Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity
Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity
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DOI：
10.1097/aln.0000000000003486
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发表时间：
2020-10-01
期刊：
影响因子：
8.8
通讯作者：
Perouansky, Misha
中科院分区：
文献类型：
--
作者：
Olufs, Zachariah P. G.;Ganetzky, Barry;Perouansky, Misha
背景资料：全身麻醉剂影响线粒体稳态，使线粒体疾病患者和可能的隐性线粒体突变携带者围手术期并发症的风险增加。在果蝇中，线粒体电子传递链复合物I的ND 23亚基突变-类似于哺乳动物NDUFS 8-复制Leigh综合征的关键特征，Leigh综合征是一种遗传性线粒体疾病。作者使用ND 23突变体来检验麻醉剂对线粒体突变携带者具有潜在毒性的假设。研究方法：作者将野生型果蝇和ND 23突变果蝇暴露于行为等效剂量的异氟烷或七氟烷（含5%、21%或75%氧气）中。作者使用暴露后24小时的死亡率百分比（平均值+/- SD，n >= 3）作为毒性和基因表达变化的读数，以研究毒性机制。结果如下：将10- 13日龄雄性ND 23果蝇暴露于含5%、21%或75%氧气的异氟烷中，分别导致16.0 +/- 14.9%（n = 10）、48.2 +/- 16.1%（n = 9）和99.2 +/- 2.0%（n = 10）的死亡率。在雌性动物中观察到的死亡率相当。相比之下，在相同条件下，暴露于七氟烷的所有雄性和雌性组的死亡率均低于5%，但10- 13日龄雄性ND 23果蝇除外，其死亡率为9.6 +/- 8.9%（n = 16）。暴露于异氟烷的10- 13日龄ND 23果蝇的死亡率被野生型ND 23的神经元或胶质细胞特异性表达所挽救。异氟醚和七氟醚对10- 13日龄ND 23果蝇抗氧化基因表达的影响不同。与野生型果蝇相比，ND 23果蝇在百草枯诱导的氧化应激中死亡率升高。在75%氧气中暴露于异氟烷的异源性ND 23果蝇的死亡率随着年龄的增长而增加，导致33至39日龄的死亡率为54.0 +/- 19.6%（n = 4），并且死亡率百分比在不同的遗传背景中有所不同。结论：果蝇线粒体复合物I亚基ND 23突变增加对异氟烷诱导毒性和氧化应激的易感性携带ND 23突变的无症状果蝇因年龄和遗传背景而对高氧异氟烷毒性敏感。
Background: General anesthetics influence mitochondrial homeostasis, placing individuals with mitochondrial disorders and possibly carriers of recessive mitochondrial mutations at increased risk of perioperative complications. InDrosophila, 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 theND23mutant for testing the hypothesis that anesthetics have toxic potential in carriers of mitochondrial mutations. Methods: The authors exposed wild-type flies andND23mutant 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 maleND23flies 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 maleND23flies with 9.6 +/- 8.9% (n = 16) mortality. The mortality of 10- to 13-day-oldND23flies exposed to isoflurane was rescued by neuron- or glia-specific expression of wild-typeND23. Isoflurane and sevoflurane differentially affected expression of antioxidant genes in 10- to 13-day-oldND23flies.ND23flies had elevated mortality from paraquat-induced oxidative stress compared with wild-type flies. The mortality of heterozygousND23flies 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 inDrosophila. Asymptomatic flies that carryND23mutations are sensitized to hyperoxic isoflurane toxicity by age and genetic background.