# Volatile Anesthetics and Metabolism

> **NIH NIH R35** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $819,975

## Abstract

Project Summary
 A true enigma of modern medicine has persisted for over 150 years; the mechanism(s) by which
volatile anesthetics (VAs) produce reversible loss of consciousness remains an unsolved mystery. Using
genetic approaches, we demonstrated that mitochondrial complex I, an entry point of the mitochondrial
electron transport chain, specifically controls the sensitivity of multiple species, including worms and
humans, to VAs. These broad phylogenetic effects indicate that an ancient mechanism is at hand, linking
mitochondrial function to synaptic silencing in the presence of VAs.
 We began mechanistic studies in mice by exploiting Ndufs4(KO), a mouse defective in complex I
function and extremely hypersensitive to VAs. Testing cell-specific Ndufs4(KO) mice, we found that VA
sensitivity was fully controlled by glutamatergic KO, with no effect of loss of NDUFS4 from GABAergic or
cholinergic neurons. Surprisingly, an astrocytic-specific KO of NDUFS4 was defective only in arousal from
VAs. Preliminary data indicate that neurons in the locus coeruleus mediate this effect. This novel role of
astrocytes offers a new approach to investigate crucial arousal pathways. In addition, we are exploring the
mechanisms underlying anesthetic induced neurotoxicity (AIN). From our work in nematodes, we have
identified new candidate molecules that can be tested as AIN therapies in mice. We showed that inhibition
of the unfolded protein response in the endoplasmic reticulum, or inhibition of mTOR, a cellular metabolic
switch, alleviated AIN in worms. We are exploring the roles of these pathways in AIN, and relating them to
exciting new data which indicate that VAs themselves produce metabolic changes specific to neonatal mice.
 Many questions remain unanswered. 1. How do complex I defects control VA sensitivity. We
showed that excitatory neurotransmission in Ndufs4(KO) was hypersensitive to isoflurane inhibition
compared to WT. Our recent data suggest that isoflurane inhibits synaptic endocytosis in both WT and KO
animals and that this inhibition results from a decrease in ATP production. Our aims are to characterize the
mechanism underlying inhibition of neurotransmitter endocytosis by VAs. 2. What pathways transduce
AIN in neonatal mice; how can those pathways be inhibited? We are extending C. elegans studies to
test exciting new small molecule candidates that may alleviate AIN in mice. We are also exploring ER-stress
and mTOR activity as potential signaling pathways mediating AIN in mice. 3. How does mitochondrial
function in astrocytes control arousal from the anesthetized state? We are studying astrocyte
signaling to determine how astrocytes affect synaptic function during and following VA exposure.
 Astrocyte/neural pathways necessary for emergence from the anesthetized state will be
investigated. Mitochondrial function is linked to behavior in VAs in worms, mice, and man. Our proposed
studies are aimed to identify the basic, molecular mechanisms of action ...

## Key facts

- **NIH application ID:** 10086242
- **Project number:** 1R35GM139566-01
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** PHILIP G MORGAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $819,975
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086242

## Citation

> US National Institutes of Health, RePORTER application 10086242, Volatile Anesthetics and Metabolism (1R35GM139566-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10086242. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*