Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I
Open accessAbstract
Anesthetics are in routine use, yet the mechanisms underlying their function are incompletely understood. Studies in vitro demonstrate that both GABA(A) and NMDA receptors are modulated by anesthetics, but whole animal models have not supported the role of these receptors as sole effectors of general anesthesia. Findings in C. elegans and in children reveal that defects in mitochondrial complex I can cause hypersensitivity to volatile anesthetics. Here, we tested a knockout (KO) mouse with reduced complex I function due to inactivation of the Ndufs4 gene, which encodes one of the subunits of complex I. We tested these KO mice with two volatile and two non-volatile anesthetics. KO and wild-type (WT) mice were anesthetized with isoflurane, halothane, propofol or ketamine at post-natal (PN) days 23 to 27, and tested for loss of response to tail clamp (isoflurane and halothane) or loss of righting reflex (propofol and ketamine). KO mice were 2.5 - to 3-fold more sensitive to isoflurane and halothane than WT mice. KO mice were 2-fold more sensitive to propofol but resistant to ketamine. These changes in anesthetic sensitivity are the largest recorded in a mammal.
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Among human mitochondrial respiratory deficits, only complex I disorders are associated with anesthetic hypersensitivity.
“only human patients with complex I disorders, in contrast to those with other mitochondrial respiratory deficits, are affected [93, 94].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [94]
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Archives of Biochemistry and Biophysics
Carter, H. E., Bhattacharyya, P., Weidman, K. R., & Fraenkel, G. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.1981.tb06727.x · Cited by 1,895 · see citing works
Molecular and cellular mechanisms of general anaesthesia
Franks, N. P., & Lieb, W. R. (1994) · Nature · doi:10.1038/367607a0 · Cited by 1,786 · cited 1× · see citing works
“A large number of compelling in vitro studies substantiated these hypotheses, since volatile anesthetics could potentiate inhibitory currents through GABAA channels, or inhibit excitatory transmission in glutamatergic neurons [1,4].”
BackgroundGeneral Anesthesia, Sleep, and Coma
Brown, E. N., Lydic, R., & Schiff, N. D. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0808281 · Cited by 1,346 · cited 1× · see citing works
“Ketamine anesthetic action may be unique, as it has been suggested to involve increased activation and cortical synchronization rather than neuronal inactivation [32].”
BackgroundMechanisms of Actions of Inhaled Anesthetics
Campagna, J. A., Miller, K. W., & Forman, S. A. (2003) · New England Journal of Medicine · doi:10.1056/nejmra021261 · Cited by 805 · cited 8× · see citing works
“Mice with selective loss of Ndufs4 function within the CNS have the same behavioral phenotype as the total KO mice [16].”
BackgroundInfluentialThe NADH:ubiquinone oxidoreductase (complex I) of respiratory chains
Walker, J. E. (1992) · Quarterly Reviews of Biophysics · doi:10.1017/s003358350000425x · Cited by 777 · cited 3× · see citing works
“Complex I also has the potential to generate reactive oxygen species (ROS), which can result in deleterious oxidation events and/or serve as a critical signaling molecule, when not functioning optimally [34].”
BackgroundTREK-1, a K+ channel involved in neuroprotection and general anesthesia
Heurteaux, C., Guy, N., Laigle, C., Blondeau, N., Duprat, F., Mazzuca, M., Lang‐Lazdunski, L., Widmann, C., Zanzouri, M., Romey, G., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600234 · Cited by 534 · cited 2× · see citing works
“To date the largest change in a mammal to a volatile anesthetic is a 40% decrease in sensitivity to halothane in a mouse that lacks a 2-pore potassium channel, TREK-1 [7].”
BackgroundMice with Mitochondrial Complex I Deficiency Develop a Fatal Encephalomyopathy
Kruse, S. E., Watt, W. C., Marcinek, D. J., Kapur, R. P., Schenkman, K. A., & Palmiter, R. D. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.02.004 · Cited by 420 · cited 1× · see citing works
“This subunit is not directly involved in electron transport, but appears to play a role in assembly or stability of the complex [15,16].”
BackgroundSelf-citationMolecular targets underlying general anaesthesia
Franks, N. P. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706441 · Cited by 376 · cited 4× · see citing works
“This sensitivity extended to the non-volatile GABAA facilitator and agonist, propofol [17], but not to the NMDA antagonist, ketamine [18,19].”
BackgroundInfluentialHCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine
Chen, X., Shu, S., & Bayliss, D. A. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3481-08.2009 · Cited by 279 · cited 1× · see citing works
“Inhibition of HCN1 channels has also been recently suggested as a contributing factor in the hypnotic actions of ketamine further indicating that ketamine function is more complicated than usually thought [33].”
BackgroundQuintana, A., Kruse, S. E., Kapur, R. P., Sanz, E., & Palmiter, R. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006214107 · Cited by 269 · cited 9× · see citing works
“Mice with selective loss of Ndufs4 function within the CNS have the same behavioral phenotype as the total KO mice [16].”
BackgroundInfluentialSelf-citationON BIOLOGICAL ASSAYS INVOLVING QUANTAL RESPONSES
Waud, D. R. (1972) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)29374-0 · Cited by 247 · see citing works
Thalamic Microinjection of Nicotine Reverses Sevoflurane-induced Loss of Righting Reflex in the Rat
Alkire, M. T., McReynolds, J. R., Hahn, E. L., & Trivedi, A. N. (2007) · Anesthesiology · doi:10.1097/01.anes.0000270741.33766.24 · Cited by 228 · see citing works
Modulation of NMDA Receptor Function by Ketamine and Magnesium: Part I
Liu, H., Hollmann, M. W., Liu, W., Hönemann, C., & Durieux, M. E. (2001) · Anesthesia & Analgesia · doi:10.1097/00000539-200105000-00019 · Cited by 176 · cited 2× · see citing works
“This sensitivity extended to the non-volatile GABAA facilitator and agonist, propofol [17], but not to the NMDA antagonist, ketamine [18,19].”
BackgroundMitochondrial Expression and Function of GAS-1 in Caenorhabditis elegans
Kayser, E., Morgan, P. G., Hoppel, C. L., & Sedensky, M. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011066200 · Cited by 171 · cited 3× · see citing works
“In both worms and in mammals, movement of electrons through complex I is clearly the most sensitive step within the mitochondrial respiratory chain to disruption by volatile anesthetics [9,38,39] whereas defects in respiratory complexes II, III, and IV do not affect anesthetic sensitivity [12–14,40].”
BackgroundSelf-citationKayser (1999) · doi:10.1097/00000542-199902000-00031 · Cited by 159 · cited 2× · see citing works
“transport chain (83% similar to the human orthologue NDUFS2) [9,10].”
BackgroundSelf-citationMitochondrial defects and anesthetic sensitivity
Morgan, P. G., Hoppel, C. L., & Sedensky, M. M. (2002) · Anesthesiology · doi:10.1097/00000542-200205000-00036 · Cited by 148 · cited 1× · see citing works
“Children with defects in complex I function were hypersensitive to sevoflurane, whereas children with defects in other steps of electron transport within the mitochondrion were not, even though they were indistinguishable in symptoms of mitochondrial disease from the complex I-deficient patients [14].”
BackgroundSelf-citationHollmann, M. W., Liu, H.-T., Hönemann, C., Liu, W., & Durieux, M. E. (2001) · Anesthesia & Analgesia · doi:10.1097/00000539-200105000-00020 · Cited by 147 · cited 2× · see citing works
“This sensitivity extended to the non-volatile GABAA facilitator and agonist, propofol [17], but not to the NMDA antagonist, ketamine [18,19].”
BackgroundNaturally Occurring Variability in Anesthetic Potency Among Inbred Mouse Strains
Sonner, J. M., Gong, D., & Eger, E. I. (2000) · Anesthesia & Analgesia · doi:10.1097/00000539-200009000-00042 · Cited by 144 · cited 3× · see citing works
“The EC50 values of WT mice were similar to that previously reported for the C57Bl/6 strain [20].”
MethodResultInfluentialHartman, P. S., Ishii, N., Kayser, E., Morgan, P. G., & Sedensky, M. M. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(01)00259-7 · Cited by 117 · cited 1× · see citing works
“In both worms and in mammals, movement of electrons through complex I is clearly the most sensitive step within the mitochondrial respiratory chain to disruption by volatile anesthetics [9,38,39] whereas defects in respiratory complexes II, III, and IV do not affect anesthetic sensitivity [12–14,40].”
BackgroundSelf-citationFatal breathing dysfunction in a mouse model of Leigh syndrome
Quintana, A., Zanella, S., Koch, H., Kruse, S. E., Lee, D., Ramirez, J., & Palmiter, R. D. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62923 · Cited by 115 · cited 1× · see citing works
“complex, yet are also affected by the mitochondrial defect [16,45].”
BackgroundSelf-citationMultiple sites of action of volatile anesthetics in Caenorhabditis elegans.
Morgan, P. G., Sedensky, M. M., & Meneely, P. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.8.2965 · Cited by 110 · cited 1× · see citing works
“As we have noted previously, we believe that mitochondrial defects affect a downstream target relative to the leak channels, such that sensitivities to all volatile anesthetics are affected [26].”
BackgroundSelf-citationAlkire, M. T., Asher, C. D., Franciscus, A. M., & Hahn, E. L. (2009) · Anesthesiology · doi:10.1097/aln.0b013e31819c461c · Cited by 105 · cited 1× · see citing works
“Although many authors hypothesize that anesthetics act diffusely throughout the CNS, others attribute their actions to specific brain regions; for example, a portion of the rat brainstem has been dubbed the ‘‘mesopontine tegmental anesthesia area’’ since injection of GABAA receptor agonists into this region produces a…”
BackgroundNaturally Occurring Variability in Anesthetic Potency Among Inbred Mouse Strains
Sonner, J. M., Gong, D., & Eger, E. I. (2000) · Anesthesia & Analgesia · doi:10.1213/00000539-200009000-00042 · Cited by 105 · see citing works
Sonner, J. M., Gong, D., Li, J., Eger, E. I., & Laster, M. J. (1999) · Anesthesia & Analgesia · doi:10.1097/00000539-199910000-00039 · Cited by 100 · see citing works
Sonner, J. M., Gong, D., Li, J., Eger, E. I., & Laster, M. J. (1999) · Anesthesia & Analgesia · doi:10.1213/00000539-199910000-00039 · Cited by 100 · see citing works
Action of halothane upon mitochondrial respiration
Harris, R. A., Munroe, J., Farmer, B. B., Kim, K. C., & Jenkins, P. (1971) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(71)90507-8 · Cited by 88 · cited 1× · see citing works
“In both worms and in mammals, movement of electrons through complex I is clearly the most sensitive step within the mitochondrial respiratory chain to disruption by volatile anesthetics [9,38,39] whereas defects in respiratory complexes II, III, and IV do not affect anesthetic sensitivity [12–14,40].”
BackgroundComplex I Function Is Defective in Complex IV-deficient Caenorhabditis elegans
Suthammarak, W., Yang, Y.-Y., Morgan, P. G., & Sedensky, M. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805733200 · Cited by 86 · cited 1× · see citing works
“elegans to volatile anesthetics, even though animals carrying these mutations share many other phenotypes with gas-1 [12,13].”
BackgroundSelf-citationSonner, J. M., Werner, D. F., Elsen, F. P., Xing, Y., Liao, M., Harris, R. A., Harrison, N. L., Fanselow, M. S., Eger, E. I., & Homanics, G. E. (2007) · Anesthesiology · doi:10.1097/00000542-200701000-00019 · Cited by 82 · see citing works
Mutations Conferring New Patterns of Sensitivity to Volatile Anesthetics in Caenorhabditis elegans
Morgan, P. G., & Sedensky, M. M. (1994) · Anesthesiology · doi:10.1097/00000542-199410000-00016 · Cited by 70 · cited 2× · see citing works
“elegans, we identified a mutation, gas-1(fc21), that caused a very significant hypersensitivity to all volatile anesthetics [8].”
BackgroundMethodSelf-citationGeneral Anesthetics and Molecular Mechanisms of Unconsciousness
Forman, S. A., & Chin, V. A. (2008) · International Anesthesiology Clinics · doi:10.1097/aia.0b013e3181755da5 · Cited by 63 · cited 2× · see citing works
“However, for a number of different possible reasons, whole animal models have not supported the hypothesis that NMDA and GABAA receptors mediate all aspects of general anesthesia produced by volatile anesthetics [5,6].”
BackgroundResultMutations in Mitochondrial Complex III Uniquely Affect Complex I in Caenorhabditis elegans
Suthammarak, W., Morgan, P. G., & Sedensky, M. M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159608 · Cited by 54 · cited 1× · see citing works
“elegans to volatile anesthetics, even though animals carrying these mutations share many other phenotypes with gas-1 [12,13].”
BackgroundSelf-citationInhalational anesthetic-binding proteins in rat neuronal membranes
Xi, J., Liu, R., Asbury, G. R., Eckenhoff, M. F., & Eckenhoff, R. G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313864200 · Cited by 54 · cited 2× · see citing works
“elegans and children) with complex I deficiency is due to the direct actions of these compounds on defective complex I [37], Figure 2.”
BackgroundPetrenko, A. B., Yamakura, T., Fujiwara, N., Askalany, A. R., Baba, H., & Sakimura, K. (2004) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000131729.54986.30 · Cited by 53 · see citing works
Liao, M. Y., Sonner, J. M., Jurd, R., Rudolph, U., Borghese, C. M., Harris, R. A., Laster, M. J., & Eger, E. I. (2005) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000154196.86587.35 · Cited by 49 · see citing works
Gamma-Aminobutyric AcidA Receptors Do Not Mediate the Immobility Produced by Isoflurane
Zhang, Y., Sonner, J. M., Eger, E. I., Stabernack, C. R., Laster, M. J., Raines, D. E., & Harris, R. A. (2004) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000118108.64886.42 · Cited by 48 · cited 1× · see citing works
“However, when putative targets that were thought to be resistant to anesthetic action were tested in genetically engineered mice, the responses to volatile anesthetics were insufficiently affected [5,27–29].”
BackgroundMechanisms of Actions of Inhaled Anesthetics
Seutin, V. (2003) · New England Journal of Medicine · doi:10.1056/nejm200308283490917 · Cited by 47 · see citing works
Abulafia, R., Zalkind, V. I., & Devor, M. G. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1357-08.2009 · Cited by 47 · see citing works
Jinks, S. L., Bravo, M., & Hayes, S. G. (2008) · Anesthesiology · doi:10.1097/aln.0b013e3181730297 · Cited by 46 · see citing works
Kilbride, S. M., Telford, J. E., Tipton, K. F., & Davey, G. P. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05441.x · Cited by 40 · cited 1× · see citing works
“Most notable is the finding that presynaptic function in glutamatergic neurons is extremely sensitive to complex I function [36].”
BackgroundEger, E. I., Liao, M. Y., Laster, M. J., Won, A., Popovich, J., Raines, D. E., Solt, K., Dutton, R. C., Cobos, F. V., & Sonner, J. M. (2006) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000219019.91281.51 · Cited by 40 · see citing works
Werner, D. F., Swihart, A., Rau, V., Jia, F., Borghese, C. M., McCracken, M. L., Iyer, S. V., Fanselow, M. S., Oh, I., Sonner, J. M., et al. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.170431 · Cited by 36 · see citing works
Subcomplex Iλ Specifically Controls Integrated Mitochondrial Functions in Caenorhabditis elegans
Falk, M. J., Rosenjack, J. R., Polyák, E., Suthammarak, W., Chen, Z., Morgan, P. G., & Sedensky, M. M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006607 · Cited by 35 · cited 1× · see citing works
“RNAi inhibition of most complex I subunits also increased volatile anesthetic sensitivity [11].”
BackgroundSelf-citationUnderstanding anesthesia: making genetic sense of the absence of senses
Humphrey, J. A. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.10.1241 · Cited by 34 · cited 1× · see citing works
“there is little agreement as to how this phenomenon occurs [1–3].”
BackgroundThe cortical energy needed for conscious perception
Schölvinck, M. L., Howarth, C., & Attwell, D. (2008) · NeuroImage · doi:10.1016/j.neuroimage.2008.01.032 · Cited by 33 · cited 2× · see citing works
“The mitochondrial TCA cycle generates glutamate and the precursors of GABA and, while a small part of total energy requirements, the glutamate/glutamine cycle between neurons and glia is dependent on glycolysis and oxidative phosphorylation [35].”
BackgroundOptical Reversal of Halothane-Induced Immobility in C. elegans
Singaram, V. K., Somerlot, B. H., Falk, S. A., Falk, M. J., Sedensky, M. M., & Morgan, P. G. (2011) · Current Biology · doi:10.1016/j.cub.2011.10.042 · Cited by 22 · cited 1× · see citing works
“elegans [25].”
Self-citationInhaled Anesthetic Potency in Aged Alzheimer Mice
Bianchi, S. L., Caltagarone, B. M., LaFerla, F. M., Eckenhoff, R. G., & Kelz, M. B. (2010) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e3181b5a292 · Cited by 22 · cited 1× · see citing works
“[30,31].”
Kubo, K., Nishikawa, K., Hardy-Yamada, M., Ishizeki, J., Yanagawa, Y., & Saito, S. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.151456 · Cited by 20 · see citing works
Eckel, B. A., Richtsfeld, M., Starker, L., & Blobner, M. (2010) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e3181b76383 · Cited by 19 · cited 1× · see citing works
“[30,31].”
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- [45]Quintana A, Zanella S, Koch H, Kruse SE, Lee D, et al (2012) Fatal breathing dysfunction in a mouse model of Leigh Syndrome. Journal of Clinical Investigation In Press. PMC3387817 22653057
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OXPHOS mutations and neurodegeneration
Koopman, W. J. H., Distelmaier, F., Smeitink, J. A. M., & Willems, P. H. G. M. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.300 · Cited by 254 · see citing works
“For example, mice with fatal encephalomyopathy due to mitochondrial dysfunction were 2.5-to 3-fold more sensitive to the volatile anaesthetics isoflurane and halothane than wild-type (wt) mice (Quintana et al , 2012).”
InfluentialOpa1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models
Civiletto, G., Varanita, T., Cerutti, R., Gorletta, T., Barbaro, S., Marchet, S., Lamperti, C., Viscomi, C., Scorrano, L., & Zeviani, M. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.04.016 · Cited by 216 · see citing works
“…the Opa1tg mouse with (i) a constitutive knockout mouse for Ndufs4 (Ndufs4–/–) (Karamanlidis et al., 2013; Kruse et al., 2008; Quintana et al., 2010; Quintana et al., 2012), encoding the 18 kDa subunit of complex I (cI), and (ii) a skeletal-muscle-specific knockout mouse for Cox15, in which the…”
BackgroundMethodAnesthetic considerations in patients with mitochondrial defects
Niezgoda, J., & Morgan, P. G. (2013) · Pediatric Anesthesia · doi:10.1111/pan.12158 · Cited by 165 · see citing works
Self-citationHypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome
Ferrari, M., Jain, I. H., Goldberger, O., Rezoagli, E., Thoonen, R., Cheng, K., Sosnovik, D. E., Scherrer‐Crosbie, M., Mootha, V. K., & Zapol, W. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1621511114 · Cited by 165 · see citing works
“3% isoflurane owing to their increased sensitivity to anesthetic agents (17).”
BackgroundThe Biology of General Anesthesia from Paramecium to Primate
Kelz, M. B., & Mashour, G. A. (2019) · Current Biology · doi:10.1016/j.cub.2019.09.071 · Cited by 151 · see citing works
Anesthesia and the neurobiology of consciousness
Mashour, G. A. (2024) · Neuron · doi:10.1016/j.neuron.2024.03.002 · Cited by 127 · see citing works
Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention
van de Wal, M. A. E., Adjobo-Hermans, M. J. W., Keijer, J., Schirris, T. J. J., Homberg, J. R., Wieckowski, M. R., Grefte, S., van Schothorst, E. M., van Karnebeek, C., Quintana, A., et al. (2021) · Brain · doi:10.1093/brain/awab426 · Cited by 89 · see citing works
“The increased volatile anaesthetic sensitivity of Ndufs4-WB mice may be due to volatile anaesthetic-induced CI inhibition(89,90) and the key role played by CI function in maintaining neuronal activity.(84) These findings suggest that excitatory glutamatergic transmission is the major contributor to the volatile anaest…”
Self-citationIsoflurane disrupts excitatory neurotransmitter dynamics via inhibition of mitochondrial complex I
Zimin, P. I., Woods, C. B., Kayser, E. B., Ramirez, J. M., Morgan, P. G., & Sedensky, M. M. (2018) · British Journal of Anaesthesia · doi:10.1016/j.bja.2018.01.036 · Cited by 76 · see citing works
Self-citationVenâncio, C. A. S., Félix, L. M., Almeida, V., Coutinho, J., Antunes, L. M., Peixoto, F., & Summavielle, T. (2014) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000000539 · Cited by 67 · see citing works
Isoflurane inhibition of endocytosis is an anesthetic mechanism of action
Jung, S., Zimin, P. I., Woods, C. B., Kayser, E., Haddad, D., Reczek, C. R., Nakamura, K., Ramirez, J., Sedensky, M. M., & Morgan, P. G. (2022) · Current Biology · doi:10.1016/j.cub.2022.05.037 · Cited by 62 · see citing works
Self-citationChouchani, E. T., Methner, C., Buonincontri, G., Hu, C.-H., Logan, A., Sawiak, S. J., Murphy, M. P., & Krieg, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094157 · Cited by 48 · see citing works
“These mice exhibit increasing ataxia and failure to thrive early in life, and typically die by post-natal day 55 [19,20].”
Olufs, Z. P. G., Loewen, C. A., Ganetzky, B., Wassarman, D. A., & Perouansky, M. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-20720-7 · Cited by 45 · see citing works
Myopathy reversion in mice after restauration of mitochondrial complex I
Pereira, C. V., Peralta, S., Arguello, T., Bacman, S. R., Díaz, F., & Moraes, C. T. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201910674 · Cited by 43 · see citing works
“…CI subunits have been reported, including NADH-ubiquinone oxidoreductase subunit S4 ( Ndufs4 ) (Kruse et al , 2008; Ingraham et al , 2009; Quintana et al , 2010, 2012; Chen et al , 2017), S6 ( Ndufs6 ) (Ke et al , 2012), and NADH-ubiquinone oxidoreductase 1 alpha subcomplex subunit 5 (…”
Zimin, P. I., Woods, C. B., Quintana, A., Ramirez, J., Morgan, P. G., & Sedensky, M. M. (2016) · Current Biology · doi:10.1016/j.cub.2016.06.020 · Cited by 40 · see citing works
Self-citationRegion-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain
Kayser, E., Sedensky, M. M., & Morgan, P. G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148219 · Cited by 37 · see citing works
“The primary defect in complex I causes a progressive encephalomyopathy leading to death within 2 months and mirroring many aspects of human LS [8, 9] [14, 15], including focal damage to the CNS.”
BackgroundSelf-citationMitochondrial Function in Astrocytes Is Essential for Normal Emergence from Anesthesia in Mice
Ramadasan-Nair, R., Hui, J., Itsara, L. S., Morgan, P. G., & Sedensky, M. M. (2019) · Anesthesiology · doi:10.1097/aln.0000000000002528 · Cited by 36 · see citing works
Self-citationDeal, S. L., & Yamamoto, S. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2018.00700 · Cited by 34 · see citing works
“(2015, 2017) found that the mice with defects in the ETC Complex I (Ndufs4-/-, Kruse et al., 2008; Quintana et al., 2012) as well as in a mouse neuron-astrocyte cell coculture system with ROS induction via rotenone exhibit glial (astrocyte, microglia) lipid droplet accumulation.”
BackgroundEffect of Anesthesia Gases on the Oxygen Reduction Reaction
Gupta, A., Sang, Y., Fontanesi, C., Turin, L., & Naaman, R. (2023) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.2c03753 · Cited by 31 · see citing works
Anesthetic Hypersensitivity in a Case-Controlled Series of Patients With Mitochondrial Disease
Hsieh, V. C., Niezgoda, J., Sedensky, M. M., Hoppel, C. L., & Morgan, P. G. (2021) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000005430 · Cited by 31 · see citing works
Self-citationHypoxia ameliorates brain hyperoxia and NAD+ deficiency in a murine model of Leigh syndrome
Grange, R. M. H., Sharma, R., Shah, H., Reinstadler, B. M., Goldberger, O., Cooper, M. K., Nakagawa, A., Miyazaki, Y., Hindle, A. G., Batten, A. J., et al. (2021) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2021.03.005 · Cited by 30 · see citing works
“In our study, anesthesia depth may have differed between the Ndufs4−/− and WT mice because Ndufs4−/− mice are known to have a slight insensitivity to ketamine [14].”
BackgroundMethodMitochondrial Function and Anesthetic Sensitivity in the Mouse Spinal Cord
Woods, C. B., Spencer, K. A., Jung, S., Worstman, H. M., Ramirez, J., Morgan, P. G., & Sedensky, M. M. (2021) · Anesthesiology · doi:10.1097/aln.0000000000003794 · Cited by 29 · see citing works
“In response to a nondamaging tail clamp, the MAC for Ndufs4(KO) mice is approximately one third that of controls for both isoflurane and halothane.(17) This behavior led us to investigate the action of isoflurane on the spinal cord of this model animal.”
BackgroundMethodInfluentialSelf-citationChen, Y., & Zhang, J. (2021) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2021.648860 · Cited by 27 · see citing works
“As a result, transgenic mice lacking a subunit of mitochondrial complex I Ndufs4 are extremely hypersensitive to volatile anesthetics and propofol (Quintana et al., 2012).”
BackgroundCollapse of Global Neuronal States in Caenorhabditis elegans under Isoflurane Anesthesia
Awal, M. R., Wirak, G. S., Gabel, C. V., & Connor, C. W. (2020) · Anesthesiology · doi:10.1097/aln.0000000000003304 · Cited by 25 · see citing works
Mechanisms Revealed Through General Anesthetic Photolabeling
Weiser, B. P., Woll, K. A., Dailey, W. P., & Eckenhoff, R. G. (2013) · Current anesthesiology reports · doi:10.1007/s40140-013-0040-7 · Cited by 25 · see citing works
“General anesthetics affect mitochondrial respiration [39, 40], and genetic modulation of respiratory complexes alters mammalian sensitivity to anesthetics, including injectable drugs [41].”
BackgroundAwal, M. R., Austin, D., Florman, J., Alkema, M., Gabel, C. V., & Connor, C. W. (2018) · Anesthesiology · doi:10.1097/aln.0000000000002342 · Cited by 22 · see citing works
Regional knockdown of NDUFS4 implicates a thalamocortical circuit mediating anesthetic sensitivity
Ramadasan-Nair, R., Hui, J., Zimin, P. I., Itsara, L. S., Morgan, P. G., & Sedensky, M. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0188087 · Cited by 22 · see citing works
Self-citation2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice
Wang, H., Xu, Z., Wu, A., Dong, Y., Zhang, Y., Yue, Y., & Xie, Z. (2014) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000000520 · Cited by 21 · see citing works
Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs
Dwyer, D. S., Aamodt, E. J., Cohen, B. M., & Buttner, E. A. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00177 · Cited by 19 · see citing works
Ip, C.-T., de Bardeci, M., Kronenberg, G., Pinborg, L. H., Seifritz, E., Brunovský, M., & Olbrich, S. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02761-x · Cited by 18 · see citing works
Feeding difficulties, a key feature of the Drosophila NDUFS4 mitochondrial disease model
Foriel, S., Beyrath, J., Eidhof, I., Rodenburg, R. J., Schenck, A., & Smeitink, J. A. M. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.032482 · Cited by 18 · see citing works
“Aside from these two models, one can find mentioned in the literature food provided ad libitum to facilitate the nutrition of weak animals, such as Ndufs4 − / − mice (Alam et al., 2015; Choi et al., 2017; Karamanlidis et al., 2013; Kruse et al., 2008; Quintana et al., 2010, 2012).”
Effects of a Mitochondrial Genetic Variant on Sevoflurane Hypersensitivity
Sanz‐Pons, J., Aladrén-Herrer, C., Ortigoza‐Escobar, J. D., López‐Gallardo, E., Martín‐Navarro, A., Lanz-Martínez, C. A., Camacho-Medina, Y. A., Fernández-González, I., Urbano, J., Montoya, J., et al. (2026) · Anesthesiology · doi:10.1097/aln.0000000000006029 · Cited by 15 · see citing works
Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics
Stokes, J., Freed, A., Bornstein, R., Su, K. N., Snell, J., Pan, A., Sun, G. X., Park, K. Y., Jung, S., Worstman, H. M., et al. (2021) · eLife · doi:10.7554/elife.65400 · Cited by 16 · see citing works
Self-citationAnaesthetics disrupt complex I-linked respiration and reverse the ATP synthase
Rodríguez, E., Peng, B., & Lane, N. J. (2024) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2024.149511 · Cited by 14 · see citing works
Ktena, Y. P., Ramstad, T., Baker, E. H., Sloan, J. L., Mannes, A. J., Manoli, I., & Venditti, C. P. (2015) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-015-9816-x · Cited by 14 · see citing works
Modelling biochemical features of mitochondrial neuropathology
Bird, M., Thorburn, D. R., & Frazier, A. E. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.10.017 · Cited by 14 · see citing works
Manjeri, G. R., Rodenburg, R. J., Blanchet, L., Roelofs, S., Nijtmans, L. G. J., Smeitink, J. A. M., Driessen, J. J., Koopman, W. J. H., & Willems, P. H. G. M. (2015) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-015-9885-x · Cited by 12 · see citing works
Finley, J. (2019) · Medical Hypotheses · doi:10.1016/j.mehy.2019.01.014 · Cited by 10 · see citing works
Perouansky, M. A., Johnson-Schlitz, D. M., Sedensky, M. M., & Morgan, P. G. (2023) · Experimental Biology and Medicine · doi:10.1177/15353702231165025 · Cited by 10 · see citing works
Self-citationCarspecken, C. W., Chanprasert, S., Kalume, F. K., Sedensky, M. M., & Morgan, P. G. (2018) · Anesthesiology · doi:10.1097/aln.0000000000002368 · Cited by 10 · see citing works
Self-citationVolatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome
Spencer, K. A., Mulholland, M. T., Snell, J., Howe, M., James, K., Hanaford, A. R., Morgan, P. G., Sedensky, M. M., & Johnson, S. C. (2023) · British Journal of Anaesthesia · doi:10.1016/j.bja.2023.08.009 · Cited by 9 · see citing works
Self-citationBorchardt, L. A., Scharenbrock, A. R., Olufs, Z. P. G., Wassarman, D. A., & Perouansky, M. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031843 · Cited by 8 · see citing works
“[4] Animal models of LS reproduce its key pathological characteristics including hypersensitivity to behavioral effects of VGAs that can be used for a better understanding of risk factors for AiN .”
InfluentialRoelofs, S., Manjeri, G. R., Willems, P. H. G. M., Scheffer, G. J., Smeitink, J. A. M., & Driessen, J. J. (2014) · Journal of Anesthesia · doi:10.1007/s00540-014-1791-0 · Cited by 8 · see citing works
Voss, L. J., & SLEIGH, J. W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134703 · Cited by 7 · see citing works
Frailty and intraoperative hypotension: is the risk significant and modifiable?
Schnetz, M. P., Zakaria, L., Ahuja, S., & Khanna, A. K. (2025) · British Journal of Anaesthesia · doi:10.1016/j.bja.2025.05.002 · Cited by 7 · see citing works
Gong, C., Zhang, D., Ou, W., Ou, M., Liang, P., Liao, D., Zhang, W., Zhu, T., Liu, J., & Zhou, C. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.583542 · Cited by 6 · see citing works
“Although no difference was found in the activity of complex I between S group and R group, the effects of complex I on anesthetics sensitivity should not be ignored because defects of complex I can increase anesthetics sensitivity (Quintana et al., 2012).”
BackgroundAnesthesia: Synaptic power failure
van Swinderen, B., & Kelz, M. B. (2022) · Current Biology · doi:10.1016/j.cub.2022.06.043 · Cited by 6 · see citing works
Wake Up, Neurons! Astrocytes Calling
Perouansky, M. A., MacIver, M. B., & Pearce, R. A. (2019) · Anesthesiology · doi:10.1097/aln.0000000000002589 · Cited by 6 · see citing works
Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome
Spencer, K. A., Howe, M., Mulholland, M. T., Truong, V. B., Liao, R. W., Chen, Y., Setha, M., Snell, J. C., Hanaford, A. R., James, K., et al. (2024) · Pediatric Anesthesia · doi:10.1111/pan.14855 · Cited by 5 · see citing works
Self-citationOlufs, Z. P. G., Wassarman, D. A., & Perouansky, M. A. (2023) · Anesthesiology · doi:10.1097/aln.0000000000004874 · Cited by 5 · see citing works
“7,8 A model of Leigh syndrome in the fruit fly ( Drosophila melanogaster ) is caused by a hypomorphic mutation in ND23 ( ND23 60114 ), the orthologue of mammalian Ndufs8 .”
BackgroundTREK-1 and TREK-2 Knockout Mice Are Not Resistant to Halothane or Isoflurane
Spencer, K. A., Woods, C. B., Worstman, H. M., Johnson, S. C., Ramirez, J., Morgan, P. G., & Sedensky, M. M. (2023) · Anesthesiology · doi:10.1097/aln.0000000000004577 · Cited by 5 · see citing works
“In Ndufs4 in pilot studies, we observed that this battery of two long repeated exposures of one individual animal introduced confounding morbidity and mortality, something not observed in our previous paradigm of a single anesthetic exposure for one endpoint in one individual.(22,33) In addition, the rare births of th…”
BackgroundSelf-citationTargeted Mitochondrial Genome Elimination
Bacman, S. R., Pereira, C. V., & Moraes, C. T. (2018) · Springer eBooks · doi:10.1007/978-3-319-73344-9_24 · Cited by 4 · see citing works
Hadjipavlou, G., Warnaby, C. E., FitzGerald, J. J., & SLEIGH, J. W. (2021) · British Journal of Anaesthesia · doi:10.1016/j.bja.2021.01.034 · Cited by 4 · see citing works
The Expanding Genetic Toolkit for Exploring Mechanisms of General Anesthesia
Forman, S. A. (2013) · Anesthesiology · doi:10.1097/aln.0b013e318287b7e4 · Cited by 4 · see citing works
Jung, S., Ramirez, J., Sedensky, M. M., & Morgan, P. G. (2025) · Anesthesiology · doi:10.1097/aln.0000000000005910 · Cited by 3 · see citing works
Self-citationZhang, H., Fang, P., Qiu, G., Wang, D., Zhang, J., Yang, Z., Liu, H., Shen, Q., & Liu, X. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70453 · Cited by 3 · see citing works
“Previous studies have shown that disruption of mitochondrial complex I results in hypersensitivity to volatile anesthetic agents in humans, nematodes, and mice [32–34].”
The Blood–Brain Barrier Is Unaffected in the Ndufs4−/− Mouse Model of Leigh Syndrome
Reynaud-Dulaurier, R., Clément, R., Yjjou, S., Cresson, C., Saoudi, Y., Faideau, M., & Decressac, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094828 · Cited by 3 · see citing works
“One-month-old Ndufs4 -/- mice, aged-matched littermates and 18-month-old Ndufs4 +/+ mice were anesthetized with isoflurane (2% for control mice and 0.5% for Ndufs4 − / − mice due to their hypersensitivity to volatile anesthetics) [41,42].”
MethodInfluentialSystematized Serendipity: Fishing Expeditions for Anesthetic Drugs and Targets
Crowder, C. M., & Forman, S. A. (2024) · Anesthesiology · doi:10.1097/aln.0000000000005153 · Cited by 3 · see citing works
Effects of the Quinone Analog Ubiquinone-5 on Murine Mitochondria and Hypnosis
Somnay, Y. R., Wang, A., Lim, H., Griffiths, K. K., Zandkarimi, F., Chen, K., Yang, G., Wasilczuk, A. Z., Kelz, M. B., Larr, D., et al. (2025) · Anesthesiology · doi:10.1097/aln.0000000000005549 · Cited by 3 · see citing works
A Guide to Understanding “State-of-the-Art” Basic Research Techniques in Anesthesiology
Obal, D., Wu, S., McKinstry-Wu, A. R., & Tawfik, V. L. (2020) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000004801 · Cited by 3 · see citing works
Can age-related mitochondrial dysfunction affect volatile anesthetic potency?
Yamakage, M. (2014) · Journal of Anesthesia · doi:10.1007/s00540-014-1907-6 · Cited by 3 · see citing works
“[13] recently reported almost identical data, with higher anesthetic sensitivity in Ndufs4 knockout mice than in wild-type mice.”
ResultPerouansky, M. A., & SLEIGH, J. W. (2021) · Anesthesiology · doi:10.1097/aln.0000000000003761 · Cited by 3 · see citing works
Yu, X., Qiu, Z., Nashrah, F., Garg, A., Chang, A., Schieber, A., Wu, S., Magavi, V., & Wiest, M. C. (2026) · Experimental Cell Research · doi:10.1016/j.yexcr.2026.114938 · Cited by 3 · see citing works
The Physical Basis of FeelingsPreprint
Lane, N. J., & Rodríguez, E. (2025) · doi:10.31234/osf.io/pnqw9_v1 · Cited by 2 · see citing works
Mandel, A., SooHoo, J. F., Deitelzweig, C., Patkar, I., Han, D., Farag, M., & McKinstry-Wu, A. R. (2026) · British Journal of Anaesthesia · doi:10.1016/j.bja.2026.02.045 · Cited by 1 · see citing works
Bioblasts, anaesthesia, and power failure: rein in the excitement
Perouansky, M. A., & Hemmings, H. C. (2018) · British Journal of Anaesthesia · doi:10.1016/j.bja.2018.02.018 · Cited by 1 · see citing works
Scharenbrock, A. R., Borchardt, L. A., Olufs, Z. P. G., Wassarman, D. A., & Perouansky, M. A. (2024) · Pediatric Anesthesia · doi:10.1111/pan.14999 · Cited by 1 · see citing works
“Complex I mutations presenting with behavioral hypersensitivity are associated with AiN in fly and other animal models of LS. 3,6,8,22 However, hypersensitivity and toxicity have been reported only from models harboring mutations of the matrix, oxidoreductase arm of Complex I that catalyzes the…”
Steele, L. M., & Morgan, P. G. (2018) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2018.01.005 · Cited by 1 · see citing works
Self-citationThe Power of Unbiased Genetic Screens to Discover Novel Anesthetic Targets
Morgan, P. G., & Sedensky, M. M. (2013) · Anesthesiology · doi:10.1097/aln.0b013e3182a4465c · Cited by 1 · see citing works
Self-citationAnesthesia Mechanisms: A Patchwork Quilt rather than a Wet Blanket?
Voss, L. J., & SLEIGH, J. W. (2021) · Anesthesiology · doi:10.1097/aln.0000000000003879 · Cited by 1 · see citing works
Eckenhoff, R. G., & Morgan, P. G. (2015) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000000534
Self-citationMacIver, M. B. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734986474.793555990
Hudson, A. E. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.733633723.793552642
Mulkey, D. K., & Cleary, C. M. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734986474.793573875
Forman, S. A. (2013) · Anesthesiology · doi:10.1097/aln.0b013e3182a46271
Hsieh, V. C., & Morgan, P. G. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-34125-7.00049-8
Self-citationWoods, C. B., Predoi, B., Howe, M., Reczek, C. R., Kayser, E., Ramirez, J., Morgan, P. G., & Sedensky, M. M. (2023) · Anesthesiology · doi:10.1097/aln.0000000000004891
“14,15 19 Ndufs4 carries a critical mutation in complex I 20 that alters anesthetic sensitivity in the mouse 16 and also sensitizes TREK currents to volatile anesthetics.”
BackgroundInfluentialSelf-citationYou Don’t Always Get What You Want!
Morgan, P. G., & Sedensky, M. M. (2024) · Anesthesiology · doi:10.1097/aln.0000000000005143
Self-citationRekuvienė, E., Ivanovienė, L., Borutaitė, V., & Morkūnienė, R. (2024) · Biomedicines · doi:10.3390/biomedicines12102342
“Other authors have shown that knockout mice with deficient mitochondrial complex I function showed increased resistance to ketamine [55].”
BackgroundDubey, P., Datta, R., Eckenhoff, R. G., & Bedell, V. M. (2026) · PLoS ONE · doi:10.1371/journal.pone.0316959
“When considering neuron energy homeostasis, previous studies within mice on the loss of a critical protein in the electron transport complex 1 (ndufs4), caused an increase in sensitivity to propofol and a resistance to ketamine [30].”
Ip, C.-T., de Bardeci, M., Kronenberg, G., Brunovský, M., & Olbrich, S. (2025) · Neuromethods · doi:10.1007/978-1-0716-4603-8_13
Sedative-hypnotic properties and mitochondrial effects of coenzyme Q2 in mice
Lim, H., Lu, R., Patel, S. N., Zinn, S., García, P. S., & Levy, R. J. (2025) · Current Molecular Pharmacology · doi:10.1016/j.cmp.2025.12.001
“Loss-of-function studies linking genetic mutations of Complex I with anesthetic hypersensitivity in various species across evolutionary biology have elucidated a role that mitochondria play in mediating the anesthetic response [5,6,9,10].”
Chang, A. S., Mazuera, L., Connor, C. W., & Gabel, C. V. (2026) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2026.1795887
Perianesthetic Complications in Genetic Mitochondrial Disease: A Review of Case Reports
Johnson, B. M., & Johnson, S. C. (2026) · Pediatric Anesthesia · doi:10.1002/pan.70257
Hernández-Castillo, Y., & Ruiz-Pesini, E. (2026) · Revista Española de Anestesiología y Reanimación · doi:10.1016/j.redar.2026.502197
Mitochondrial hypersensitivity to sevoflurane: Pharmacogenetics and the role of scientific societies
Hernández-Castillo, Y., & Ruiz-Pesini, E. (2026) · Revista Española de Anestesiología y Reanimación (English Edition) · doi:10.1016/j.redare.2026.502197
- Authors
- Quintana, A., Morgan, P. G., Kruse, S. E., Palmiter, R. D., & Sedensky, M. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- Corresponding author
- Morgan, Philip G.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-08-17
- Volume
- 7
- Issue
- 8
- Pages
- e42904
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3422219
- OpenAlex
- W2058463420
- Cited by
- 86
- References
- 46
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 2 · 2021: 9 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 1
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- Mitochondrial Research Guild
- Ministerio de Ciencia e Innovación
- National Institutes of Health
- National Institute of General Medical Sciences (GM58881, R01GM058881)
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- NDUFS4, mitochondrial complex I, anesthetic sensitivity, general anesthesia, isoflurane, halothane, propofol, ketamine, knockout mice, mitochondrial dysfunction, volatile anesthetics, righting reflex
- MeSH terms
- Animals, Halothane, Isoflurane, Ketamine, Pain Measurement, Propofol, Mice, Knockout, Anesthetics, General, Electron Transport Complex I, Mice, Reflex, Righting
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