Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity

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 What This Article Tells Us That Is New

Atorvastatin Attenuates Isoflurane-Induced Activation of ROS-p38MAPK/ATF2 Pathway, Neuronal Degeneration, and Cognitive Impairment of the Aged Mice

“…Both our preliminary work and previous studies found that isoflurane anesthesia could induce oxidative stress and neuroinflammation, further leading to cognitive impairment in aged mice ( Neghab et al, 2020 ; Olufs et al, 2020 ). However, the potential signaling pathways involved in isoflurane-induced d neuroinflammation and apoptosis in the aged brain remain unclear.…”

Mutations in Complex I of the mitochondrial electron-transport chain sensitize the fruit fly (Drosophila melanogaster) to ether and non-ether volatile anesthetics

“…Previously, we showed that ISO toxicity in the ND-23 60114 model is caused by injury to the brain and is not specific to the ND-23 60114 allele. [11] We hypothesize that mortality from HAL is also caused by AiN because of the phenotypic similarity: the dose of HAL was equipotent to that of ISO, death occurred within 24 h after initial recovery from the anesthetic and mortality was modulated by the O 2 concentration. Furthermore, neither HAL nor ISO are toxic to Canton S flies under normoxic and hyperoxic conditions.…”

“…[11] AiN is the likely cause because this phenotype is rescued by neuron-specific overexpression of wildtype ND-23. [11] Interestingly, heterozygous ND-23 60114 flies are asymptomatic and have a normal lifespan indicating haplosufficiency of ND-23. [8] However, at 30-35 days of age, ND-23 60114 /+ flies develop an AiN-like lethal phenotype after exposure to ISO in 75% O 2 (hyperoxic ISO), indicating that effects of aging may result in haploinsufficiency of the core Complex I subunit under environmental stress conditions.…”

“…[8] However, at 30-35 days of age, ND-23 60114 /+ flies develop an AiN-like lethal phenotype after exposure to ISO in 75% O 2 (hyperoxic ISO), indicating that effects of aging may result in haploinsufficiency of the core Complex I subunit under environmental stress conditions. [11]…”

Role of Genetics in Anesthesiology

“…Changes in the protein ND-23 subunit of complex one mitochondrial electron carrier string like mammalian species NDUFS-8 replicate essential features of Leigh syndrome. 10 Leigh syndrome is a genetic condition where there is changes/mutations in one's mitochondrial DNA. When the mitochondrial DNA is mutated, it will interfere with the energy sources that run cells in an area of the brain that plays a role in motor movements.…”