RT Journal Article
SR Electronic
T1 Extended Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4418
OP 4431
DO 10.1523/JNEUROSCI.5025-12.2014
VO 34
IS 12
A1 Zhang, Jing
A1 Zhu, Yan
A1 Zhan, Guanxia
A1 Fenik, Polina
A1 Panossian, Lori
A1 Wang, Maxime M.
A1 Reid, Shayla
A1 Lai, David
A1 Davis, James G.
A1 Baur, Joseph A.
A1 Veasey, Sigrid
YR 2014
UL http://www.jneurosci.org/content/34/12/4418.abstract
AB 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.