The Essence of Nature Can Be the Simplest (5)–Sleep: Transition From Extracellular Fenton Chemistry to Intracellular ATP

Sleep is a ubiquitous biological phenomenon observed throughout the animal kingdom, serving essential restorative and regulatory functions. Although it is one of the most compelling frontiers in neuroscience and physiology, the molecular mechanisms of the intrinsic drive to sleep after prolonged wakefulness remain poorly understood. Recent research indicates that, beyond the conventional synthesis of adenosine triphosphate (ATP) via oxidative phosphorylation, cells also engage in aerobic glycolysis to facilitate extracellular Fenton reactions, a process for the systemic energy demands of multicellular organisms. This paper synthesizes current evidence on the distinct roles of glycolysis and oxidative phosphorylation in energy metabolism during sleep and wakefulness, as well as the regulatory influence of wakefulness and sleep on ATP degradation and replenishment, iron and oxygen homeostasis, phosphorylation, and myelination. We propose that, during wakefulness, cells predominantly utilize extracellular Fenton chemistry, whereas sleep is characterized by a metabolic shift toward intracellular ATP production. This metabolic transition between two energy modalities helps understand wakefulness‐mediated neurotransmitter and cofactor biosynthesis, heme formation, and phosphorylation‐associated myelination and synaptic plasticity. Furthermore, the transformation of these two energy patterns underpins the maintenance of neuronal function and skin stem cells and offers insights into the pathogenesis of neurodegenerative diseases related to sleep disturbances.