Distinguished Professor Emeritus
Showalter Professor Emeritus
Sagamore of the Wabash

Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
Richard L. Roudebush VA Medical Center
1481 W. 10th Street, Room D3034
Indianapolis, Indiana 46202

Phone: (317) 988-4544
Facsimile: (317) 988-3180
E-mail: raharris@iupui.edu

Area of Study

Selected Recent Publications

Jeoung, N.H., Wu, P., Joshi, M.A., Jaskiewicz, J., Bock, C.B., DePaoli-Roach, A.A., and Harris, R.A. Role of pyruvate dehydrogenase kinae 4 (PDK4) in glucose homeostasis during starvation. Biochem. J. 397, 417-425 (2006).

Jeoung, N. H., Sanghani, P.C., Zhai, L., and Harris, R.A. Assay of the pyruvate dehydrogenase complex by coupling with recombinant chicken liver arylamine N-acetyltransferase. Anal. Biochem. 356, 44-50 (2006).

Joshi, M.A., Jeouong, N.H., Obayashi, M., Hattab, E.M., Bracken, E.G., Liechty, E.A., Kubek, M.J., Vattem, K.M., Wek, R.C., and Harris, R.A. Impaired growth and neurological abnormalities in branched-chain α-keto acid dehydrogenase kinase-deficient mice. Biochem. J. 400, 153-162 (2006).

Johnson, D.T., Harris, R.A., French, S., Blair, P.V., You, J., Bemis, K.G., Wang, M., and Balaban, R.S. Tissue heterogeneity of the mammalian mitochondrial proteome. Am. J. Physiol. 292, C689-C697 (2007).

Johnson, D.T., Harris, R.A., Blair, P.V., and Balaban, R.S. Functional consequences of mitochondrial proteome heterogeneity between tissues. Am. J. Physiol. 292, C698-C707 (2007).

Joshi, M., Jeoung, N.H., Popov, K.M., and Harris, R.A. Identification of a novel PP2C-type mitochondrial phosphatase. Biochem. Biophys. Res. Communs. 356, 38-44 (2007).

LeBlanc, P.J., Harris, R.A., and Peters, S.J.  Skeletal muscle fiber-type comparison of pyruvate dehydrogenase phosphatase activity and isoform expression in fed and food deprived rats.  Am. J. Physiol. 292, E571-E576 (2007).

Aragonés, J., Schneider, M., van Geyte, K., Fraisl, P., Dresselaers, T., Mazzone, M., Dirkx, R., Zacchigna, S., Lemieux, H., Jeoung, N.H., Lambrechts, D., Bishop, T., Lafuste, P., Diez-Juan, A., Harten, S.K., VanNoten, P., De Bock, K., Willam, C., Tjwa, M., Grosfeld, A., Navet, R., Moons, L., Deroose, C., Wijeyekoon, B., Nuytsl, J., Jordan, B.,  Silasi-Mansat, R., Lupu, F. Dewerchin, M., Pugh, C., Salmon, Pl, Mortelmans, L. Gallez, B., Gours, F., Byuse, J., Sluse, F., Harris, R.A., Gnaiger, E., Hespe, P., Van Hecke, P.V., Schuit, F. Van Veldhoven, P., Ratcliffe, P., Baes, M., Maxwell, P., and Carmeliet, P. Deficiency or inhibition of the oxygen sensor PHD1 induces hypoxia tolerance by reprogramming basal metabolism. Nature Genetics 40, 170-180 (2008).   

Harris, R.A., Jeoung, N.H., Joshi, M., and Hwang, B. The α-keto acid dehydrogenase complexes and the glycine cleavage system: their involvement in pathways of carbohydrate, protein, and fat metabolism.  In Alpha-Lipoic Acid: Energy Production, Antioxidant Activity, and Health Effects (eds: Mulchand S. Patel and Lester Packer) Taylor and Francis, pp. 99-148 (2008).

Burgess, S.C., Iizuka, K., Jeoung, N.H., Harris, R.A., Kashiwaya, Y., Veech, R.L., Kitazume, T., and Uyeda, K. Carbohydrate response element binding protein deletion alters substrate utilization producing an energy deficient liver. J. Biol. Chem.  283, 1670-1678 (2008).

Zhao, G., Jeoung, N.H., Burgess, S.C., Rosaaen-Stowe, K.A., Inagaki, T., Latif, S., Shelton, J.M. McAnally, J., Bassel-Duby, R., Harris, R.A., Richardson, J.A., and Kliewer, S.A. Overexpression of Pyruvate Dehydrogenase Kinase 4 in Heart Perturbs Metabolism and Exacerbates Calcineurin-Induced Cardiomyopathy. Am. J. Physiol. 294, H936-H943 (2008).

Jeoung, N.H. and Harris, R.A. Pyruvate Dehydrogenase Kinase 4 (PDK4) Deficiency Lowers Blood Glucose and Improves Glucose Tolerance in Diet-Induced Obese Mice.  Am. J. Physiol. 295, E46-E54 (2008).

Geelen, M.J.H., Harris, R.A., and Van den Bergh, S.G. The enigmatic effect of cellular energy state on fatty acid synthesis. Stimulation by moderate decrease and inhibition by increase of cellular ATP. FEBS Lett. 582, 2242-2246 (2008).

McFate, T., Mohyeldin, A., Lu,  H., Thakar,  J., Henriques, J., Halim, N., Wu, H., Schell, M., Tsang, T.M., Teahan, O., Zhou, S., Califano, J.A., Jeoung, N.H., Harris, R.A, Verma, A.J., Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells.  J. Biol. Chem. 283: 22700-22708 (2008).

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Research Interests

The activity of the pyruvate dehydrogenase complex (PDC) is regulated by interconversion of phosphorylated (inactive) and non-phosphorylated (active) forms of the complex. Phosphorylation is catalyzed by four pyruvate dehydrogenase kinase (PDK) isoenzymes; dephosphorylation by two pyruvate dehydrogenase phosphatase (PDP) isoenzymes. Unique regulatory properties of these isoenzymes and differences in their levels of expression in different cell types provide tissue specific control of the activity of PDC. Current work is based on our recent finding that one of the PDK isoenzymes, PDK4, is markedly increased in the tissues of insulin-deficient rats. We propose that altered expression of this PDK isoenzyme is an important component of the regulatory mechanisms triggered by insulin deficiency to conserve glucose and the three-carbon compounds required for glucose synthesis. Our working hypothesis is that alterations in the expression of the genes encoding the PDK isoenzymes are responsible for the hyperphosphorylation and therefore inactivation of PDC in metabolically important tissues during insulin deficiency. The hypothesis is being tested by: (a) quantifying the changes that occur in expression of the PDK isoenzymesin metabolically important tissues in insulin deficient and resistant states, (b) identifying the physiologically important factors that regulate PDK4 expression, and (c) determining the molecular mechanism responsible for the large increase in ,message level of PDK4 that occurs in tissues in response to insulin deficiency. We believe the findings of this study will provide new insight with respect to a regulatory mechanism crucial for glucose homeostasis. It will also contribute to our understanding of why consumption of the typical Western diet inappropriately spares carbohydrate from oxidation and promotes the development of type 2 diabetes.