Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well documented, and there has been significant concern regarding the impact of VAs on neonat...

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Bibliographic Details
Published in:eLife 2021-07, Vol.10
Main Authors: Stokes, Julia, Freed, Arielle, Bornstein, Rebecca, Su, Kevin N, Snell, John, Pan, Amanda, Sun, Grace X, Park, Kyung Yeon, Jung, Sangwook, Worstman, Hailey, Johnson, Brittany M, Morgan, Philip G, Sedensky, Margaret M, Johnson, Simon C
Format: Article
Language:English
Subjects:
3-Hydroxybutyric Acid
Acetyl-CoA carboxylase
Acetyl-CoA Carboxylase - metabolism
Anesthesia
Anesthetics
Anesthetics - metabolism
Anesthetics - pharmacology
Animals
Citrates - metabolism
Citric acid
Citric Acid - metabolism
Electron transport
Electron transport chain
fatty acid oxidation
Fatty Acids - metabolism
Female
Glucose
Glucose - metabolism
Hypoglycemia
Infants (Newborn)
Ion channels
Isoflurane - metabolism
ketogenesis
Ketosis
Male
Malonyl Coenzyme A - metabolism
Medicine
Metabolism
Mice
Mice, Inbred C57BL
Mitochondria
neonate
Neonates
Newborn babies
Oxidation
Oxidation-Reduction
Pediatric anesthesia
Young adults
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Summary:Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood β-hydroxybutarate (β-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.65400