The mitochondrial theory of sleep: an integrative framework for understanding sleep-wake regulation

Sleep is an essential biological function with unclear mechanisms. Recent research links the circadian clock, energy metabolism, calcium handling, reactive oxygen species (ROS) production, and synaptic plasticity to cognitive performance. Given that mitochondria regulate cellular energy production, calcium buffering, and ROS dynamics, it stands to reason that mitochondrial function plays a significant role in sleep regulation. Here, we propose an enhanced integrative framework "the mitochondrial theory of sleep" that synthesizes disease models, mechanistic details, and gene enrichment analysis based on bioinformatics. We identified nine crucial mitochondrial protein-coding genes that are highly enriched in pathways linked to oxidative phosphorylation, synaptic processes, and sleep characteristics by closely analyzing data sets using Gene Ontology, KEGG, and Reactome databases. Our analysis suggests that sleep deprivation is associated with calcium signaling, mitochondrial genes expression, reactive oxygen species (ROS) generation, and ATP production. Additionally, coherent mitochondrial genes cluster linked to neuroprotective and sleep-inducing effects are revealed by functional clustering and network topology analysis. This study offers a testable model for the control of wakefulness and sleep by the mitochondria. This mechanistic model incorporates findings from research on humans and animals, psychiatric conditions including bipolar disorder, and evolutionary theories. This framework identifies promising therapeutic targets for future investigation, including (MCU1, CPT1A, and antioxidant regulators) to treat sleep disorders in addition to bringing disparate findings together from a biological perspectives. While much of the current evidence remains correlative, this framework provides a roadmap for future studies. By highlighting the function of mitochondrial dynamics as an integrating point for metabolic and neurophysiological mechanisms of sleep, our findings advance our theoretical and practical understanding of sleep.