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Isoflurane anesthetic hypersensitivity and progressive respiratory depression in a mouse model with isolated mitochondrial complex I deficiency

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Abstract

Background

Children with mitochondrial disorders are frequently anesthetized for a wide range of operations. These disorders may interfere with the response to surgery and anesthesia. We examined anesthetic sensitivity to and respiratory effects of isoflurane in the Ndufs4 knockout (KO) mouse model. These mice exhibit an isolated mitochondrial complex I (CI) deficiency of the respiratory chain, and they also display clinical signs and symptoms resembling those of patients with mitochondrial CI disease.

Methods

We investigated seven Ndufs4−/− knockout (KO), five Ndufs4+/− heterozygous (HZ) and five Ndufs4+/+ wild type (WT) mice between 22 and 25 days and again between 31 and 34 days post-natal. Animals were placed inside an airtight box, breathing spontaneously while isoflurane was administered in increasing concentrations. Minimum alveolar concentration (MAC) was determined with the bracketing study design, using the response to electrical stimulation to the hind paw.

Results

MAC for isoflurane was significantly lower in KO mice than in HZ and WT mice: 0.81 % ± 0.01 vs 1.55 ± 0.05 % and 1.55 ± 0.13 %, respectively, at 22–25 days, and 0.65 ± 0.05 %, 1.65 ± 0.08 % and 1.68 ± 0.08 % at 31–34 days. The KO mice showed severe respiratory depression at lower isoflurane concentrations than the WT and HZ mice.

Conclusion

We observed an increased isoflurane anesthetic sensitivity and severe respiratory depression in the KO mice. The respiratory depression during anesthesia was strongly progressive with age. Since the pathophysiological consequences from complex I deficiency are mainly reflected in the central nervous system and our mouse model involves progressive encephalopathy, further investigation of isoflurane effects on brain mitochondrial function is warranted.

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References

  1. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2:342–52.

    Article  CAS  PubMed  Google Scholar 

  2. Distelmaier F, Koopman WJ, van den Heuvel LP, Rodenburg RJ, Mayatepek E, Willems PH, Smeitink JA. Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain. 2009;132:833–42.

    Article  PubMed  Google Scholar 

  3. Driessen JJ. Neuromuscular and mitochondrial disorders: what is relevant to the anaesthesiologist? Curr Opin Anaesthesiol. 2008;21:350–5.

    Article  PubMed  Google Scholar 

  4. Morgan PG, Hoppel CL, Sedensky MM. Mitochondrial defects and anesthetic sensitivity. Anesthesiology. 2002;96:1268–70.

    Article  PubMed  Google Scholar 

  5. Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat. 2000;15:123–34.

    Article  CAS  PubMed  Google Scholar 

  6. Koene S, Willems PH, Roestenberg P, Koopman WJ, Smeitink JA. Mouse models for nuclear DNA-encoded mitochondrial complex I deficiency. J Inherit Metab Dis. 2011;34:293–307.

    Article  CAS  PubMed  Google Scholar 

  7. Kayser EB, Suthammarak W, Morgan PG, Sedensky MM. Isoflurane selectively inhibits distal mitochondrial complex I in Caenorhabditis elegans. Anesth Analg. 2011;112:1321–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Allen GC. Bispectral index and mitochondrial myopathies. Anesthesiology. 2003;98:282 (Author reply 283).

    Article  PubMed  Google Scholar 

  9. Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008;7:312–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Budde SM, van den Heuvel LP, Smeets RJ, Skladal D, Mayr JA, Boelen C, Petruzzella V, Papa S, Smeitink JA. Clinical heterogeneity in patients with mutations in the NDUFS4 gene of mitochondrial complex I. J Inherit Metab Dis. 2003;26:813–5.

    Article  CAS  PubMed  Google Scholar 

  11. Koene S, Smeitink J. Metabolic manipulators: a well founded strategy to combat mitochondrial dysfunction. J Inherit Metab Dis. 2011;34:315–25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Drexler B, Antkowiak B, Engin E, Rudolph U. Identification and characterization of anesthetic targets by mouse molecular genetics approaches. Can J Anaesth. 2011;58:178–90.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Eger EI 2nd, Raines DE, Shafer SL, Hemmings HC Jr, Sonner JM. Is a new paradigm needed to explain how inhaled anesthetics produce immobility? Anesth Analg. 2008;107:832–48.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Laster MJ, Liu J, Eger EI 2nd, Taheri S. Electrical stimulation as a substitute for the tail clamp in the determination of minimum alveolar concentration. Anesth Analg. 1993;76:1310–2.

    Article  CAS  PubMed  Google Scholar 

  15. Irifune M, Katayama S, Takarada T, Shimizu Y, Endo C, Takata T, Morita K, Dohi T, Sato T, Kawahara M. MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility. Can J Anaesth. 2007;54:998–1005.

    Article  PubMed  Google Scholar 

  16. Sonner JM. Issues in the design and interpretation of minimum alveolar anesthetic concentration (MAC) studies. Anesth Analg. 2002;95:609–14 (Table of contents).

    CAS  PubMed  Google Scholar 

  17. Quasha AL, Eger EI 2nd, Tinker JH. Determination and applications of MAC. Anesthesiology. 1980;53:315–34.

    Article  CAS  PubMed  Google Scholar 

  18. Quintana A, Morgan PG, Kruse SE, Palmiter RD, Sedensky MM. Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I. PLoS One. 2012;7:e42904.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Driessen J, Willems S, Dercksen S, Giele J, van der Staak F, Smeitink J. Anesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects. Paediatr Anaesth. 2007;17:16–21.

    Article  PubMed  Google Scholar 

  20. Quintana A, Zanella S, Koch H, Kruse SE, Lee D, Ramirez JM, Palmiter RD. Fatal breathing dysfunction in a mouse model of Leigh syndrome. J Clin Invest. 2012;122:2359–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Humphrey JA, Sedensky MM, Morgan PG. Understanding anesthesia: making genetic sense of the absence of senses. Hum Mol Genet. 2002;11:1241–9.

    Article  CAS  PubMed  Google Scholar 

  22. Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci. 2008;9:370–86.

    Article  CAS  PubMed  Google Scholar 

  23. Cohen PJ. Effect of anesthetics on mitochondrial function. Anesthesiology. 1973;39:153–64.

    Article  CAS  PubMed  Google Scholar 

  24. Hanley PJ, Ray J, Brandt U, Daut J. Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria. J Physiol. 2002;544:687–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Rottenberg H. Uncoupling of oxidative phosphorylation in rat liver mitochondria by general anesthetics. Proc Natl Acad Sci USA. 1983;80:3313–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Kohro S, Hogan QH, Nakae Y, Yamakage M, Bosnjak ZJ. Anesthetic effects on mitochondrial ATP-sensitive K channel. Anesthesiology. 2001;95:1435-340.

    Article  PubMed  Google Scholar 

  27. Roestenberg P, Manjeri GR, Valsecchi F, Smeitink JA, Willems PH, Koopman WJ. Pharmacological targeting of mitochondrial complex I deficiency: the cellular level and beyond. Mitochondrion. 2012;12:57–65.

    Article  CAS  PubMed  Google Scholar 

  28. Kayser EB, Sedensky MM, Morgan PG. The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans. Mech Ageing Dev. 2004;125:455–64.

    Article  CAS  PubMed  Google Scholar 

  29. Hirata N, Shim YH, Pravdic D, Lohr NL, Pratt PF Jr, Weihrauch D, Kersten JR, Warltier DC, Bosnjak ZJ, Bienengraeber M. Isoflurane differentially modulates mitochondrial reactive oxygen species production via forward versus reverse electron transport flow: implications for preconditioning. Anesthesiology. 2011;115:531–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Zhang J, Zhou W, Qiao H. Bioenergetic homeostasis decides neuroprotection or neurotoxicity induced by volatile anesthetics: a uniform mechanism of dual effects. Med Hypotheses. 2011;77:223–9.

    Article  CAS  PubMed  Google Scholar 

  31. Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, Jevtovic-Todorovic V. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology. 2011;115:992–1002.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Bains R, Moe MC, Larsen GA, Berg-Johnsen J, Vinje ML. Volatile anaesthetics depolarize neural mitochondria by inhibition of the electron transport chain. Acta Anaesthesiol Scand. 2006;50:572–933.

    Article  CAS  PubMed  Google Scholar 

  33. Berg-Johnsen J, Langmoen IA. The effect of isoflurane on excitatory synaptic transmission in the rat hippocampus. Acta Anaesthesiol Scand. 1992;36:350–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful for the help of Francien van de Pol, Ing., and Ilona van den Brink, Ing. (laboratory technicians, Department of Anesthesiology, Radboud University Medical Centre, Nijmegen, the Netherlands) for their technical assistance in performing the animal experiments. Funding was provided solely from institutional and/or departmental sources.

Conflict of interests

J Smeitink is CEO of Khondrion, a spin-off company of the Radboud University Medical Centre, Nijmegen, The Netherlands.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Suzanne Roelofs, Gert Jan Scheffer & Jacques J. Driessen

  2. Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Ganesh R. Manjeri & Peter H. Willems

  3. Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Ganesh R. Manjeri & Jan A. Smeitink

Authors
  1. Suzanne Roelofs
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  2. Ganesh R. Manjeri
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  3. Peter H. Willems
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  4. Gert Jan Scheffer
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  5. Jan A. Smeitink
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  6. Jacques J. Driessen
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Corresponding author

Correspondence to Jacques J. Driessen.

Additional information

S. Roelofs and G. R. Manjeri contributed equally.

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Roelofs, S., Manjeri, G.R., Willems, P.H. et al. Isoflurane anesthetic hypersensitivity and progressive respiratory depression in a mouse model with isolated mitochondrial complex I deficiency. J Anesth 28, 807–814 (2014). https://doi.org/10.1007/s00540-014-1791-0

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  • DOI: https://doi.org/10.1007/s00540-014-1791-0

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