Carriers of mutations in the mitochondrial electron transport chain are at increased risk of anesthetic-induced neurotoxicity. To investigate the neurotoxicity mechanism and to test preconditioning as a protective strategy, this study used a Drosophila melanogaster model of Leigh syndrome. Model flies carried a mutation in ND23 (ND2360114) that encodes a mitochondrial electron transport chain complex I subunit. This study investigated why ND2360114 mutants become susceptible to lethal, oxygen-modulated neurotoxicity within 24 h of exposure to isoflurane but not sevoflurane.
This study used transcriptomics and quantitative real-time reverse transcription polymerase chain reaction to identify genes that are differentially expressed in ND2360114 but not wild-type fly heads at 30 min after exposure to high- versus low-toxicity conditions. This study also subjected ND2360114 flies to diverse stressors before isoflurane exposure to test whether isoflurane toxicity could be diminished by preconditioning.
The ND2360114 mutation had a greater effect on isoflurane- than sevoflurane-mediated changes in gene expression. Isoflurane and sevoflurane did not affect expression of heat shock protein (Hsp) genes (Hsp22, Hsp27, and Hsp68) in wild-type flies, but isoflurane substantially increased expression of these genes in ND2360114 mutant flies. Furthermore, isoflurane and sevoflurane induced expression of oxidative (GstD1 and GstD2) and xenobiotic (Cyp6a8 and Cyp6a14) stress genes to a similar extent in wild-type flies, but the effect of isoflurane was largely reduced in ND2360114 flies. In addition, activating stress response pathways by pre-exposure to anesthetics, heat shock, hyperoxia, hypoxia, or oxidative stress did not suppress isoflurane-induced toxicity in ND2360114 mutant flies.
Mutation of a mitochondrial electron transport chain complex I subunit generates differential effects of isoflurane and sevoflurane on gene expression that may underlie their differential effects on neurotoxicity. Additionally, the mutation produces resistance to preconditioning by stresses that protect the brain in other contexts. Therefore, complex I activity modifies molecular and physiologic effects of anesthetics in an anesthetic-specific manner.
- The fruit fly Drosophila melanogaster carrying a hypomorphic mutation in the ND23 gene, encoding a subunit of complex I in the mitochondrial electron transport chain, replicates pathologic characteristics of Leigh syndrome
- Exposure of young adult flies with the ND23 mutation to isoflurane but not to sevoflurane induces mortality that is enhanced by hyperoxia and suppressed by hypoxia
- The molecular pathways underlying increased sensitivity to isoflurane toxicity associated with the ND23 mutation are poorly understood
- Isoflurane and sevoflurane exposure differentially activated transcriptional responses to proteostatic, oxidative, and xenobiotic stress in flies with mutant ND23 but not in wild-type flies
- Preconditioning paradigms aimed at pre-emptive activation of protective responses to these stresses, however, were ineffective in suppressing isoflurane-induced mortality in the ND23 mutants
- These results suggest that inhibition of mitochondrial complex I activity modifies molecular and physiologic effects of anesthetics in a drug-specific manner
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