Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

Julia Stokes; Arielle Freed; Rebecca Bornstein; Kevin N Su; John Snell; Amanda Pan; Grace X Sun; Kyung Yeon Park; Sangwook Jung; Hailey Worstman; Brittany M Johnson; Philip G Morgan; Margaret M Sedensky; Simon C Johnson

doi:10.7554/eLife.65400

Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

Julia Stokes, Arielle Freed, Rebecca Bornstein, Kevin N Su, John Snell, Amanda Pan, Grace X Sun, Kyung Yeon Park, Sangwook Jung, Hailey Worstman, Brittany M Johnson, Philip G Morgan, Margaret M Sedensky, Simon C Johnson

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Abstract

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.

Original language	English
Number of pages	23
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.65400
Publication status	Published - 13 Jul 2021
Externally published	Yes

Keywords

3-Hydroxybutyric Acid
Acetyl-CoA Carboxylase/metabolism
Anesthetics/metabolism
Animals
Citrates/metabolism
Citric Acid/metabolism
Fatty Acids/metabolism
Female
Glucose/metabolism
Hypoglycemia
Isoflurane/metabolism
Ketosis
Male
Malonyl Coenzyme A/metabolism
Mice
Mice, Inbred C57BL
Mitochondria
Oxidation-Reduction

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10.7554/eLife.65400Licence: CC BY

elife-65400-v2Final published version, 4.26 MBLicence: CC BY

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title = "Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics",

abstract = "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.",

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author = "Julia Stokes and Arielle Freed and Rebecca Bornstein and Su, {Kevin N} and John Snell and Amanda Pan and Sun, {Grace X} and Park, {Kyung Yeon} and Sangwook Jung and Hailey Worstman and Johnson, {Brittany M} and Morgan, {Philip G} and Sedensky, {Margaret M} and Johnson, {Simon C}",

note = "Funding information: NIH Office of the Director R01GM133865; NIH Office of the Director R01GM118514; NIH Office of the Director R00GM126147",

year = "2021",

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doi = "10.7554/eLife.65400",

language = "English",

volume = "10",

journal = "eLife",

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T1 - Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

AU - Stokes, Julia

AU - Freed, Arielle

AU - Bornstein, Rebecca

AU - Su, Kevin N

AU - Snell, John

AU - Pan, Amanda

AU - Sun, Grace X

AU - Park, Kyung Yeon

AU - Jung, Sangwook

AU - Worstman, Hailey

AU - Johnson, Brittany M

AU - Morgan, Philip G

AU - Sedensky, Margaret M

AU - Johnson, Simon C

N1 - Funding information: NIH Office of the Director R01GM133865; NIH Office of the Director R01GM118514; NIH Office of the Director R00GM126147

PY - 2021/7/13

Y1 - 2021/7/13

N2 - 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.

AB - 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.

KW - 3-Hydroxybutyric Acid

KW - Acetyl-CoA Carboxylase/metabolism

KW - Anesthetics/metabolism

KW - Animals

KW - Citrates/metabolism

KW - Citric Acid/metabolism

KW - Fatty Acids/metabolism

KW - Female

KW - Glucose/metabolism

KW - Hypoglycemia

KW - Isoflurane/metabolism

KW - Ketosis

KW - Male

KW - Malonyl Coenzyme A/metabolism

KW - Mice

KW - Mice, Inbred C57BL

KW - Mitochondria

KW - Oxidation-Reduction

U2 - 10.7554/eLife.65400

DO - 10.7554/eLife.65400

M3 - Article

C2 - 34254587

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

ER -

Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

Abstract

Keywords

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