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KIN-29 SIK regulates stress-induced sleep through mitochondrial redox signaling

McIntire, P.; Farrell, L. N.; Haroon, S.; Raizen, D.; van der Linden, A. M.

2026-07-29 neuroscience
10.64898/2026.07.27.740804 bioRxiv
Show abstract

The C. elegans SIK3 homolog KIN-29 regulates the interaction between sleep and metabolism, but mechanisms underlying this regulation are not understood. Here, we show that KIN-29 regulates sleep that is induced by cellular stress (stress-induced sleep or SIS) through mitochondrial reactive oxygen species (ROS) signaling. Following sleep-promoting ultraviolet-C (UVC) irradiation, mitochondrial ROS rises in concert with sleep in wild-type but not in sleepless kin-29 mutants. kin-29 mutants have reduced mitochondrial ROS, reduced oxygen consumption rates, and are resistant to oxidative stress. Transcriptomic and proteomic profiling of kin-29 mutants reveal enrichment for genes involved in ROS mitigation such as the mitochondrial superoxide dismutase SOD-3. Consistent with the notion that ROS promotes sleep, genetic disruption of mitochondrial SODs enhances UVC-induced SIS. Increasing mitochondrial ROS using the optogenetic tool SuperNova partially restores SIS in kin-29 mutants but not in mutants with defective function of the sleep-inducing ALA neuron; this suggests that mitochondrial ROS act downstream of kin-29 but upstream of ALA. The identification of mitochondrial ROS as a nematode sleep regulator supports a phylogenetically conserved mechanism by which metabolic stress and SIKs promote sleep.

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