# A mouse model linking anesthetic sensitivity to mitochondrial function

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $541,248

## Abstract

PROJECT ABSTRACT
 The mechanism by which volatile anesthetics (VAs) produce reversible loss of consciousness and
render an organism insensate to pain remains an unsolved mystery of medicine for over 150 years. We
demonstrated that mitochondrial complex I, an entry point and rate limiting component of the mitochondrial
electron transport chain, controls anesthetic sensitivity across the animal kingdom, from worms to mice
to humans. The implication is that an ancient mechanism is at hand, linking mitochondrial function to synaptic
silencing by VAs.
 Ndufs4(KO) mice lack a subunit of mitochondrial complex I, which increases sensitivity of the complex
to isoflurane inhibition. For either isoflurane or halothane, the KO mice became unresponsive to a tail pinch at
a dose ~3-fold lower than for controls. Ndufs4(KO) was also hypersensitive to VAs using loss of righting reflex
as the endpoint. These KO mice display the greatest change in VA sensitivity described in a mammal.
We also discovered that VA sensitivity was fully controlled by glutamatergic expression of the mutation, with no
effect from GABAergic, cholinergic or astrocyte expression. We measured the EC50s for loss of righting reflex
(LORR) of the KO mice for other anesthetics whose targets are well characterized. Surprisingly, the animals
were actually resistant to the effects of ketamine. The effects of the Ndufs4(KO) are specific in terms of
anesthetic and not simply the result of generalized CNS depression.
 We wish to understand, in this proposal how complex I defects in the spinal cord cause
hypersensitivity to VAs. We discovered that TREK-1 channels in spinal cord slices from Ndufs4(KO) are
hypersensitive to isoflurane, in agreement with others who have shown that VA sensitivity of mice is dependent
on TREK-1 function. We hypothesize that the VA hypersensitivity is mediated through a mitochondrial effect on
TREK-1 channels in ventral horn neurons, and aim to characterize the mechanisms underlying mitochondrially
induced changes in TREK-1sensitivity to VAs. We will move from cellular and molecular targets to whole
animal behaviors in 3 specific aims: 1) investigating which cells must be defective in mitochondrial function in
order to produce TREK-I hypersensitivity; 2) discover the effects of Ndufs4(KO) on phosphorylation sites within
TREK-1 channels in the spinal cord, and 3) since we predict that TREK-1 activation underlies the VA
hypersensitivity of our KO response to tail clamp, construct an Ndufs4(KO) that lacks TREK-1, and test its
behavior in VAs.
 Our overarching goal is to understand the molecular targets of VAs. We have linked mitochondrial
function to behavior in VAs in worms, mice, and man, and propose that mitochondria metabolism is a novel but
very plausible mechanism underlying effects of VAs.

## Key facts

- **NIH application ID:** 10149335
- **Project number:** 5R01GM105696-08
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Margaret Mary Sedensky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $541,248
- **Award type:** 5
- **Project period:** 2014-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149335

## Citation

> US National Institutes of Health, RePORTER application 10149335, A mouse model linking anesthetic sensitivity to mitochondrial function (5R01GM105696-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10149335. Licensed CC0.

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