photo of Mills
Laboratory of Dr. Edward Mills
Assistant Professor


Ph.D., Purdue University, Department of Medicinal Chemistry and Molecular Pharmacology, 1997
Mail Code: A1915, PHR Room 5.218E
Pharmacology and Toxicology Division
Austin, TX 78712
      
Office phone (512) 471-6699
Lab phone: (512) 471-9823
Email: ted_mills@mail.utexas.edu

Laboratory Interests:

In mammals, up to 25% of overall basal metabolic rate is devoted to a futile cycle of proton extrusion from and leak back into the mitochondrial matrix during oxidative phosphorylation. Commonly referred to as bioenergetic "respiratory inefficiency", proton leak uncouples fuel oxidation from ATP synthesis, and is regulated primarily by uncoupling proteins. From a teleological perspective, the evolution of a biological pathway of energy wasting would seem surprising. However, a variety of studies indicate this process is a thermogenic mechanism that mediates adaptive heat production and antagonizes the generation of mitochondrial oxidant species along with the development of age-related disease. Projects in my laboratory incorporate rodent, nematode, cell-based, and biochemical approaches to explore the mechanisms regulating mitochondrial respiratory inefficiency, and the role of this process in normal cell function, metabolic physiology and age-related diseases. Two broad research questions guide the work in our lab: 1. What are the physiologic functions and mechanisms of regulation / action of uncoupling proteins? These projects use C. elegans and mouse gain and loss of function uncoupling protein mutants, along with cultured cells and in vitro reconstitution systems, to gain insight into the molecular regulation and function of uncoupling proteins in metabolic physiology (substrate transport/oxidation, fat storage) and age related disease (cancer, obesity, diabetes). 2. What are the mechanisms by which mitochondrial energy conversion couples to the regulation of cellular signaling pathways? Mitochondria are thought to participate in growth control and stress pathways in part by their production of approximately 85% of the cellular reactive oxidant species, including hydrogen peroxide and superoxide. These projects use cell biological and biochemical approaches to identify novel cytoplasmic sensors of mitochondrial oxidants, and to understand the physiologic relevance of these molecular interactions in the integration cellular physiology.

image from lab
Adult C. elegans nematodes (roundworms) subjected to UCP knockout or UCP RNA-inactivation are obese compared to normal worms (wild type). Live worms were fed nile red, a dye that labels fat in adipocytes and imaged by confocal microscopy. There is significantly increased nile red fluorescence in UCP deficient worms, suggesting that UCP may play a role in the regulation of body fat.
Selected Publications:

  1. Wyeth R.P., Mills E. M., Ulman A., Kenaston M.A., Burwell J., Sprague J.E. The hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is gender sensitive. Br. J. Pharmacol. (Submitted, 3-2008).


  2. Hang Wang, Yasuhiro Katagiri, Thomas McCann, Zu-Xi Yu, Fei Tan, Edward Unsworth, Paul Goldsmith, Edward M. Mills, Yu Wang, , Aviva J. Symes, and Herbert M. Geller (2007) 4-sulfation of chondroitin is essential for inhibition of axonal growth. J. Cell Biol. (In review, 3-2008).


  3. Mills E. M., Weaver K. L., Abramson E., Pfeiffer M., and Sprague J. E. (2007). Influences of dietary fats on Ecstasy-induced hyperthermia. Br. J. Pharmacol May 29 [Epub ahead of print].


  4. Sprague J. E., Yang X., and Sommers J., Gillman T.L., Mills E. M. (2007) Roles of plasma norepinephrine, free fatty acids, thyroid hormone and uncoupling protein 3 in sympathomimetic hyperthermia. J. Pharmacol. And Exper. Therapeutics 320: 274-280.


  5. Prabhakaran K., Li L., Mills E.M., Borowitz J.L., Isom G.E. (2005) Up-regulation of UCP-2 by cyanide is linked with cytotoxicity in mesencephalic cells. J. Pharmacol. Exp. Ther. 314(3): 1338-1345.


  6. Rusyniak D.E., Tandy S. L., Hekmatyar N. S., Mills E. M., Smith D. J., Bansal N., Sprague J. E. (2005) Role of mitochondrial uncoupling in MDMA-mediated skeletal muscle hyperthermia and rhabdomyolysis. J. Pharmacol. Exp. Ther. 313(2): 629-639.


  7. Sprague J. E., Moze P., Caden D., Rusyniak D. E., Mills E. M. (2005) Carvedilol rapidly reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy) Crit Care Med 33(6): 1311-1316.


  8. Li L., Prabhakaran K., Mills E. M., Borowitz J. L., Isom G. E. (2005) Uncoupling Protein-2 Switches the Mode of Cyanide-induced Death From Apoptosis to Necrosis In Cortical Cells. Toxicolog. Sci. 86(1): 116-124.


  9. Sprague J.E., Brutcher R.E., Mills E. M., Caden D., Rusyniak D.E. (2004) Attenuation of 3,4-methylenedioxymethamphetamine (ecstasy)-induced rhabdomyolysis with alpha1 plus beta3-adrenoceptor antagonists. Br J Pharmacol 142(4): 667-70.


  10. Sprague J. E., Smith R. M., Gibbs J., Liu J., Kisor D. F., Mills E. M. (2004) UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia. Biochemical Pharmacology 68(7): 1339-43.


  11. Rusyniak D. E., Banks M. L., Mills E. M., Sprague J. E. (2004) Dantrolene use in MDMA (Ecstasy) mediated hyperthermia. Anesthesiology 101(1): 263-264.


  12. Mills E. M., Rusyniak D. E., Sprague J. E. (2004) Role of uncoupling proteins in sympathomimetic-induced hyperthermia: a focus on 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). J. Mol. Medicine 82(12): 787-99.


  13. Mills E. M., Banks M. L., Sprague J. E., Finkel T. (2003) Uncoupling the agony from Ecstasy. Nature 426: 403-404.


  14. Sprague J. E., Banks M. L., Cook V. J., and Mills, E. M. (2003) Role of the hypothalamic-pituitary-thyroid (HPT) axis in hyperthermia and neurotoxicity produced by ecstasy (3,4,-methylenedioxymethamphetamine). J. Pharmacol. Exper. Therapeutics, 305(1):159-66.


  15. Mills E. M., Fergusson, M., Combs, C.A., Xu, Y., and Finkel, T. (2002) Regulation of cellular oncosis by uncoupling protein-2. J. Biol. Chem. 277 (30) 27385-92.


  16. Mills E. M., Gunasekar P. G., Li L., Borowitz J. L., and Isom G. E. (1999) Differential susceptibility of brain areas to cyanide involves different modes of cell death. Toxicol. Appl. Pharm. 156, 6-16.


  17. Mills E. M., Takeda K., Yu Z-X., Ferrans V., Katagiri Y., Jiang H., Lavigne M. C., Leto T. L., and Guroff G. (1998) Nerve growth factor treatment prevents the increase in superoxide produced by epidermal growth factor in PC12 cells. Rapid Communication: J. Biol. Chem. 273, 22165-22168.


  18. Kanthasamy A. G., Ardelt B. K., Mills E. M., Borowitz J. L., and Isom G. E. (1997). Reactive oxygen species generated by cyanide mediate toxicity in rat pheochromocytoma cells. Toxicol. Letters 93 (1) 47-54.


  19. Bojes H. K., Suresh P. K., Mills E. M., Spitz D. R., Sim J. E., and Kehrer J. P. (1998) Bcl-2 and Bcl-x-L in peroxide-resistant A549 and U87MG cells. Toxicological Sciences 42 (2), 109-116.


  20. Mills E. M. and Isom G. E. (1996) Chemical hypoxia-induced apoptosis and oxidative stress in differentiated PC12 cells. J. Neurochem. 67 (3) 1039-1046.

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