Newly Published
Perioperative Medicine  |   July 2020
Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity
Author Notes
  • From the Departments of Anesthesiology (Z.P.G.O., M.P.) and Medical Genetics (D.A.W.), School of Medicine and Public Health and the Department of Genetics, College of Agricultural and Life Sciences (B.G.), University of Wisconsin–Madison, Madison, Wisconsin.
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • This work has been presented in part at the Annual Meeting of the American Society of Anesthesiologists in Orlando, Florida, on October 21, 2019, within the framework of the Best of Basic Science Abstracts session.
    This work has been presented in part at the Annual Meeting of the American Society of Anesthesiologists in Orlando, Florida, on October 21, 2019, within the framework of the Best of Basic Science Abstracts session.×
  • Submitted for publication November 20, 2019. Accepted for publication July 1, 2020.
    Submitted for publication November 20, 2019. Accepted for publication July 1, 2020.×
  • Correspondence: Address correspondence to Dr. Perouansky: School of Medicine and Public Health, University of Wisconsin–Madison, 600 Highland Avenue, B6/319 CSC, Madison, Wisconsin 53792-3272. mperouansky@wisc.edu. Anesthesiology’s articles are made freely accessible to all readers on www.anesthesiology.org, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Pharmacology
Perioperative Medicine   |   July 2020
Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity
Anesthesiology Newly Published on July 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003486
Anesthesiology Newly Published on July 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003486
Abstract

Background: General anesthetics influence mitochondrial homeostasis, placing individuals with mitochondrial disorders and possibly carriers of recessive mitochondrial mutations at increased risk of perioperative complications. In Drosophila, mutations in the ND23 subunit of complex I of the mitochondrial electron transport chain–analogous to mammalian NDUFS8–replicate key characteristics of Leigh syndrome, an inherited mitochondrial disorder. The authors used the ND23 mutant for testing the hypothesis that anesthetics have toxic potential in carriers of mitochondrial mutations.

Methods: The authors exposed wild-type flies and ND23 mutant flies to behaviorally equivalent doses of isoflurane or sevoflurane in 5%, 21%, or 75% oxygen. The authors used percent mortality (mean ± SD, n ≥ 3) at 24 h after exposure as a readout of toxicity and changes in gene expression to investigate toxicity mechanisms.

Results: Exposure of 10- to 13-day-old male ND23 flies to isoflurane in 5%, 21%, or 75% oxygen resulted in 16.0 ± 14.9% (n = 10), 48.2 ± 16.1% (n = 9), and 99.2 ± 2.0% (n = 10) mortality, respectively. Comparable mortality was observed in females. In contrast, under the same conditions, mortality was less than 5% for all male and female groups exposed to sevoflurane, except 10- to 13-day-old male ND23 flies with 9.6 ± 8.9% (n = 16) mortality. The mortality of 10- to 13-day-old ND23 flies exposed to isoflurane was rescued by neuron- or glia-specific expression of wild-type ND23. Isoflurane and sevoflurane differentially affected expression of antioxidant genes in 10- to 13-day-old ND23 flies. ND23 flies had elevated mortality from paraquat-induced oxidative stress compared with wild-type flies. The mortality of heterozygous ND23 flies exposed to isoflurane in 75% oxygen increased with age, resulting in 54.0 ± 19.6% (n = 4) mortality at 33 to 39 days old, and the percent mortality varied in different genetic backgrounds.

Conclusions: Mutations in the mitochondrial complex I subunit ND23 increase susceptibility to isoflurane-induced toxicity and to oxidative stress in Drosophila. Asymptomatic flies that carry ND23 mutations are sensitized to hyperoxic isoflurane toxicity by age and genetic background.

Editor’s Perspective:

What We Already Know about This Topic:

  • Mitochondrial proteins are targets of general anesthetics

  • The extent to which pathogenic mutations in mitochondrial proteins increase the risk of adverse reactions from anesthetics has not been previously explored

What This Article Tells Us That Is New:

  • Isoflurane but not sevoflurane exposure increased mortality in Drosophila carrying homozygous mutations in mitochondrial complex I, and hyperoxia increased mortality associated with isoflurane administration

  • In heterozygous flies, carrying mutations in mitochondrial complex I, age, and hyperoxia rendered flies susceptible to mortality after exposure to isoflurane

  • These observations raise the possibility that heterozygous carriers of mitochondrial mutations may be more susceptible to perioperative complications after isoflurane exposure