Maik Hüttemann, Ph.D.
Associate  Professor

3214 Scott Hall
540 East Canfield
Detroit, MI 48201
Voice: 313-577-9150
FAX: 313-577-5218
mhuttema@med.wayne.edu
 
Associate Professor (also with Molecular Biology); Ph.D., Marburg (Germany), 1999. Regulation of cytochrome c oxidase and cytochrome c, oxygen sensing, cell signaling to the mitochondria, and role of mitochondria in cancer.

Research Interests

Mitochondria are organelles that began as symbiotic organisms within the eukaryotic cell. They produce most biological energy (ATP) but also most of the reactive oxygen species (ROS) that can damage biological molecules, and they are a pivotal site for cellular programmed cell death (apoptosis). It is therefore not surprising that mitochondrial dysfunction is involved in most human disease, including cancer, neurodegenerative disease, ischemia, and diabetes.

Our team studies mitochondrial function using genetic and biochemical approaches. We focus on two key components of the mitochondrial oxidative phosphorylation machinery, cytochrome c oxidase (COX) and the small electron carrier cytochrome c (Cytc). COX is the terminal enzyme of the mitochondrial respiratory chain, “burns” the oxygen we breathe to water, and pumps protons across the inner mitochondrial membrane generating the mitochondrial membrane potential, which is utilized by ATP synthase to produce energy in the form of ATP. Cytc has two distinct functions: it delivers electrons to COX, but it also participates in programmed cell death (apoptosis).

The overall goal of our work is to understand the regulation of COX and Cytc in normal and disease conditions. This regulation in turn affects energy production, free radical generation, and apoptosis. Research topics of the Hüttemann group under investigation include 1) cell signaling pathways that act on COX and Cytc, which pathways are often dysregulated in human diseases; 2) lung cancer; 3) neurodegenerative diseases; 4) gene regulation of COX subunit isoforms; and 5) novel strategies to boost mitochondrial function as a future treatment for diseases that manifest themselves in a lack of energy and increased cell death.

Selected Publications

Lee, I., Salomon, A.R., Ficarro, S., Mathes, I., Lottspeich, F., Grossman, L.I., Hüttemann, M (2005) cAMP-dependent Tyrosine Phosphorylation of Subunit I inhibits Cytochrome c Oxidase activity, J Biol Chem, 280: 6094-100.

Icksoo Lee, Arthur R. Salomon, Kebing Yu, Jeffrey W. Doan, Lawrence I. Grossman, L.I., Maik Hüttemann (2006) New Prospects for an Old Enzyme: Mammalian Cytochrome c is Tyrosine-Phosphorylated in Vivo, Biochemistry, 45(30): 9121-8

Hüttemann, M., Lee, I., Liu, J., Grossman, L.I. (2007) Transcription of cytochrome c oxidase subunit IV-2 is controlled by a novel oxygen responsive element conserved in mammals, FEBS Journal, 274 (21),5737-48.

Hüttemann, M., Lee, I., Samavati, L., Yu, H., Doan, J.W. (2007) Regulation of mitochondrial oxidative phosphorylation through cell signaling, BBA - Mol Cell Res, 1773: 1701–20

Duvigneau, J.C., Piskernik, C., Haindl, S., Burkhard, K., Hartl, R.T., Hüttemann, M., Lee, I., Ebel, T., Moldzio, R., Gemeiner, M., Redl, H., Kozlov, A.V. (2008) Iron ions cause mitochondrial dysfunction in liver of rats subjected to endotoxic shock: the role of heme oxygenase 1, Laboratory Investigation, 88(1): 70-7

Hüttemann, M., Lee, I., Kreipke, C.W., Petrov, T., (2008) Suppression of iNOS prior to traumatic brain injury improves cytochrome c oxidase activity and normalizes cellular energy levels, Neuroscience 151 (1): 148-54

Yu, H., Lee, I., Salomon, A.R., Yu, K., Huttemann, M. (2008) Mammalian liver cytochrome c is tyrosine-48 phosphorylated in vivo, inhibiting mitochondrial respiration, Biochim Biophys Acta - Bioenergetics, 1777 (7-8), 1066-71

Samavati, L., Lee, I., Mathes, I., Lottspeich, F., Huttemann, M. (2008) TNF? Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c Oxidase, J Biol Chem, 283 (30), 21134-44

Hüttemann, M., I. Lee, A. Pecinova, P. Pecina, K. Przyklenk, and J.W. Doan (2008) Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. J Bioenerg Biomembr, 40(5): 445-56.

Rastogi, R., Du, W., Hüttemann, M., Fite, A. Franchi, L., Samavati, L. (2009) STAT3 tyrosine phosphorylation is critical for interleukin 1-beta and interleukin-6 production in response to lipopolysaccharide and live bacteria. Molecular Immunology, 46(8-9),1867-77.

Lee, I., Salomon, A.R., Yu, K., Samavati, L., Pecina, P., Pecinova, A., Hüttemanna, M. (2009) Isolation of regulatory-competent, phosphorylated cytochrome c oxidase. Methods Enzymol, 457:193-210.

Acsadi, G., Lee, I., Li, X.,; Khaidakov, M., Pecinova, A., Parker, G., Hüttemann, M. (2009) Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy. J Neurosci Res, 87:2748-56.

Hüttemann, M., Zhang, Z., Mullins, C., Bessert, D., Lee, I., Armin-Narve, K., Skoff, R.P. (2009) Different proteolipid protein mutants exhibit unique metabolic defects, ASN Neuro 1(3): 165-180.

Demory, M.L., Julie L., Boerner, J.L., Davidso, R., Faust, W.,Miyake, T., Lee, I., Hüttemann, M., Douglas, R. Haddad, G., Parsons, S.J. (2009) Epidermal Growth Factor Receptor Translocation to the Mitochondria: Regulation and Effect, J Biol Chem, 284(52): 36592-604.

Lee, I., Pecinova, A., Pecina, P., Neel, B., Kucherlapati, R., Roberts, A., Hüttemann, M. (2010) A suggested role for mitochondria in Noonan syndrome, Biochim Biophys Acta Molecular Basis of Disease, 1802: 275-83.

Hüttemann, M., Nantwi, K.D., Lee, I., Liu, J., Mohiuddin, S., Petrov, T. (2010) Theophylline treatment improves mitochondrial function after upper cervical spinal cord hemisection. Experimental Neurology, 223(2): 523-8.

Barnes, V.L., Strunk, B.S., Lee, I., Hüttemann, M., Pile, L.A. (2010) Loss of the SIN3 Transcriptional Corepressor Results in Aberrant Mitochondrial, BMC Biochemistry, 11(21):1-12.

Pecina, P., Borisenko, G.G., Belikova, N.A., Tyurina, Y.Y., Pecinova, A., Lee, I., Samhan-Arias, A.K., Przyklenk, K., Kagan, V.E., Hüttemann, M. (2010) Phosphomimetic substitution of cytochrome c tyrosine 48 decreases respiration and binding to cardiolipin, and abolishes ability to trigger downstream caspase activation. Biochemistry, 9(31):6705-14.


Hüttemann, M., Pecina, P., Rainbolt, M., Sanderson, T.H., Kagan, V.E., Samavati, L., Doan, J.W., Lee, I. (2011) The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell: from respiration to apoptosis. Mitochondrion, 11(3):369-81.

 Stevens, J. B., Abdallah, B. Y., Liu, G., Ye, C. J., Horne, S. D., Wang, G., Savasan, S., Shekhar, M., Krawetz, S. A., Hüttemann, M., Tainsky, M. A., Wu, G. S., Xie, Y., Zhang, K., and Heng, H. H. (2011) Diverse system stresses: common mechanisms of chromosome fragmentation. Cell Death Dis 2: e178

Pecina, P., Borisenko, G.G., Belikova, N.A., Tyurina, Y.Y., Pecinova, A.,Lee, I., Samhan-Arias, A.K., Przyklenk, K., Kagan, V.E., Hüttemann, M. (2010) Phosphomimetic substitution of cytochrome c tyrosine 48 decreases respiration and binding to cardiolipin, and abolishes ability to trigger downstream caspase activation. Biochemistry, 9(31):6705-14.

Hüttemann, M., Pecina, P., Rainbolt, M., Sanderson, T.H., Kagan, V.E., Samavati, L., Doan, J.W., Lee, I. (2011) The multiple functions of cytochrome c and their regulation in life and death decisions of the
mammalian cell: from respiration to apoptosis. Mitochondrion, 11(3):369-81.

Pierron D., Wildman D. E., Hüttemann M., Markondapatnaikuni G. C., Aras S., and Grossman L. I. (2012) Cytochrome c oxidase: Evolution of Control via Nuclear Subunit Addition.  Biochim Biophys Acta, 1817(4):590-7.

Hüttemann M., Helling S., Sanderson T. H., Sinkler C., Samavati L., Mahapatra G., Varughese A., Lu G., Liu J., Ramzan R., Vogt S., Grossman L. I., Doan J. W., Marcus K., and Lee I. (2012) Regulation of Mitochondrial Respiration and Apoptosis Through Cell Signaling: Cytochrome c oxidase and cytochrome c in Ischemia/reperfusion Injury and Inflamation.  Invited Review.  Biochim Biophys Acta, 1817(4):598-609.

Singh L.P., Devi T.S., Lee I., Hüttemann M., Kumar A., Nantwi K.D. (2012) TXNIP Links Innate Host Defense Mechanisms to Oxidative Stress and Inflammation in Retinal Muller Glia Under Chronic Hyperglycemia.  Experimental Diabetes Research, 2012:438438

Hüttemann M., Klewer S., Lee, I., Pecinova A., Pecina P., Liu J., Lee M., Doan J.W., Larson D., Slack E., Maghsoodi B., Erickson R.P., Grossman L.I. (2012) Mice Deleted for Heart-Type Cytochrome c oxidase Subunit 7A1 Develop Dilated Cardiomyopathy that Improves with Age.  Mitochondrion, 12(2):294-304

Helling S., Hüttemann M., Ramzaan R., Kim S.H., Lee I., Müller T., Langenfeld E., Kadenbach B., Vogt S., Marcus K., (2012) Multiple Phosphorylations of Cytochrome c Oxidase and their Functions.  Proteomics, 12(7)950:9

Bauerfeld C.P., Rastogi R., Pirockinaite G., Lee I., Hüttemann M., Monks B., Birnbaum M.J., Franchi L., Nunez G., Samavati L. (2012) TLR4-mediated AKT Activation is MyD88/TRIF-dependent and Critical for Induction of OxPhos and Mitochondrial Transcription Factor A in Murine Macrophages.  J Immunol, 188(6)2847-57

Hüttemann M., Lee I., Malek M.H. (2012) (-)Epicatechin Maintains Endurance Training Adaptation in Mice After 14 Days of Detraining.  FASEB Journal, 26(4):1413-22

Joshi A.S., Thompson M.N., Fei N., Hüttemann M., Greenberg M.L. (2012) Cardiolipin and Mitochondrial Phosphatidylethanolamine Have Overlapping Functions in Mitochondrial Fusion in Saccharomyces Cerevisiae.  J Biol Chem, in press.

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