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Updated: Jul 29, 2025
Optogenetic Activation of Afferent Pathways in Brain Slices and Modulation of Responses by Volatile Anesthetics
Published on: July 23, 2020
A primordial target: Mitochondria mediate both primary and collateral anesthetic effects of volatile anesthetics
Misha Perouansky1,2, Dena Johnson-Schlitz1, Margaret M Sedensky3
1Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
Abstract:
One of the unsolved mysteries of medicine is how do volatile anesthetics (VAs) cause a patient to reversibly lose consciousness. In addition, identifying mechanisms for the collateral effects of VAs, including anesthetic-induced neurotoxicity (AiN) and anesthetic preconditioning (AP), has proven challenging. Multiple classes of molecules (lipids, proteins, and water) have been considered as potential VA targets, but recently proteins have received the most attention. Studies targeting neuronal receptors or ion channels had limited success in identifying the critical targets of VAs mediating either the phenotype of "anesthesia" or their collateral effects. Recent studies in both nematodes and fruit flies may provide a paradigm shift by suggesting that mitochondria may harbor the upstream molecular switch activating both primary and collateral effects. The disruption of a specific step of electron transfer within the mitochondrion causes hypersensitivity to VAs, from nematodes to Drosophila and to humans, while also modulating the sensitivity to collateral effects. The downstream effects from mitochondrial inhibition are potentially legion, but inhibition of presynaptic neurotransmitter cycling appears to be specifically sensitive to the mitochondrial effects. These findings are perhaps of even broader interest since two recent reports indicate that mitochondrial damage may well underlie neurotoxic and neuroprotective effects of VAs in the central nervous system (CNS). It is, therefore, important to understand how anesthetics interact with mitochondria to affect CNS function, not just for the desired facets of general anesthesia but also for significant collateral effects, both harmful and beneficial. A tantalizing possibility exists that both the primary (anesthesia) and secondary (AiN, AP) mechanisms may at least partially overlap in the mitochondrial electron transport chain (ETC).
Insights
Volatile anesthetics
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- The precise mechanisms by which volatile anesthetics (VAs) induce reversible loss of consciousness remain unclear.
- Investigating collateral effects of VAs, such as anesthetic-induced neurotoxicity (AiN) and anesthetic preconditioning (AP), presents significant challenges.
- While lipids, proteins, and water have been explored as VA targets, proteins have recently garnered the most attention, with limited success in identifying critical neuronal targets.
Purpose of the Study:
- To explore the hypothesis that mitochondria are central to the effects of volatile anesthetics.
- To investigate the role of mitochondrial electron transport chain disruption in mediating both the primary anesthetic effects and collateral impacts.
- To understand how anesthetics interact with mitochondria to influence central nervous system (CNS) function, encompassing both desired anesthetic properties and adverse/beneficial side effects.
Main Methods:
- Review of recent studies in model organisms (nematodes, fruit flies) and implications for human physiology.
- Analysis of findings suggesting mitochondrial electron transfer disruption as a key factor in VA sensitivity.
- Examination of downstream effects, including presynaptic neurotransmitter cycling and potential links to mitochondrial damage in the CNS.
Main Results:
- Disruption of mitochondrial electron transfer leads to hypersensitivity to VAs across species.
- Mitochondrial dysfunction modulates sensitivity to collateral effects of VAs.
- Inhibition of presynaptic neurotransmitter cycling is particularly sensitive to mitochondrial effects.
Conclusions:
- Mitochondria may harbor the upstream molecular switch for both primary anesthetic effects and collateral impacts of VAs.
- Mitochondrial damage is implicated in both neurotoxic and neuroprotective effects of VAs in the CNS.
- A potential overlap in mechanisms between general anesthesia, AiN, and AP may exist within the mitochondrial electron transport chain (ETC).
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