance. Artificial modulation of mitochondrial morphology and ATP production in these neurons bidirectionally alters sleep. dFBNs' elevated OxPhos expression and mitochondrial turnover render them sensitive to metabolic shifts and capable of encoding internal states. While dFBNs remain the only known neurons where mitochondrial dynamics are coupled to sleep behaviour, other populations, like mammalian cortical neurons or fly Kenyon cells, also display mitochondrial changes after sleep loss. Sleep, like other state-dependent behaviours including hunger and memory, imposes shifting energetic demands on specific neuronal populations. Mitochondrial dynamics may thus provide a conserved, cell-autonomous mechanism for tuning neural excitability and sleep pressure, enabling brain-wide coordination of metabolic and behavioural homeostasis.