# Volatile Anesthetics and Metabolism Administrative Supplement for Equipment

> **NIH NIH R35** · SEATTLE CHILDREN'S HOSPITAL · 2024 · $123,356

## Abstract

ABSTRACT
 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.
Our further work showed that exposure to isoflurane caused an acute decrease in ATP levels specifically at the
presynapse. This decrease in ATP led, in turn, to a complete failure in endocytosis, a failure to re-uptake calcium
into the endoplasmic reticulum following neuronal stimulation, and to significant hyperpolarization of the neuron
 One main question remains unanswered. 1. How do volatile anesthetics disrupt complex I activity.
We showed that excitatory neurotransmission and endocytosis in Ndufs4(KO) was hypersensitive to isoflurane
inhibition compared to WT. Our recent data show that isoflurane inhibits synaptic endocytosis in both WT and
KO animals and that this inhibition results from a decrease in ATP production. Our aim is to characterize the
mechanisms underlying inhibition of complex I by VAs. Our proposed studies are aimed to identify the basic,
molecular mechanisms of action of VAs.

## Key facts

- **NIH application ID:** 11099176
- **Project number:** 3R35GM139566-04S1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** PHILIP G MORGAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $123,356
- **Award type:** 3
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099176

## Citation

> US National Institutes of Health, RePORTER application 11099176, Volatile Anesthetics and Metabolism Administrative Supplement for Equipment (3R35GM139566-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11099176. Licensed CC0.

---

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