Serious mitochondrial injury has been proposed as underlying mechanism of many acute and chronic neurodegenerative diseases. However, how exactly mitochondria participate in the pathogenesis of neurodegeneration is unclear. Mitochondria are dynamic organelles, undergoing frequent fission (separation) and fusion. New findings in tumor cell lines, indicate that mitochondria rapidly fragment in response to apoptotic stimuli, a process that may facilitate the release of apoptogenic factors from mitochondria, an increase in reactive oxygen species (ROS), and changes in energy supply. Mitochondrial fission is regulated by evolutionary, highly conserved machinery, involving Dynamin-related GTPases. Among them is Drp-1, which mediates mitochondrial fission. The purpose of this proposal is to explore the new concept that mitochondrial fission is a key component of excitotoxic neuronal cell death. Among the specific questions that will be addressed are: (1) Do mitochondria undergo fission in neuronal cell death evoked by NMDA or NO exposure? (2) Does Drp-1 regulate mitochondrial fission in neuronal cell death? (3) How do pro- and anti-apoptotic Bcl-2 family members regulate mitochondrial fission? To address these questions primary cerebrocortical neurons will be analyzed with multi-disciplinary approaches, including cell biology, time-lapse fluorescence deconvolution microscopy, electron tomography, molecular genetics (dominant-negative mutants and siRNA), and biochemistry. This study will improve our general understanding of the cellular and molecular mechanism of neuronal cell death. In particular, it will address how mitochondria contribute to this process. In addition, it will provide new insights into how the mitochondrial fission machinery recruits the cell death program. Most importantly, drugs targeting the mitochondrial fission/fusion machinery may open new therapeutic opportunities to combat chronic and acute neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS047456-05
Application #
7472852
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Golanov, Eugene V
Project Start
2003-09-30
Project End
2009-01-31
Budget Start
2007-01-16
Budget End
2009-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$120,501
Indirect Cost
Name
University of Central Florida
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
150805653
City
Orlando
State
FL
Country
United States
Zip Code
32826
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Kushnareva, Y E; Gerencser, A A; Bossy, B et al. (2013) Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ 20:353-65
Song, Wenjun; Chen, Jin; Petrilli, Alejandra et al. (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17:377-82
Montessuit, Sylvie; Somasekharan, Syam Prakash; Terrones, Oihana et al. (2010) Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142:889-901
Perkins, Guy; Bossy-Wetzel, Ella; Ellisman, Mark H (2009) New insights into mitochondrial structure during cell death. Exp Neurol 218:183-92
Knott, Andrew B; Bossy-Wetzel, Ella (2009) Nitric oxide in health and disease of the nervous system. Antioxid Redox Signal 11:541-54
Liot, G; Bossy, B; Lubitz, S et al. (2009) Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Cell Death Differ 16:899-909
Knott, Andrew B; Bossy-Wetzel, Ella (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283-92
Gerencser, Akos A; Doczi, Judit; Torocsik, Beata et al. (2008) Mitochondrial swelling measurement in situ by optimized spatial filtering: astrocyte-neuron differences. Biophys J 95:2583-98
Knott, Andrew B; Perkins, Guy; Schwarzenbacher, Robert et al. (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505-18

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