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Nick Brustovetsky, Ph.D.

Professor of Pharmacology & Toxicology

Education/Training:
Voronezh State University, Voronezh, USSR, M.S. (1980)
Institute of Physiology, USSR Academy of Science, Tashkent, USSR, Ph.D. (1989)
Postdoc with Dr. Martin Klingenberg, Munich University, Germany (1992-1997)  

Mitochondrial bioenergetics, calcium signaling, and neuronal cell death in aging and age-related neurodegenerations.
Our lab studies the mechanisms of mitochondrial dysfunction and neuronal loss in aging and age-related neurodegenerations.

We use transgenic and knock-in mouse models of Huntington's disease and cyclophilin D-knockout mice (Ppif -/-) to study the mechanisms of Huntington's disease (HD) and the role of calcium deregulation and mitochondrial injury in HD progression.

We utilize highly purified isolated brain (synaptic and non-synaptic) mitochondria to analyze the effect of aging on mitochondrial functions. To study isolated mitochondria, we use a computerized setup for simultaneous measurements of respiration, membrane potential, swelling, and calcium uptake by mitochondria. Using isolated mitochondria, we study the mechanisms of mitochondrial injury in aging, particularly, the role of the mitochondrial permeability transition pore. We also investigate the effect of aging on reactive oxygen species (ROS) production.

In addition to isolated mitochondria, we use cultured neurons derived from newborn and adult mice and rats. We use cellular respirometry (Seahorse technology), live-cell fluorescence wide-field and a laser spinning-disk confocal microscopy to investigate mitochondrial dysfunction, calcium deregulation, and ROS production in cultured neurons. We use electron microscopy to analyze mitochondrial morphological changes. We employ western blotting and immunocytochemistry to evaluate expression of different proteins and investigate the release of mitochondrial proteins involved in programmed cell death, apoptosis.

The overall goal of our lab is to determine the mechanisms of calcium deregulation, mitochondrial dysfunction, and neuronal death in aging and age-related neurodegenerations such as Huntington's disease.

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Recent Publications:

  1. Mantel, C.R., O’Leary, H. A., Chitteti, B.R., Huang, X., Cooper, S., Hangoc, G., Brustovetsky, N., Srour, E.F., Lee, M.R., Messina-Graham, S., Haas, D.M., Falah, N., Kapur, R., Pelus, L.M., Bardeesy, N., Fitamant, J., Ivan, M., Kim, K.-S., and Hal E. Broxmeyer, H.E. (2015) Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock.  Cell 161, 1553-1565. PMID: 26073944.

  2. Hamilton, J., Pellman, J.J., Brustovetsky, T., Harris, R., and Brustovetsky, N. (2015) Oxidative metabolism in YAC128 mouse model of Huntington’s disease.  Hum. Mol. Gen.  PMID: 26041817.

  3. Pellman, J.J., Hamilton, J., Brustovetsky, T., and Brustovetsky, N. (2015) Ca2+ handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington’s disease. J. Neurochem. 134, 652-667. PMID: 25963273.

  4. Brustovetsky, N.  (2015) Mutant huntingtin and elusive defects in oxidative metabolism and mitochondrial calcium Handling.  Molecular Neurobiology doi: 10.1007/s12035-015-9188-0.  PMID: 25941077.

  5. Lakhter, A.J., Hamilton, J., Dagher, P.C., Mukkamala, S., Hato, T., Dong, X.C., Lindsey D Mayo, L.D., Harris, R.A., Shekhar, A., Ivan, M., Brustovetsky, N., and Naidu, S.R. (2014)  Ferroxitosis: a cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma.  Oncotarget  5, 12694-12703.  PMID: 25587028.

  6. Brustovetsky, T., Pellman, J.J., Yang, X.-F., Khanna, R., and Brustovetsky, N. (2014) Collapsin response mediator protein 2 interacts with NMDA receptor and Na+/Ca2+ exchanger and regulates their functional activity. J. Biol. Chem. 289, 7470-7482.  PMID: 24474686.

  7. Ashpole, N.M., Chawla, A.R., Martin, M.P., Brustovetsky, T., Brustovetsky, N., and Hudmon, A. (2013) Loss of calcium/calmodulin-dependent protein kinase II activity in cortical astrocytes decreases glutamate uptake and induces neurotoxic release of ATP.  J. Biol. Chem.  288, 14599-14611.  PMID: 23543737.

  8. Brustovetsky, T., Brittain, M.K., Sheets, P.L., Cummins, T.R., Pinelis, V., and Brustovetsky, N. (2011) KB-R7943, an inhibitor of the reverse Na+/Ca2+ exchanger, blocks N-methyl-D-aspartate receptor and inhibits mitochondrial Complex I. British Journal of Pharmacology 162, 255-270.

  9. Brustovetsky, T., Li, T., Yang, Y., Zhang, J-T., Antonsson, B., and Brustovetsky, N. (2010) BAX insertion, oligomerization, and outer membrane permeabilization in brain mitochondria: role of permeability transition and SH-redox regulation. Biochim. Biophys. Acta 1797, 1795-1806. Bioenergetics.

  10. Brustovetsky, T., Bolshakov, A., and Brustovetsky, N. (2010) Calpain activation and Na/Ca exchanger degradation occur downstream of calcium deregulation in hippocampal neurons exposed to excitotoxic glutamate. J. Neurosci. Res. 88, 1317-1328.

  11. Storozhevykh, TP, Senilova, YE, Brustovetsky, T, Pinelis, VG, and Brustovetsky, N. (2010) Neuroprotective effect of KB-R7943 against glutamate excitotoxicity is related to mild mitochondrial depolarization. Neurochem. Res. 35, 323-335.

  12. Li, T., Brustovetsky, T., Antonsson, B., and Brustovetsky, N.  (2010) Dissimilar mechanisms of cytochrome c release induced by octyl glucoside-activated BAX and by BAX activated with truncated BID.  Biochim. Biophys. Acta - Bioenergetics  1797, 52-62.

  13. Li V., Brustovetsky T., and Brustovetsky N.  (2009) Role of cyclophilin D-dependent mitochondrial permeability transition in glutamate-induced calcium deregulation and excitotoxic neuronal death. Experimental Neurology  218, 171-182.

  14. Brustovetsky, T., Li, V., and Brustovetsky, N.  (2009) Stimulation of glutamate receptors in cultured hippocampal neurons causes Ca2+-dependent mitochondrial contraction. Cell Calcium 46, 18-29.

  15. Li, T., Brustovetsky, T., Antonsson, B., and Brustovetsky, N.  (2008) Oligomeric BAX induces mitochondrial permeability transition and complete cytochrome c release without oxidative stress.  Biochim. Biophys. Acta - Bioenergetics, 1777, 1409-1421.

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