Expansion of Electron Transport Chain Mutants That Cause Anesthetic-Induced Toxicity in Drosophila melanogaster

Abstract

The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places individuals with mETC mutations at risk for anesthetic complications, as exemplified by patients with Leigh syndrome (LS). The Drosophila melanogaster homozygous mutant for ND-23, which encodes a subunit of mETC Complex I, replicates numerous characteristics of LS, including neurodegeneration, shortened lifespan, behavioral anesthetic hypersensitivity, and toxicity. The anesthetic phenotype of toxicity (lethality) is also observed in flies homozygous for mutations in other Complex I subunits. By contrast, mutations conferring sensitivity have not yet been identified for subunits of Complexes II–V. Furthermore, anesthetic phenotypes are thought to be recessive; that is, risk is not conferred by heterozygous mutations. However, at older ages, exposure of heterozygous mutant ND-23 flies to the VGA isoflurane in 75% oxygen (hyperoxia) results in toxicity. It is also unknown whether combinations of heterozygous mutations in different subunits of the mETC can result in anesthetic toxicity. Here, we show that, following exposure to isoflurane in hyperoxia, flies carrying heterozygous mutations in two Complex I subunits, ND-23 and ND-SGDH (NADH dehydrogenase (ubiquinone) SGDH subunit), had a level of anesthetic toxicity that exceeded the added toxicities of the individual heterozygous mutations. In addition, we show that flies heterozygous for two different alleles of the Complex II gene SdhB were susceptible to isoflurane/hyperoxia-induced anesthetic toxicity. Finally, a mutation in the SdhC subunit of Complex II of Caenorhabditis elegans resulted in isoflurane-induced mortality, supporting the role of Complex II in anesthetic toxicity. These data expand the landscape of mutations in the mETC that increase sensitivity to anesthetic toxicity.