The long-term goal of this laboratory is to understand at the molecular level how the volatile anesthetics work. We have exploited the many advantages of the nematode C. elegans to identify genes that control its behavior in volatile anesthetics. We have determined that a point mutation in a single subunit of the first complex of mitochondrial electron transport causes C. elegans to be profoundly hypersensitive to all volatile anesthetics. This gene, gas-1, encodes the 49Kda subunit of NADH ubiquinone oxidoreductase. Multiple aspects of metabolism are severely affected by this mutation. In addition, free radical damage is a significant feature of this animal's hypersensitivity to volatile anesthetics. A small group of children with metabolic defects that are related to the function of Complex I are hypersensitive to sevoflurane. In this proposal we will extend our studies to test our hypothesis that decreased metabolism and increased free radical formation both play a role in the anesthetic hypersensitivity of gas-1, and the either of these may affect downstream, presynaptic targets.
The specific aims of the present application are to: 1. Compare the effect of halothane on oxidative phosphorylation in nematode strains with known mitochondrial defects, but with different anesthetic sensitivities. This will determine the contribution of metabolic changes on anesthetic sensitivity. 2. Characterize the damage from reactive oxygen species in three strains of worms with mutations that affect mitochondria. We will identify specific molecules affected by reactive oxygen species that affect anesthetic sensitivity. 3. Determine gas-1's effect on multiple markers of synaptic structure and function in C. elegans. Antibodies to presynaptic proteins, as well as transgenic animals carrying marked presynaptic proteins, will be used to test the effects of gas-1 on neuronal proteins that are key to synaptic function. The function of mitochondria represents a novel mechanism that contributes to the control of behavior of a whole animal in volatile anesthetics. Study of the nematode can lead to a molecular understanding of how volatile anesthetics work. In addition, this proposal has a clear clinical correlate in the anesthetic response of patients with mitochondrial myopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058881-07
Application #
6838255
Study Section
Special Emphasis Panel (ZRG1-SSS-W (39))
Program Officer
Cole, Alison E
Project Start
1999-01-01
Project End
2005-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
7
Fiscal Year
2005
Total Cost
$399,586
Indirect Cost
Name
Case Western Reserve University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Dancy, Beverley M; Sedensky, Margaret M; Morgan, Philip G (2015) Mitochondrial bioenergetics and disease in Caenorhabditis elegans. Front Biosci (Landmark Ed) 20:198-228
Morgan, P G; Higdon, R; Kolker, N et al. (2015) Comparison of proteomic and metabolomic profiles of mutants of the mitochondrial respiratory chain in Caenorhabditis elegans. Mitochondrion 20:95-102
Suthammarak, Wichit; Somerlot, Benjamin H; Opheim, Elyce et al. (2013) Novel interactions between mitochondrial superoxide dismutases and the electron transport chain. Aging Cell 12:1132-40
Quintana, Albert; Morgan, Philip G; Kruse, Shane E et al. (2012) Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I. PLoS One 7:e42904
Yang, Yu-Ying; Vasta, Valeria; Hahn, Sihoun et al. (2011) The role of DMQ(9) in the long-lived mutant clk-1. Mech Ageing Dev 132:331-9
Chen, Xiulian; Thorburn, David R; Wong, Lee-Jun et al. (2011) Quality improvement of mitochondrial respiratory chain complex enzyme assays using Caenorhabditis elegans. Genet Med 13:794-9
Singaram, Vinod K; Somerlot, Benjamin H; Falk, Scott A et al. (2011) Optical reversal of halothane-induced immobility in C. elegans. Curr Biol 21:2070-6
Pfeiffer, Matthew; Kayzer, Ernst-Bernhard; Yang, Xianmei et al. (2011) Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport. J Biol Chem 286:37712-20
Kayser, Ernst-Bernhard; Suthammarak, Wichit; Morgan, Phil G et al. (2011) Isoflurane selectively inhibits distal mitochondrial complex I in Caenorhabditis elegans. Anesth Analg 112:1321-9
Vasta, V; Sedensky, M; Morgan, P et al. (2011) Altered redox status of coenzyme Q9 reflects mitochondrial electron transport chain deficiencies in Caenorhabditis elegans. Mitochondrion 11:136-8

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