Maik Huettemann (ah6179)

Ph.D., Marburg (Germany), 1999

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Dr. Huttemann's research includes cytochrome c and cytochrome c oxidase, the regulation of mitochondrial oxidative phosphorylation through cell signaling pathways, and mitochondria as a target for therapy and diagnostics in human diseases including ischemia reperfusion injury in the heart and brain and cancer.

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).

• Mahapatra G, Varughese A, Ji Q, Lee I, Liu J, Vaishnav A, Sinkler C, Kapralov AA, Moraes CT, Sanderson TH, Stemmler TL, Grossman LI, Kagan VE, Brunzelle JS, Salomon AR, Edwards BF, Hüttemann M (2017) Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE. J Biol Chem 292: 64-79.
• Aras S, Arrabi H, Purandare N, Hüttemann M, Kamholz J, Zuchner S, Grossman LI (2017) Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration. Biochim Biophys Acta 1864: 440-448.
• Zhang K, Wang G, Zhang X, Hüttemann PP, Qiu Y, Liu J, Mitchell A, Lee I, Zhang C, Lee JS, Pecina P, Wu G, Yang ZQ, Huttemann M, Grossman LI (2016) COX7AR is a Stress-inducible Mitochondrial COX Subunit that Promotes Breast Cancer Malignancy. Sci Rep 6: 31742.
• Lee I, Hüttemann M, Malek MH (2016) (-)-Epicatechin Attenuates Degradation of Mouse Oxidative Muscle Following Hindlimb Suspension. J Strength Cond Res 30: 1-10.
• Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Hüttemann M, Podgorski I (2016) Bone marrow adipocytes promote the warburg phenotype in metastatic prostate tumors via HIF-1alpha activation. Oncotarget 7: 64854-64877.
• Shay J, Elbaz HA, Lee I, Zielske SP, Malek MH, Hüttemann M (2015) Molecular mechanisms and therapeutic effects of (-)-epicatechin and other polyphenols in cancer, inflammation, diabetes, and neurodegeneration. Oxid Med Cell Longev in press.
• Maurer SF, Fromme T, Grossman LI, Hüttemann M, Klingenspor M (2015) The brown and brite adipocyte marker Cox7a1 is not required for non-shivering thermogenesis in mice. Sci Rep 5: 17704.
• Marshall J, Wong KY, Rupasinghe CN, Tiwari R, Zhao X, Berberoglu ED, Sinkler C, Liu J, Lee I, Parang K, Spaller MR, Hüttemann M, Goebel DJ (2015) Inhibition of N-Methyl-D-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential. J Biol Chem 290: 22030-22048.
• Kadenbach B, Hüttemann M 2015) The subunit composition and function of mammalian cytochrome c oxidase. Mitochondrion 24: 64-76.
• Horsch M, Aguilar-Pimentel JA, Bonisch C, Come C, Kolster-Fog C, Jensen KT, Lund AH, Lee I, Grossman LI, Sinkler C, Hüttemann M, Bohn E, Fuchs H, Ollert M, Gailus-Durner V, de Angelis MH, Beckers J (2015) Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines. PLoS One 10: e0134503.
• Elbaz HA, Lee I, Antwih DA, Liu J, Hüttemann M, Zielske SP (2014) Epicatechin stimulates mitochondrial activity and selectively sensitizes cancer cells to radiation. PloS One 9: e88322.
• Sanderson TH, Mahapatra G, Pecina P, Ji Q, Yu K, Sinkler C, Varughese A, Kumar R, Bukowski MJ, Tousignant RN, Salomon AR, Lee I, Hüttemann M (2013) Cytochrome c is tyrosine 97 phosphorylated by neuroprotective insulin treatment. PLoS One 8: e78627.
• Lee I, Hüttemann M, Liu J, Grossman LI, Malek MH (2012) Deletion of heart-type cytochrome c oxidase subunit 7a1 impairs skeletal muscle angiogenesis and oxidative phosphorylation. J Physiol 590: 5231-5243.
• Hüttemann M, Lee I, Gao X, Pecina P, Pecinova A, Liu J, Aras S, Sommer N, Sanderson TH, Tost M, Neff F, Aguilar-Pimentel JA, Becker L, Naton B, Rathkolb B, Rozman J, Favor J, Hans W, Prehn C, Puk O, Schrewe A, Sun M, Hofler H, Adamski J, Bekeredjian R, Graw J, Adler T, Busch DH, Klingenspor M, Klopstock T, Ollert M, Wolf E, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Weissmann N, Doan JW, Bassett DJ, Grossman LI (2012) Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology. FASEB J 26: 3916-3930.
• Hüttemann M, Klewer S, Lee I, Pecinova A, Pecina P, Liu J, Lee M, Doan JW, Larson D, Slack E, Maghsoodi B, Erickson RP, Grossman LI (2012) Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy. Mitochondrion 12: 294-304.

Professor

3214 Scott Hall
540 East Canfield
Detroit, MI 48201 

Center for Molecular Medicine and Genetics, Biochemistry and Molecular Biology 

http://www.genetics.wayne.edu/faculty/maik-huttemann 

• Effect of cell signaling on mitochondrial metabolism, cytochrome c, and cytochrome c oxidase.
• Mitochondrial metabolism in cancer.
• Development of mitochondria-targeted therapies for ischemia/reperfusion injury as seen in stroke and myocardial infarction.
 

Dr. Hüttemann's team studies mitochondrial function using genetic, biochemical, and functional approaches. The group focuses 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). Together the two proteins play a key role in life and death decisions of the cell via energy production under healthy conditions and free radical generation and apoptosis under conditions of cellular stress. The overall goal is to understand the regulation of COX and Cytc in normal and disease conditions including cancer, and to apply this knowledge for diagnosis and treatment.

Strubakos, C.D., Malik, M., Wider, J.M., Lee, I., Mitsias, P., Hüttemann, M., Sanderson, T.H. Non-Invasive mitochondrial modulation with near-infrared light reduces brain injury after stroke. J Cereb Blood Flow Metab, 2020;40:833-44.

Erickson, R. P., Aras, S., Purandare, N., Hüttemann, M., Liu, J., Dragotto, J., Fiorenza, M. T., and Grossman, L. I. Decreased membrane cholesterol in liver mitochondria of the point mutation mouse model of juvenile Niemann-Pick C1, Npc1(nmf164). Mitochondrion 2020;51:15-21.

Kalpage H.A., Wan J., Morse, P.T., Zurek, M.P., Turner, A.A., Khobeir, A., Yazdi, N., Hakim, L., Liu J., Vaishnav A., Sanderson T.H., Recanati M.A., Grossman L.I., Lee I., Edwards B.F., Hüttemann M.  Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis. Int J Biochem Cell Biol. 2020;121:105704.

Moreno-Domínguez, A., Ortega-Sáenz, P., Gao, L., Colinas, O., García-Flores, P., Bonilla-Henao, V., Aragonés, J., Hüttemann, M., Grossman, L.I., Weissmann, N., Sommer, N., López-Barneo, J.  Acute O2 sensing through HIF2a-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors. Sci Signal. 2020;13:eaay9452.

Dekhne A.S., Ning C., Nayeen, M.J., Shah, K., Kalpage, H.A., Fruhauf, J.. , Wallace-Povirk, A., O'Connor, C., Hou, Z., Kim, S., Hüttemann, M., Gangjee, A., Matherly, L.H. Cellular pharmacodynamics of a novel pyrrolo[3,2-d]pyrimidine inhibitor targeting mitochondrial and cytosolic one-carbon metabolism. Mol Pharmacol. 2020;97:9-22.

Kalpage H.A., Bazylianska V., Recanati M.A., Fite A., Liu J., Wan J., Mantena N., Malek M.H., Podgorski I., Heath E.I., Vaishnav A., Edwards B.F., Grossman L.I., Sanderson T.H., Lee I., Hüttemann M. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J. 2019; 33:1540-53.

Wan, J., Kalpage, H.A., Vaishnav, A., Liu, J., Lee, I., Mahapatra, G., Turner, A.A., Zurek, M.P., Ji, Q., Moraes, C.T., Recanati, M.A., Grossman, L.I., Salomon, A.R., Edwards, B.F.P., Hüttemann, M. Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation. Sci Rep.  2019;9:15815.

Kalpage, H. A., Vaishnav, A., Liu, J., Varughese, A., Wan, J., Turner, A. A., Ji, Q., Zurek, M. P., Kapralov, A. A., Kagan, V. E., Brunzelle, J. S., Recanati, M. A., Grossman, L. I., Sanderson, T. H., Lee, I., Edwards, B. F., and Hüttemann, M. Serine-47 Phosphorylation of Cytochrome c in the Mammalian Brain Regulates Cytochrome c Oxidase and Caspase-3 Activity. FASEB J. 2019;33:13503-14.

Meng, F., Wu, L., Dong, L., Mitchell, A., Block, CJ., Liu, J., Zhang, H., Lu, Q., Song, W, Zhang, B., Chen, W., Hu, J., Wang, J., Yang, Q., Hüttemann, M., Wu, G. EGFL9 Promotes Breast Cancer Metastasis by Inducing cMET Activation and Metabolic Reprogramming. Nat Commun. 2019;10:5033.

Dekhne, A. S., Shah, K., Ducker, G. S., Katinas, J. M., Wong-Roushar, J., Nayeen, M. J., Doshi, A., Ning, C., Bao, X., Fruhauf, J., Liu, J., Wallace-Povirk, A., O'Connor, C., Dzinic, S. H., White, K., Kushner, J., Kim, S., Hüttemann, M., Polin, L., Rabinowitz, J. D., Li, J., Hou, Z., Dann, C. E., 3rd, Gangjee, A., and Matherly, L. H. Novel Pyrrolo[3,2-d]pyrimidine Compounds Target Mitochondrial and Cytosolic One-carbon Metabolism with Broad-spectrum Antitumor Efficacy. Mol Cancer Ther. 2019;18:1787-99.

Dean, J., Kramer, K. J., Akbary, F., Wade, S., Hüttemann, M., Berman, J. M., and Recanati, M. A. Norethindrone is superior to combined oral contraceptive pills in short-term delay of menses and onset of breakthrough bleeding: a randomized trial. BMC Womens Health 2019;19:70.

Raja, V., Salsaa, M., Joshi, A.S., Li, Y., van Roermund, C.W.T., Saadat, N., Lazcano, P., Schmidtke, M., Hüttemann, M., Gupta, S.V., Wanders, R.J.A., Greenberg, M.L. Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function. Biochim Biophys Acta Mol Cell Biol Lipids 2019;1864:654-61.

BS in Chemistry (1992): Philipps-University Marburg, Germany
MS in Chemistry and Biochemistry (1995): Philipps-University Marburg, Germany
PhD in Biochemistry and Molecular Biology (1999): Philipps-University Marburg, Germany 

CB7220 Molecular Biology of Cancer Development
CB7700 Recent Developments in Cancer Biology