Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile Anesthetics
The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The <i>ND-23<sup>60114</sup></i> and mt:<i>ND2<sup>del1</sup></i&...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-01-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/3/1843 |
| _version_ | 1797624531078086656 |
|---|---|
| author | Luke A. Borchardt Amanda R. Scharenbrock Zachariah P. G. Olufs David A. Wassarman Misha Perouansky |
| author_facet | Luke A. Borchardt Amanda R. Scharenbrock Zachariah P. G. Olufs David A. Wassarman Misha Perouansky |
| author_sort | Luke A. Borchardt |
| collection | DOAJ |
| description | The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The <i>ND-23<sup>60114</sup></i> and mt:<i>ND2<sup>del1</sup></i> lines of fruit flies (<i>Drosophila melanogaster</i>) that carry mutations in core subunits of Complex I of the mETC replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS. <i>ND-23<sup>60114</sup></i> flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II–V of the mETC cause AiN. We found that (i) <i>ND-23<sup>60114</sup></i> and mt:<i>ND2<sup>del1</sup></i> were susceptible to toxicity from halothane; (ii) in wild-type flies, halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II–V did not result in an AiN phenotype. We conclude that AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I. |
| first_indexed | 2024-03-11T09:43:38Z |
| format | Article |
| id | doaj.art-379c6e5f0f55476ea5dd64942a78dfe1 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:43:38Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-379c6e5f0f55476ea5dd64942a78dfe12023-11-16T16:48:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243184310.3390/ijms24031843Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile AnestheticsLuke A. Borchardt0Amanda R. Scharenbrock1Zachariah P. G. Olufs2David A. Wassarman3Misha Perouansky4Department of Anesthesiology, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Anesthesiology, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Anesthesiology, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USADepartment of Anesthesiology, University of Wisconsin-Madison, Madison, WI 53792, USAThe mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The <i>ND-23<sup>60114</sup></i> and mt:<i>ND2<sup>del1</sup></i> lines of fruit flies (<i>Drosophila melanogaster</i>) that carry mutations in core subunits of Complex I of the mETC replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS. <i>ND-23<sup>60114</sup></i> flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II–V of the mETC cause AiN. We found that (i) <i>ND-23<sup>60114</sup></i> and mt:<i>ND2<sup>del1</sup></i> were susceptible to toxicity from halothane; (ii) in wild-type flies, halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II–V did not result in an AiN phenotype. We conclude that AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.https://www.mdpi.com/1422-0067/24/3/1843mitochondriaelectron transport chainvolatile anestheticsmutationsComplex Itoxicity |
| spellingShingle | Luke A. Borchardt Amanda R. Scharenbrock Zachariah P. G. Olufs David A. Wassarman Misha Perouansky Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile Anesthetics International Journal of Molecular Sciences mitochondria electron transport chain volatile anesthetics mutations Complex I toxicity |
| title | Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile Anesthetics |
| title_full | Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile Anesthetics |
| title_fullStr | Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile Anesthetics |
| title_full_unstemmed | Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile Anesthetics |
| title_short | Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (<i>Drosophila melanogaster</i>) to Ether and Non-Ether Volatile Anesthetics |
| title_sort | mutations in complex i of the mitochondrial electron transport chain sensitize the fruit fly i drosophila melanogaster i to ether and non ether volatile anesthetics |
| topic | mitochondria electron transport chain volatile anesthetics mutations Complex I toxicity |
| url | https://www.mdpi.com/1422-0067/24/3/1843 |
| work_keys_str_mv | AT lukeaborchardt mutationsincomplexiofthemitochondrialelectrontransportchainsensitizethefruitflyidrosophilamelanogasteritoetherandnonethervolatileanesthetics AT amandarscharenbrock mutationsincomplexiofthemitochondrialelectrontransportchainsensitizethefruitflyidrosophilamelanogasteritoetherandnonethervolatileanesthetics AT zachariahpgolufs mutationsincomplexiofthemitochondrialelectrontransportchainsensitizethefruitflyidrosophilamelanogasteritoetherandnonethervolatileanesthetics AT davidawassarman mutationsincomplexiofthemitochondrialelectrontransportchainsensitizethefruitflyidrosophilamelanogasteritoetherandnonethervolatileanesthetics AT mishaperouansky mutationsincomplexiofthemitochondrialelectrontransportchainsensitizethefruitflyidrosophilamelanogasteritoetherandnonethervolatileanesthetics |