Mitochondria Need Their Sleep: Redox, Bioenergetics, and Temperature Regulation of Circadian Rhythms and the Role of Cysteine-Mediated Redox Signaling, Uncoupling Proteins, and Substrate Cycles

HIGHLIGHTS: What are the main findings? Hypothesis: Redox, bioenergetic and temperature regulation is critical in maintaining cellular circadian rhythms; wakefulness is mainly “nucleorestorative” and sleep is mainly “mitorestorative”. Wakefulness: High metabolic rate induces oxidative stress and redox imbalance. Sleep: Fusion remodels mitochondria and the cellular redox balance is restored. Sleep: Mitochondria aid activation of rapid immune, inflammatory and heat shock responses. What is the implication of the main findings? Sleep-wake cycling: Provides insights into the role of cysteine-mediated redox signaling, uncoupling and substrate cycles. Disorders of human development and aging: Perturbations of circadian tripartite-interactome signaling and mitochondrial-nuclear coregulation are implicated. ABSTRACT: Although circadian biorhythms of mitochondria and cells are highly conserved and crucial for the well-being of complex animals, there is a paucity of studies on the reciprocal interactions between oxidative stress, redox modifications, metabolism, thermoregulation, and other major oscillatory physiological processes. To address this limitation, we hypothesize that circadian/ultradian interaction of the redoxome, bioenergetics, and temperature signaling strongly determine the differential activities of the sleep–wake cycling of mammalians and birds. Posttranslational modifications of proteins by reversible cysteine oxoforms, S-glutathionylation and S-nitrosylation are shown to play a major role in regulating mitochondrial reactive oxygen species production, protein activity, respiration, and metabolomics. Nuclear DNA repair and cellular protein synthesis are maximized during the wake phase, whereas the redoxome is restored and mitochondrial remodeling is maximized during sleep. Hence, our analysis reveals that wakefulness is more protective and restorative to the nucleus (nucleorestorative), whereas sleep is more protective and restorative to mitochondria (mitorestorative). The “redox–bioenergetics–temperature and differential mitochondrial–nuclear regulatory hypothesis” adds to the understanding of mitochondrial respiratory uncoupling, substrate cycling control and hibernation. Similarly, this hypothesis explains how the oscillatory redox–bioenergetics–temperature–regulated sleep–wake states, when perturbed by mitochondrial interactome disturbances, influence the pathogenesis of aging, cancer, spaceflight health effects, sudden infant death syndrome, and diseases of the metabolism and nervous system.