A potassium channel β-subunit couples mitochondrial electron transport to sleep.

The essential but enigmatic functions of sleep^1,2 must be reflected in molecular changes sensed by the brain's sleep-control systems. In the fruitfly Drosophila, about two dozen sleep-inducing neurons³ with projections to the dorsal fan-shaped body (dFB) adjust their electrical output to sleep need⁴, via the antagonistic regulation of two potassium conductances: the leak channel Sandman imposes silence during waking, whereas increased A-type currents through Shaker support tonic firing during sleep⁵. Here we show that oxidative byproducts of mitochondrial electron transport^6,7 regulate the activity of dFB neurons through a nicotinamide adenine dinucleotide phosphate (NADPH) cofactor bound to the oxidoreductase domain^8,9 of Shaker's K_Vβ subunit, Hyperkinetic^10,11. Sleep loss elevates mitochondrial reactive oxygen species in dFB neurons, which register this rise by converting Hyperkinetic to the NADP⁺-bound form. The oxidation of the cofactor slows the inactivation of the A-type current and boosts the frequency of action potentials, thereby promoting sleep. Energy metabolism, oxidative stress, and sleep-three processes implicated independently in lifespan, ageing, and degenerative disease^6,12-14-are thus mechanistically connected. K_Vβ substrates^8,15,16 or inhibitors that alter the ratio of bound NADPH to NADP⁺ (and hence the record of sleep debt or waking time) represent prototypes of potential sleep-regulatory drugs.

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