Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (Drosophila melanogaster) to Ether and Non-Ether Volatile Anesthetics

The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. TheND-2360114andmt:ND2del1lines of fruit flies (Drosophila melanogaster) that carry mutations in core subunits of Complex I of the mETC, replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS.ND-2360114flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II-V of the mETC cause AiN. We found that (i)ND-2360114andmt:ND2del1were susceptible to toxicity from halothane; (ii) in wildtype flies halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II-V did not result in an AiN phenotype. We conclude AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.Previous presentationsparts of the data were presented in abstract form at the 63rdAnnual Drosophila Research Conference in San Diego, March 2022.