Saturday, November 23, 2024
11/23/2024
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.
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