Isoflurane inhibition of endocytosis is an anesthetic mechanism of action

Jung et al., Isoflurane inhibition of endocytosis is an anesthetic mechanism of action, Current Biology (2022), https://doi.org/10.1016/j.cub.2022.05.037

Online publication date: June 9, 2022

Answering a century-old question: How do gas anesthetics work in the brain?

While anesthetic gases have been used in surgery for nearly 200 years, how they reliably cause unconsciousness and block pain has been a perplexing mystery.

Drs. Phil Morgan and Margaret Sedensky, principal investigators in the Center for Integrative Brain Research at Seattle Children’s Research Institute, and professors in the Department of Anesthesiology and Pain Medicine at the University of Washington, have pursued this question for decades. They are the first to discover that at the cellular level, these anesthetic gases affect the mitochondria—the power plant of cells—and block information transfer between cells, causing unconsciousness.

Their findings, published in Current Biology, describe how loss of mitochondrial function blocks a particular step in signaling between neurons. This block causes signaling neurons to run out of the molecules needed to communicate with other neurons. When this information transfer is interrupted by anesthesia, communication between neurons shuts down.

This bench-to-bedside work has broad implications for identifying children (and adults) who might be more sensitive to both the desired and undesired effects of inhaled anesthetics. It should also help in identifying new and safer anesthetics.

Morgan and Sedensky are longtime collaborators and recognized leaders in understanding anesthetic interactions in mitochondrial dysfunction. Children with mitochondrial diseases are often hypersensitive to anesthetics and need much lower doses, which led the researchers to question if the genetic mutations that affect mitochondria might also change sensitivity to anesthesia. They found in model organisms and in children, the same mitochondrial abnormalities caused the same change in sensitivity.

“This is a very important contribution because volatile anesthetics are used daily around the world but we don’t know how they work,” said Dr. Nino Ramirez, director of the Center for Integrative Brain Research and a contributing author on the paper. “These findings turn the prevailing hypothesis on its head about how anesthetics inhibit the brain.”

In future work, the researchers hope to pinpoint exactly how shutting down the mitochondria shuts down the neuron. “We need to understand how the anesthetics specifically disrupt mitochondrial function,” Morgan said.

Seattle Children’s contributing authors include Sangwook Jung, PhD, Pavel Zimin, PhD, Christian Woods and Ernst-Bernhard Kayser, PhD. The research was funded by the National Institutes of Health and the Northwest Mitochondrial Research Guild.

— Colleen Steelquist