766C Poster - 12. Physiology, metabolism and aging
Saturday April 09, 1:30 PM - 3:30 PM
General anesthetics are toxic to flies mutant for a mitochondrially-encoded subunit of the electron transport chain.
Authors: Amanda Scharenbrock; Zachariah Olufs; David Wassarman; Misha Perouansky
Affiliation: University of Wisconsin-Madison, Madison, WI
Keywords: h. mitochondria; a. stress responses
Animals with mutations in Complex I of the mitochondrial electron transport chain (mETC) exhibit behavioral sensitivity to volatile general anesthetics (VGAs) and may be at increased risk of VGA-induced deleterious collateral effects. To investigate the toxicity of VGAs in mitochondrial mutants, we studied flies carrying a mutation in ND2, a gene in the mitochondrial genome that encodes a protein in the intermembrane arm of Complex I. We examined two commonly used VGAs isoflurane (ISO) and sevoflurane (SEVO), halogenated ethers, as well as various oxygen (O2) concentrations. ISO proved to be toxic in hypoxic (5% O2), normoxic, and hyperoxic (75% O2) conditions while SEVO was only toxic in hyperoxic conditions. Interestingly, our previous work has shown that flies carrying a mutation in a nuclearly-encoded Complex I subunit, ND23, die when exposed to ISO in normoxia and hyperoxia, but ISO in hypoxia and SEVO under any oxygen conditions were not toxic. We have also expanded our anesthetics to include halothane (HALO), an alkane anesthetic, which like SEVO is non-pungent. Unlike SEVO, we found that HALO is toxic to both ND2 and ND23 mutants, with greater toxicity in ND2 mutants. These data indicate that mutations in different subunits of Complex I of the mETC confer differential susceptibility to VGA-induced toxicity. To investigate the underlying mechanism, we have begun examining whether heterozygous mutations in candidate genes enhance or suppress VGA-induced toxicity in ND2 mutants. To date, we have found that mutation of sima, which encodes a subunit of Hypoxia Inducible Factor (HIF) that transcriptionally regulates the response to hypoxia, enhanced the lethality of ND2 mutants exposed to ISO under normoxic or hypoxic conditions, indicating that HIF functions to prevent VGA toxicity. This work is part of an ongoing project aimed at identifying modifiers of VGA toxicity in mitochondrial mutants.