Phylogenetic conservation of the interdependent homeostatic relationship of sleep regulation and redox metabolism

Abstract

Sleep is an essential and evolutionarily conserved process that affects many biological functions that are also strongly regulated by cellular metabolism. The interdependence between sleep homeostasis and redox metabolism, in particular, is such that sleep deprivation causes redox metabolic imbalances in the form of over-production of ROS. Likewise (and vice versa), accumulation of ROS leads to greater sleep pressure. Thus, it is theorized that one of the functions of sleep is to act as the brain's "antioxidant" at night by clearing oxidation built up from daily stress of the active day phase. In this review, we will highlight evidence linking sleep homeostasis and regulation to redox metabolism by discussing (1) the bipartite role that sleep-wake neuropeptides and hormones have in redox metabolism through comparing cross-species cellular and molecular mechanisms, (2) the evolutionarily metabolic changes that accompanied the development of sleep loss in cavefish, and finally, (3) some of the challenges of uncovering the cellular mechanism underpinning how ROS accumulation builds sleep pressure and cellularly, how this pressure is cleared.

Keywords: Cavefish; Homeostasis; Metabolism; Redox; Sleep; Zebrafish.

Fig. 1

Summary of major intracellular ROS sources and antioxidant systems. The major intracellular ROS sources (upper panel) include: NADPH oxidases, peroxisomes, oxidative phosphorylation in mitochondria, xanthine oxidases, and the endoplasmic reticulum stress response towards unfolded proteins (UPR). The major antioxidant systems (lower panel) include enzymatic (grey): catalase, superoxide dismutase (SOD), glutathione peroxidases; and nonenzymatic (orange): glutathione (GSH), vitamin C, and vitamin E

Fig. 2

Schematics of redox-related changes during sleep–wake cycle. ROS accumulates from high cellular activity and increased NADH during the wake period (top left), creating sleep pressure (top right) in the form of membrane lipid peroxidation, redox imbalances and DNA damage. The effects of the wake period are ameliorated during the sleep period (bottom left), where DNA damaged during the day period is repaired and membrane lipids and redox systems are replenished and returned to homeostatic levels. Inadequate sleep and sleep deprivation (bottom right) worsen the redox imbalance with lower antioxidant systems (GSH, SOD, catalase) that cannot prevent further ROS accumulation