635 Barnhill Drive
Medical Science Building Rm 549
Indianapolis, IN 46202
nbrous@iupui.edu
Research Focus
Molecular Mechanisms of Excitotoxicity and
Neuronal Apopstosis.
The studies in my lab are focused on the molecular mechanisms of excitotocixity
and neuronal apoptosis. Currently, we are particularly interested in the role of
mitochondria in neuronal injury induced by a variety of stimuli. In the recent
years, substantial progress has been made in our understanding of the role of
mitochondria in neuronal apoptosis. It has been convincingly demonstrated that
mitochondria are not only “power plants” of the cell but also "decision-making
centers" which determine the cell fate in various situations. Release of
mitochondrial apoptogenic proteins such as cytochrome c, Smac/DIABLO, and
Omi/HtrA2 in response to external stimuli causes activation of caspase cascade
leading to cell death. Release of mitochondrial proteins could be initiated by
the mitochondrial permeability transition (mPT) induced by Ca2+ and/or oxidative
stress or by interaction of pro-apoptotic proteins such as activated (truncated)
BID and/or BAX with the outer mitochondrial membrane (Brustovetsky et al. 2002;
2003). The mPT occurs as a result of activation of gigantic non-selective
channels in the inner mitochondrial membrane formed by calcium modified adenine
nucleotide translocase (Brustovetsky and Klingenberg 1996; Brustovetsky et al.
2002) in combination with some other mitochondrial proteins. However, additional
mechanisms might contribute to the mPT as well. Understanding of the mechanisms
involved in the induction of the mPT and release of mitochondrial proteins may
help to develop a therapeutic strategy to protect neurons in various
neurodegenerative diseases and stroke. Moreover, the knowledge of these
mechanisms may help to fight a drug resistance of cancer cells to increase an
efficacy of chemotherapy. Modern biophysical, biochemical, and cell biological
methods are utilized in my lab in experiments with cultured neurons as well as
with isolated purified brain mitochondria to study protein-protein and
protein-lipid interactions leading to permeabilization of mitochondrial
membranes and eventually to cell death.
Publications
Brustovetsky, T., Antonsson, B., Jemmerson, R., Dubinsky, J.M., and
Brustovetsky, N. (2005) Activation of calcium-independent phospholipase
A2 (iPLA2) in brain mitochondria and release of apoptogenic factors by BAX and
truncated BID. J.Neurochemistry (in press).
Brustovetsky, N., LaFrance, R., Purl, K.J., Brustovetsky, T.,
Keene, C.D., Low, W.C., and Dubinsky, J.M. (2005) Age-dependent changes in the
calcium sensitivity of striatal mitochondria in mouse models of Huntington's
Disease. J. Neurochemistry (in press).
Ronald Jemmerson, R., Dubinsky, J.M, and Brustovetsky, N.
(2005) Cytochrome c release from CNS mitochondria and potential for clinical
intervention in apoptosis-mediated diseases. Antioxidants and Redox Signaling
(in press).
LaFrance, R., Brustovetsky, N., Sherburne, C., DeLong, D., and
Dubinsky, J.M. (2005) Age-Related Changes in Regional Brain Mitochondria from
Fischer 344 Rats. Aging Cell (in press).
Dubinsky, J.M., Brustovetsky, N., and LaFrance, R. (2004)
Protective roles of CNS mitochondria. J.Bioenerg.Biomembr. 36, 299-302.
Brustovetsky, N., Brustovetsky, T., Purl, K.J., Capano, M.,
Crompton, M., and Dubinsky, J .M. (2003) Increased susceptibility of striatal
mitochondria to calcium- induced permeability transition J.Neuroscience. 23,
4858-4867.
Brustovetsky, N., Dubinsky, J.M., Antonsson, B., and Jemmerson,
R. (2003) Two pathways for tRill-induced cytochrome c release from brain
mitochondria: BAK- versus BAX-dependent. J.Neurochem. 84, 196-207.
Brustovetsky, N., Tropschug, M., Heimpel, S., Heidkamper, D.,
and Klingenberg, M. (2002) A large Ca2+-dependent channel formed by
recombinant ADP/ATP carrier from Neurospora crassa resembles the mitochondrial
permeability transition pore. Biochemistry, 41, 11804-11811.
Brustovetsky, N., Brustovetsky, T., Jemmerson, R., and Dubinsky, J.M.
(2002) Calcium-induced cytochrome c release from CNS mitochondria is associated
with the permeability transition and rupture of the outer membrane. J.Neurochem.
80, 207- 218.
Brustovetsky, N., Brustovetsky, T., and Dubinsky, J.M. (2001)
On the mechanism of neuroprotection by creatine and phosphocreatine. J.Neurochem.
76, 425-434.
Brustovetsky, N., and Dubinsky, J .M. (2000) Limitations of
cyclosporin A inhibition of the permeability transition in CNS mitochondria.
J.Neuroscience 20, 8229-8237.
Brustovetsky, N., and Dubinsky, J.M. (2000) Dual responses of
CNS mitochondria to elevated calcium. J.Neuroscience 20,103-113.
Gropp, T., Brustovetsky, N., Klingenberg, M., Muller, V.,
Fendler, K., and Bamberg, E. (1999) Kinetics of electrogenic transport by the
ADP/ATP carrier. Biophys.J. 77, 714-726.
Brustovetsky, N., Bamberg, E., Gropp, T., and Klingenberg, M.
(1997) Biochemical and physical parameters of the electrical currents measured
with the ADP/ATP carrier by photolysis of caged ADP and ATP. Biochemistry 36,
13865-13872.
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