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

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.

Insomnia in Forensic Detainees: Is Salience Network the Common Pathway for Sleep, Neuropsychiatric, and Neurodegenerative Disorders?

“…AhR is the master regulator of cellular senescence, a phenotype conducive to aging and neurodegeneration and is expressed by the mitochondrion [ 19 , 20 , 21 ]. Oxidized lipids in the mitochondrial membrane are AhR ligands, which in conjunction with senescence-upregulated intracellular iron, can trigger ferroptosis and organelle demise [ 131 , 132 , 133 , 134 ]. Indeed, lipid peroxides and oxysterols, such as 7KCl, are mitoAhR ligands, contributing to mitochondrial dysfunction and autophagic elimination [ 135 ].…”

“…Other AhR ligands include somnogens, such as phenazines, melatonin, and tryptophan derivatives, which participate in the physiology of sleep, wakefulness, and the circadian rhythm [ 136 , 137 , 138 ]. In addition, reactive oxygen species (ROS), known to induce sleep via a redox-sensitive potassium channel, are AhR ligands, bringing this transcription factor in the arena of slumber, mental illness, and neurodegeneration [ 131 , 139 ]. Indeed, microbial phenazines, including pyocyanin and 1-hydroxyphenazine, activate AhR, influencing the transcription of many genes, including those involved in sleep regulation [ 140 , 141 ].…”

“…Interestingly, serotonin (5-HT) promotes mitochondrial transport in hippocampal neurons, suggesting that antidepressant drugs, serotonin reuptake inhibitors (SSRIs), may “exert their action by supplying healthy mitochondria to stressed neurons [ 155 ]. This may imply that ROS accumulation during wakefulness may induce slumber to repair oxidized lipids and import mitochondria from glial cells [ 120 , 131 , 139 ]. In addition, the accumulation of intracellular microtubule-associated protein tau (MAPT) in VENs likely impairs mitochondrial transport, contributing to bvFTD pathogenesis [ 156 ].…”

Mitochondrial Dynamics in Pulmonary Hypertension

“…On the other hand, increasing fission because of MFN2 knockdown strongly reduces mitochondrial Ca 2+ [25]. Altered mitochondrial dynamics play a direct role in pulmonary vascular dysfunction in PH through various switches such as increased oxidative stress and inflammation [19,26,27].…”

Deciphering the relationship between temperature and immunity

“…Further connecting to HSR, metabolism is proposed as a link between circadian rhythm, immunity, and body temperature. Redox, bioenergetic, and temperature regulation is critical in maintaining cellular circadian rhythms; wakefulness is mainly ‘nucleorestorative’, whereas sleep is mainly ‘mitorestorative’ [ 29 ]. Keeping circadian homeostasis, including immune and thermal homeostasis, is considered the largest component of human energy expenditure, comprising around 65% for a sedentary individual [ 46 ].…”