Mitochondrial complex I function modulates volatile anesthetic sensitivity in C. elegans.
Despite 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.
Falk
Marni J
MJ
Department of Pediatrics, University Hospitals of Cleveland, CASE School of Medicine, Cleveland, OH 44106, USA.
Kayser
Ernst-Bernhard
EB
Morgan
Philip G
PG
Sedensky
Margaret M
MM
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics*; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics* / Q000378:metabolism; D005820:Genetic Testing; D006221:Halothane; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D034622:RNA Interference
D000777:Anesthetics; D045222:Electron Transport Chain Complex Proteins; D006221:Halothane