Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons
Open accessAbstract
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.
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SIRT3 maintains defenses against oxidative damage in the wakefulness-driving nucleus accumbens.
“Recent work on sleep-related cognitive decline found a role in for SIRT3 in maintaining defenses against oxidative damage in the wakefulness-driving nucleus accumbens ((Zhang et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Zhang et al. 2014
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“Extensive deprivation of sleep is related to reduced levels of SirT3 in young adult wild type mice locus coeruleus neurons while oxidative stress levels increase presumably as a result of a combined increase in metabolic activity and decline in antioxidant response [330].”
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- Authors
- Zhang, J., Zhu, Y., Zhan, G., Fenik, P., Panossian, L., Wang, M. M., Reid, S., Lai, D., Davis, J. G., Baur, J. A., & Veasey, S.
- Affiliations
- Peking University First Hospital (CN)
- Institute of Nutrition, Metabolism and Diabetes (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-03-19
- Volume
- 34
- Issue
- 12
- Pages
- 4418-4431
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3960479
- OpenAlex
- W2007944863
- Cited by
- 171
- References
- 59
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 11 · 2023: 14 · 2022: 9 · 2021: 12 · 2020: 16 · 2019: 18 · 2018: 26 · 2017: 13 · 2016: 14 · 2015: 10 · 2014: 7
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (RF1AG054104)
- National Heart, Lung, and Blood Institute (R01HL096037, R01HL124576, HL096037, R01HL079588, R01HL079555)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098656)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- extended wakefulness, SIRT3, oxidative stress, neurodegeneration, mitochondrial protein acetylation, electron transport chain complex I, apoptosis, antioxidant response, metabolic homeostasis, sleep deprivation
- MeSH terms
- Animals, Corticosterone, Locus Coeruleus, Male, Mitochondria, Nerve Degeneration, Neurons, Sleep, Sleep Deprivation, Wakefulness, Up-Regulation, Mice, Knockout, Oxidative Stress, Mice, Sirtuin 3
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