Mitochondrial Effects on Sensitivity to Anesthetics

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DESCRIPTION (provided by applicant): The long-term goal of this laboratory is to understand at the molecular level how the volatile anesthetics work. We have exploited the many advantages of the nematode C. elegans to identify genes that control its behavior in volatile anesthetics. We have determined that a point mutation in a single subunit of the first complex of mitochondrial electron transport causes C. elegans to be profoundly hypersensitive to all volatile anesthetics. This gene, gas-1, encodes the 49Kda subunit of NADH ubiquinone oxidoreductase. Multiple aspects of metabolism are severely affected by this mutation. In addition, free radical damage is a significant feature of this animal's hypersensitivity to volatile anesthetics. A small group of children with metabolic defects that are related to the function of Complex I are hypersensitive to sevoflurane. In this proposal we will extend our studies to test our hypothesis that decreased metabolism and increased free radical formation both play a role in the anesthetic hypersensitivity of gas-1, and the either of these may affect downstream, presynaptic targets. The specific aims of the present application are to: 1. Compare the effect of halothane on oxidative phosphorylation in nematode strains with known mitochondrial defects, but with different anesthetic sensitivities. This will determine the contribution of metabolic changes on anesthetic sensitivity. 2. Characterize the damage from reactive oxygen species in three strains of worms with mutations that affect mitochondria. We will identify specific molecules affected by reactive oxygen species that affect anesthetic sensitivity. 3. Determine gas-1's effect on multiple markers of synaptic structure and function in C. elegans. Antibodies to presynaptic proteins, as well as transgenic animals carrying marked presynaptic proteins, will be used to test the effects of gas-1 on neuronal proteins that are key to synaptic function. The function of mitochondria represents a novel mechanism that contributes to the control of behavior of a whole animal in volatile anesthetics. Study of the nematode can lead to a molecular understanding of how volatile anesthetics work. In addition, this proposal has a clear clinical correlate in the anesthetic response of patients with mitochondrial myopathies.