Links between mutations in functionally separate arms of mitochondrial complex I and responses to volatile anesthetics.

Background: Individuals with mitochondrial defects, especially those in Complex I of the electron transport chain, exhibit behavioral hypersensitivity and toxicity to volatile anesthetics. In Drosophila melanogaster, mutation of ND23 (NDUFS8 in mammals), which encodes a subunit of the matrix arm of Complex I, sensitizes flies to toxicity from isoflurane but not an equipotent dose of sevoflurane. Also, in ND23 flies, both anesthetics activate expression of stress response genes, but to different extents. Here, we investigated the generality of these findings by examining flies mutant for ND2 (ND2 in mammals), which encodes a subunit of the membrane arm of Complex I.

Methods: The serial anesthesia array was used to expose ND2^del1 and ND23⁶⁰¹¹⁴ flies to precise doses of isoflurane, sevoflurane, and oxygen. Behavioral sensitivity was assessed by a climbing assay and toxicity by percent mortality within 24 h of exposure. Changes in expression were determined by qRT-PCR of RNA isolated from heads at 0.5 h after anesthetic exposure.

Results: Unlike ND23⁶⁰¹¹⁴, ND2^del1 did not affect behavioral sensitivity to isoflurane or sevoflurane. Furthermore, sevoflurane in hyperoxia as well as anoxia caused mortality of ND2^del1 but not ND23⁶⁰¹¹⁴ flies. Finally, the mutations had different effects on induction of stress response gene expression by the anesthetics.

Conclusion: Mutations in different arms of Complex I resulted in different behavioral sensitivities and toxicities to isoflurane and sevoflurane, indicating that (i) the anesthetics have mechanisms of action that involve arms of Complex I to different extents and (ii) the lack of behavioral hypersensitivity does not preclude susceptibility to anesthetic toxicity.