title: Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons.
abstract: Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor to LCns and that, with extended wakefulness, adaptive mitochondrial metabolic responses fail and injury ensues. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) coordinates mitochondrial energy production and redox homeostasis. We find that brief wakefulness upregulates SirT3 and antioxidants in LCns, protecting metabolic homeostasis. Strikingly, mice lacking SirT3 lose the adaptive antioxidant response and incur oxidative injury in LCns across brief wakefulness. When wakefulness is extended for longer durations in wild-type mice, SirT3 protein declines in LCns, while oxidative stress and acetylation of mitochondrial proteins, including electron transport chain complex I proteins, increase. In parallel with metabolic dyshomeostasis, apoptosis is activated and LCns are lost. This work identifies mitochondrial stress in LCns upon wakefulness, highlights an essential role for SirT3 activation in maintaining metabolic homeostasis in LCns across wakefulness, and demonstrates that extended wakefulness results in reduced SirT3 activity and, ultimately, degeneration of LCns.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing 100034, China, Center for Sleep and Circadian Neurobiology, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Guanxia
authors.initials: G
authors.lastname: Zhan
authors.forename: Polina
authors.initials: P
authors.lastname: Fenik
authors.forename: Lori
authors.initials: L
authors.lastname: Panossian
authors.forename: Maxime M
authors.initials: MM
authors.lastname: Wang
authors.forename: Shayla
authors.initials: S
authors.lastname: Reid
authors.forename: David
authors.initials: D
authors.lastname: Lai
authors.forename: James G
authors.initials: JG
authors.lastname: Davis
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.forename: Sigrid
authors.initials: S
authors.lastname: Veasey
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000097:blood; D008125:Locus Coeruleus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism; D012890:Sleep / Q000502:physiology*; D012892:Sleep Deprivation / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D014851:Wakefulness / Q000502:physiology*
chemical_list: D056566:Sirtuin 3; D003345:Corticosterone
keywords: acetylation; locus ceruleus; metabolics; mitochondria; oxidative stress; sleep deprivation