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• W2018676384 abstract "Despite the widespread clinical use of volatile anesthetics, their mechanisms of action remain unknown [1Morgan P.G. Sedensky M. Meneely P.M. Multiple sites of action of volatile anesthetics in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 1990; 87: 2965-2969Crossref PubMed Scopus (93) Google Scholar, 2Humphrey J.A. Sedensky M.M. Morgan P.G. Understanding anesthesia: Making genetic sense of the absence of senses.Hum. Mol. Genet. 2002; 11: 1241-1249Crossref PubMed Scopus (26) Google Scholar, 3Gomez R.S. Guatimosim C. Mechanism of action of volatile anesthetics: Involvement of intracellular calcium signaling.Curr. Drug Targets CNS Neurol. Disord. 2003; 2: 123-129Crossref PubMed Scopus (17) Google Scholar, 4Hulme N.A. Krantz Jr., J.C. Anesthesia. XLVIII. Anesthetic potency and the uncoupling of oxidative phosphorylation.Anesthesiology. 1956; 17: 43-46Crossref PubMed Scopus (2) Google Scholar, 5Miro O. Barrientos A. Alonso J.R. Casademont J. Jarreta D. Urbano-Marquez A. Cardellach F. Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle.Eur. J. Clin. Pharmacol. 1999; 55: 35-41Crossref PubMed Scopus (48) Google Scholar, 6Hanley P.J. Ray J. Brandt U. Daut J. Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria.J. Physiol. 2002; 544: 687-693Crossref PubMed Scopus (159) Google Scholar]. An unbiased genetic screen in the nematode C. elegans for animals with altered volatile anesthetic sensitivity identified a mutant in a nuclear-encoded subunit of mitochondrial complex I [7Kayser E.B. Morgan P.G. Hoppel C.L. Sedensky M.M. Mitochondrial expression and function of GAS-1 in Caenorhabditis elegans.J. Biol. Chem. 2001; 276: 20551-20558Crossref PubMed Scopus (131) Google Scholar, 8Morgan P.G. Sedensky M.M. Mutations conferring new patterns of sensitivity to volatile anesthetics in Caenorhabditis elegans.Anesthesiology. 1994; 81: 888-898Crossref PubMed Scopus (56) Google Scholar]. This raised the question of whether mitochondrial dysfunction might be the primary mechanism by which volatile anesthetics act, rather than an untoward secondary effect [9Kayser E.B. Morgan P.G. Sedensky M.M. Mitochondrial complex I function affects halothane sensitivity in Caenorhabditis elegans.Anesthesiology. 2004; 101: 365-372Crossref PubMed Scopus (27) Google Scholar, 10Kayser E.B. Sedensky M.M. Morgan P.G. The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans.Mech. Ageing Dev. 2004; 125: 455-464Crossref PubMed Scopus (85) Google Scholar]. We report here analysis of additional C. elegans mutations in orthologs of human genes that contribute to the formation of complex I, complex II, complex III, and coenzyme Q [11Feng J. Bussiere F. Hekimi S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans.Dev. Cell. 2001; 1: 633-644Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 12Grad L.I. Lemire B.D. Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis.Hum. Mol. Genet. 2004; 13: 303-314Crossref PubMed Scopus (96) Google Scholar, 13Ishii N. Fujii M. Hartman P.S. Tsuda M. Yasuda K. Senoo-Matsuda N. Yanase S. Ayusawa D. Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes.Nature. 1998; 394: 694-697Crossref PubMed Scopus (560) Google Scholar, 14Kayser E.B. Morgan P.G. Sedensky M.M. GAS-1: A mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans.Anesthesiology. 1999; 90: 545-554Crossref PubMed Scopus (121) Google Scholar]. To further characterize the specific contribution of complex I, we generated four hypomorphic C. elegans mutants encoding different complex I subunits [15Timmons L. Court D.L. Fire A. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans.Gene. 2001; 263: 103-112Crossref PubMed Scopus (1265) Google Scholar]. Our main finding is the identification of a clear correlation between complex I-dependent oxidative phosphorylation capacity and volatile anesthetic sensitivity. These extended data link a physiologic determinant of anesthetic action in a tractable animal model to similar clinical observations in children with mitochondrial myopathies [16Morgan P.G. Hoppel C.L. Sedensky M.M. Mitochondrial defects and anesthetic sensitivity.Anesthesiology. 2002; 96: 1268-1270Crossref PubMed Scopus (101) Google Scholar]. This work is the first to specifically implicate complex I-dependent oxidative phosphorylation function as a primary mediator of volatile anesthetic effect. Despite the widespread clinical use of volatile anesthetics, their mechanisms of action remain unknown [1Morgan P.G. Sedensky M. Meneely P.M. Multiple sites of action of volatile anesthetics in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 1990; 87: 2965-2969Crossref PubMed Scopus (93) Google Scholar, 2Humphrey J.A. Sedensky M.M. Morgan P.G. Understanding anesthesia: Making genetic sense of the absence of senses.Hum. Mol. Genet. 2002; 11: 1241-1249Crossref PubMed Scopus (26) Google Scholar, 3Gomez R.S. Guatimosim C. Mechanism of action of volatile anesthetics: Involvement of intracellular calcium signaling.Curr. Drug Targets CNS Neurol. Disord. 2003; 2: 123-129Crossref PubMed Scopus (17) Google Scholar, 4Hulme N.A. Krantz Jr., J.C. Anesthesia. XLVIII. Anesthetic potency and the uncoupling of oxidative phosphorylation.Anesthesiology. 1956; 17: 43-46Crossref PubMed Scopus (2) Google Scholar, 5Miro O. Barrientos A. Alonso J.R. Casademont J. Jarreta D. Urbano-Marquez A. Cardellach F. Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle.Eur. J. Clin. Pharmacol. 1999; 55: 35-41Crossref PubMed Scopus (48) Google Scholar, 6Hanley P.J. Ray J. Brandt U. Daut J. Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria.J. Physiol. 2002; 544: 687-693Crossref PubMed Scopus (159) Google Scholar]. An unbiased genetic screen in the nematode C. elegans for animals with altered volatile anesthetic sensitivity identified a mutant in a nuclear-encoded subunit of mitochondrial complex I [7Kayser E.B. Morgan P.G. Hoppel C.L. Sedensky M.M. Mitochondrial expression and function of GAS-1 in Caenorhabditis elegans.J. Biol. Chem. 2001; 276: 20551-20558Crossref PubMed Scopus (131) Google Scholar, 8Morgan P.G. Sedensky M.M. Mutations conferring new patterns of sensitivity to volatile anesthetics in Caenorhabditis elegans.Anesthesiology. 1994; 81: 888-898Crossref PubMed Scopus (56) Google Scholar]. This raised the question of whether mitochondrial dysfunction might be the primary mechanism by which volatile anesthetics act, rather than an untoward secondary effect [9Kayser E.B. Morgan P.G. Sedensky M.M. Mitochondrial complex I function affects halothane sensitivity in Caenorhabditis elegans.Anesthesiology. 2004; 101: 365-372Crossref PubMed Scopus (27) Google Scholar, 10Kayser E.B. Sedensky M.M. Morgan P.G. The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans.Mech. Ageing Dev. 2004; 125: 455-464Crossref PubMed Scopus (85) Google Scholar]. We report here analysis of additional C. elegans mutations in orthologs of human genes that contribute to the formation of complex I, complex II, complex III, and coenzyme Q [11Feng J. Bussiere F. Hekimi S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans.Dev. Cell. 2001; 1: 633-644Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 12Grad L.I. Lemire B.D. Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis.Hum. Mol. Genet. 2004; 13: 303-314Crossref PubMed Scopus (96) Google Scholar, 13Ishii N. Fujii M. Hartman P.S. Tsuda M. Yasuda K. Senoo-Matsuda N. Yanase S. Ayusawa D. Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes.Nature. 1998; 394: 694-697Crossref PubMed Scopus (560) Google Scholar, 14Kayser E.B. Morgan P.G. Sedensky M.M. GAS-1: A mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans.Anesthesiology. 1999; 90: 545-554Crossref PubMed Scopus (121) Google Scholar]. To further characterize the specific contribution of complex I, we generated four hypomorphic C. elegans mutants encoding different complex I subunits [15Timmons L. Court D.L. Fire A. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans.Gene. 2001; 263: 103-112Crossref PubMed Scopus (1265) Google Scholar]. Our main finding is the identification of a clear correlation between complex I-dependent oxidative phosphorylation capacity and volatile anesthetic sensitivity. These extended data link a physiologic determinant of anesthetic action in a tractable animal model to similar clinical observations in children with mitochondrial myopathies [16Morgan P.G. Hoppel C.L. Sedensky M.M. Mitochondrial defects and anesthetic sensitivity.Anesthesiology. 2002; 96: 1268-1270Crossref PubMed Scopus (101) Google Scholar]. This work is the first to specifically implicate complex I-dependent oxidative phosphorylation function as a primary mediator of volatile anesthetic effect. We previously observed that two mutations that decreased mitochondrial complex I function also increased sensitivity to volatile anesthetics. Conversely, a mutation that decreased complex II function did not alter anesthetic sensitivity. These results correlated with limited clinical findings in children with mitochondrial defects. This raised the question of whether the dependence of anesthetic sensitivity on complex I function is of general significance. We present here our determination of anesthetic sensitivity in a variety of C. elegans mitochondrial mutants generated either by classical means or by RNAi (Table 1).Table 1Mutations in Mitochondrial Subunits of C. elegansGene NameaStrain names follow Caenorhabditis Genetics Center (CGC) gene names for genomic mutants and CGC sequence names for RNAi knockdown mutants.MRC ComplexSubunitMutation TypeN2Wild-typen/an/agas-1(fc21)I49 kDaMissenseK09A9.5I49 kDaRNAiC09H10.3I51 kDaRNAiT20H4.5I23 kDaRNAiF22D6.4I13 kDaRNAiclk-1(qm30)Coenzyme Qn/aDeletionisp-1(qm150)IIIISPMissensemev-1(kn1)IICytochrome bMissensedaf-2(e1368)n/aInsulin receptorMissenseSingle mutations studied were either known defects within the MRC 11Feng J. Bussiere F. Hekimi S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans.Dev. Cell. 2001; 1: 633-644Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 13Ishii N. Fujii M. Hartman P.S. Tsuda M. Yasuda K. Senoo-Matsuda N. Yanase S. Ayusawa D. Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes.Nature. 1998; 394: 694-697Crossref PubMed Scopus (560) Google Scholar, 14Kayser E.B. Morgan P.G. Sedensky M.M. GAS-1: A mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans.Anesthesiology. 1999; 90: 545-554Crossref PubMed Scopus (121) Google Scholar, 22Kayser E.B. Sedensky M.M. Morgan P.G. Hoppel C.L. Mitochondrial oxidative phosphorylation is defective in the long-lived mutant clk-1.J. Biol. Chem. 2004; 279: 54479-54486Crossref PubMed Scopus (81) Google Scholar or RNAi-generated hypomorphs corresponding to highly conserved orthologs implicated in humans mitochondrial disease 23Holt I.J. Genetics of Mitochondrial Diseases. Oxford University Press, Oxford2003Google Scholar. RNAi protocols were performed with worms grown for two generations in culture containing bacteria induced to produce a dsRNA corresponding to a gene encoding a specific complex I subunit 15Timmons L. Court D.L. Fire A. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans.Gene. 2001; 263: 103-112Crossref PubMed Scopus (1265) Google Scholar, 24May R.C. Plasterk R.H. RNA Interference Spreading in C. elegans.Methods Enzymol. 2005; 392: 308-315Crossref PubMed Scopus (41) Google Scholar. A nonmitochondrial mutant displaying volatile anesthetic resistance, daf-2, was also studied 25Kimura K.D. Tissenbaum H.A. Liu Y. Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.Science. 1997; 277: 942-946Crossref PubMed Scopus (1612) Google Scholar. Integrated oxidative phosphorylation capacity was measured by polarography in intact, coupled mitochondria from each mutant. See Supplemental Data for greater detail.a Strain names follow Caenorhabditis Genetics Center (CGC) gene names for genomic mutants and CGC sequence names for RNAi knockdown mutants. Open table in a new tab Single mutations studied were either known defects within the MRC 11Feng J. Bussiere F. Hekimi S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans.Dev. Cell. 2001; 1: 633-644Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 13Ishii N. Fujii M. Hartman P.S. Tsuda M. Yasuda K. Senoo-Matsuda N. Yanase S. Ayusawa D. Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes.Nature. 1998; 394: 694-697Crossref PubMed Scopus (560) Google Scholar, 14Kayser E.B. Morgan P.G. Sedensky M.M. GAS-1: A mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans.Anesthesiology. 1999; 90: 545-554Crossref PubMed Scopus (121) Google Scholar, 22Kayser E.B. Sedensky M.M. Morgan P.G. Hoppel C.L. Mitochondrial oxidative phosphorylation is defective in the long-lived mutant clk-1.J. Biol. Chem. 2004; 279: 54479-54486Crossref PubMed Scopus (81) Google Scholar or RNAi-generated hypomorphs corresponding to highly conserved orthologs implicated in humans mitochondrial disease 23Holt I.J. Genetics of Mitochondrial Diseases. Oxford University Press, Oxford2003Google Scholar. RNAi protocols were performed with worms grown for two generations in culture containing bacteria induced to produce a dsRNA corresponding to a gene encoding a specific complex I subunit 15Timmons L. Court D.L. Fire A. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans.Gene. 2001; 263: 103-112Crossref PubMed Scopus (1265) Google Scholar, 24May R.C. Plasterk R.H. RNA Interference Spreading in C. elegans.Methods Enzymol. 2005; 392: 308-315Crossref PubMed Scopus (41) Google Scholar. A nonmitochondrial mutant displaying volatile anesthetic resistance, daf-2, was also studied 25Kimura K.D. Tissenbaum H.A. Liu Y. Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.Science. 1997; 277: 942-946Crossref PubMed Scopus (1612) Google Scholar. Integrated oxidative phosphorylation capacity was measured by polarography in intact, coupled mitochondria from each mutant. See Supplemental Data for greater detail. Both classical gene mutants and RNAi-induced hypomorphs inhibited mitochondrial respiration in a specific manner appropriate to the individual complex involved as well as to the site of electron entry into the mitochondrial respiratory chain (MRC). Inhibition of complex I-dependent oxidative phosphorylation capacity was observed in the complex I mutant gas-1, in isp-1 (complex III mutant), and in clk-1 (defect in coenzyme Q synthesis) (Figure 1). This capacity was measured as state 3 respiration rates in the presence of malate and internally normalized to complex IV-dependent rates measured with tetramethyl-p-phenylenediamine (TMPD) and ascorbate as combined electron donors. The effects of RNAi were studied first in K09A9.5 (the gene locus of the gas-1 allele) to demonstrate that an RNAi knockdown could mimic the phenotype of the corresponding missense mutant. Impairment in complex I-dependent oxidative phosphorylation capacity was seen, although to a lesser degree than is typical of gas-1. All of the other mutants with RNAi-induced complex I defects similarly demonstrated complex I-dependent oxidative phosphorylation capacity impairment (Figure 1A). However, complex I-dependent oxidative phosphorylation capacity was normal in the complex II mutant (mev-1), in agreement with previous reports from our laboratory [10Kayser E.B. Sedensky M.M. Morgan P.G. The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans.Mech. Ageing Dev. 2004; 125: 455-464Crossref PubMed Scopus (85) Google Scholar]. Complex II-dependent oxidative phosphorylation capacity, measured as state 3 respiration rates in the presence of succinate, was significantly impaired in the complex II (mev-1) mutant and somewhat diminished in the complex III (isp-1) mutant, but appeared increased in all mutants with primary complex I defects (Figure 1B). No significant variation in complex IV-dependent oxidative phosphorylation, as measured in the presence of TMPD and ascorbate, was observed in any of the strains (Figure 1C). All mutants that inhibited complex I function were hypersensitive to halothane. Complex I classical mutants had increased sensitivity to halothane as measured by a lower EC50, the effective concentration required to produce immobility in fifty percent of animals. However, their degree of hypersensitivity varied (Figure 2A). Anesthetic hypersensitivity was most pronounced for gas-1, whereas clk-1, seg-1;gas-1, and seg-2;gas-1 displayed more moderate increases in sensitivity. The complex II and III classical mutants, mev-1 and isp-1, respectively, had normal sensitivities to halothane. daf-2 was resistant to halothane. RNAi-induced hypomorphs of specific complex I subunits were all sensitive to halothane (Figure 2B). When only complex I mutants were considered, the correlation between complex I-dependent oxidative phosphorylation capacity and anesthetic sensitivity was strongly positive (r = 0.69, p = 0.056) (Figure 3). The magnitude of the correlation diminished when the non-complex I respiratory-chain mutants (clk-1, isp-1, mev-1) were also taken into consideration (r = 0.58, p = 0.063). Two of these mutants had decreased complex I-dependent rates (clk-1, isp-1), but no defects within complex I itself. These results implicate complex I specifically as a mediator of anesthetic sensitivity; the data imply that directly inhibiting complex I function increases anesthetic sensitivity. Interestingly, an increased maximal capacity of complex I-dependent oxidative phosphorylation was noted in the nonmitochondrial mutant with a defect in the insulin-like receptor (daf-2) (165 nAO/min/mg protein versus 112 nAO/min/mg protein for N2). In general, high ADP rates are similar to state 3 rates for a given strain (see the Supplemental Data available online). In daf-2 mitochondria, however, use of a higher concentration of ADP further stimulated the mitochondria over what is typical of their state 3 rates. Their degree of increased complex-I dependent oxidative phosphorylation capacity correlated with their degree of anesthetic resistance (Figure 3). Inclusion of daf-2 with the complex I mutants strengthened the magnitude of the overall correlation between capacity of complex I-dependent respiration and sensitivity to the volatile anesthetic halothane (r = 0.87, p = 0.002). This implies that in a simple linear regression model, 76% of the variation in anesthetic sensitivity can be accounted for solely by the state 3 rate of complex I-dependent oxidative phosphorylation. To further characterize this correlation, we determined whether a graded variation in the degree of RNAi in one and the same gene would incrementally decrease respiratory capacity and increase anesthetic sensitivity. RNAi was induced to varying extents for the complex I subunit gene nuo-1 (C09H10.3) by using three different concentrations of IPTG. Increasing concentrations of IPTG led to increasing sensitivity to halothane (Figure 4A) and increasing inhibition of complex I-dependent oxidative phosphorylation capacity (Figure 4B), although no difference in oxidative phosphorylation capacity or anesthetic sensitivity was seen between the 5 mM and 10 mM IPTG RNAi mutants. Previous studies demonstrated that the increased sensitivity to halothane of the complex I mutant gas-1(fc21) can be reverted by expressing the wild-type gas-1 gene under control of its own promoter (Pgas-1) from an extrachromosomal array. Pgas-1 is active in the nervous system and muscle [7Kayser E.B. Morgan P.G. Hoppel C.L. Sedensky M.M. Mitochondrial expression and function of GAS-1 in Caenorhabditis elegans.J. Biol. Chem. 2001; 276: 20551-20558Crossref PubMed Scopus (131) Google Scholar]. Here, expression of the wild-type gas-1 gene was placed under the control of either a neuronal-specific promoter (ric-19) or a muscle-specific promoter (myo-3). Both new constructs, introduced into the gas-1(fc21) mutant background, also partially restored halothane EC50s toward normal (gas-1(fc21), 1.0% ± 0.05%; Pric-19::gas-1(+), 1.5% ± 0.2%∗; Pmyo-3::gas-1(+), 1.8% ± 0.2%∗; Pgas-1::gas-1(+), 2.1% ± 0.1%∗; and N2, 3.2% ± 0.02%∗. EC50s + standard deviation; ∗ indicates different than value for gas-1, p < 0.05 with a Bonferroni correction). None of the stable lines carrying these constructs were integrated into the genome; generally, the muscle-specific promoter showed stronger overall expression. Thus, the increased anesthetic sensitivity seen in gas-1 mutants results from changes in both muscle and neuronal tissues. The relative contribution of these tissues to anesthetic sensitivity in the RNAi-induced mutant strains is not known. A clear correlation exists between mitochondrial complex I oxidative phosphorylation capacity and volatile anesthetic sensitivity in C. elegans. In particular, the extent of complex I oxidative phosphorylation dysfunction is directly proportional to the degree of volatile anesthetic sensitivity (Figure 3). Some impairment of complex I-dependent oxidative phosphorylation function is seen in coenzyme Q biosynthesis and complex III structural-subunit mutants. This is not unexpected, given that these downstream components are assayed when testing integrated oxidative phosphorylation capacity with substrates that donate electrons through complex I. However, secondary complex I dysfunction (due to mutations affecting downstream respiratory-chain components, i.e., clk-1 and isp-1) does not correlate with increased volatile anesthetic sensitivity as strongly as does primary complex I dysfunction (due to mutations affecting complex I itself). Furthermore, despite having impaired complex II-dependent oxidative phosphorylation capacity, the complex II mutant mev-1 has normal complex I-dependent oxidative phosphorylation capacity and normal anesthetic behavior. This demonstrates that only those defects that directly impair complex I strongly increase anesthetic sensitivity." @default.
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• W2018676384 title "Mitochondrial Complex I Function Modulates Volatile Anesthetic Sensitivity in C. elegans" @default.
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