• Marni J Falk, Ernst-Bernhard Kayser, Philip G Morgan, and Margaret M Sedensky.
• Department of Pediatrics, University Hospitals of Cleveland, CASE School of Medicine, Cleveland, OH 44106, USA.
• Curr. Biol. 2006 Aug 22; 16 (16): 1641-5.

AbstractDespite the widespread clinical use of volatile anesthetics, their mechanisms of action remain unknown [1-6]. An unbiased genetic screen in the nematode C. elegans for animals with altered volatile anesthetic sensitivity identified a mutant in a nuclear-encoded subunit of mitochondrial complex I [7,8]. This raised the question of whether mitochondrial dysfunction might be the primary mechanism by which volatile anesthetics act, rather than an untoward secondary effect [9,10]. We report here analysis of additional C. elegans mutations in orthologs of human genes that contribute to the formation of complex I, complex II, complex III, and coenzyme Q [11-14]. To further characterize the specific contribution of complex I, we generated four hypomorphic C. elegans mutants encoding different complex I subunits [15]. Our main finding is the identification of a clear correlation between complex I-dependent oxidative phosphorylation capacity and volatile anesthetic sensitivity. These extended data link a physiologic determinant of anesthetic action in a tractable animal model to similar clinical observations in children with mitochondrial myopathies [16]. This work is the first to specifically implicate complex I-dependent oxidative phosphorylation function as a primary mediator of volatile anesthetic effect.

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