Mitochondrial Manganese Superoxide Dismutase Prevents Neural Apoptosis and Reduces Ischemic Brain Injury: Suppression of Peroxynitrite Production, Lipid Peroxidation, and Mitochondrial Dysfunction 27/11/2009 05:40:44
Jeffrey N. Keller,1,2 Mark S. Kindy,2,3 Fredrick W. Holtsberg,1 Daret K. St. Clair,4 Hsiu-Chuan Yen,4
Arriane Germeyer,2 Sheldon M. Steiner,1 Annadora J. Bruce-Keller,2 James B. Hutchins,6
and Mark P. Mattson2,5
1Molecular and Cell Biology Division, Department of Biological Sciences, 2Sanders-Brown Research Center on Aging,
3Department of Biochemistry, 4Department of Toxicology, 5Department of Anatomy and Neurobiology, University of
Kentucky, Lexington, Kentucky 40536, and 6Department of Anatomy, University of Mississippi Medical Center,
Jackson, Mississippi 39216
Oxidative stress is implicated in neuronal apoptosis that occurs
in physiological settings and in neurodegenerative disorders.
Superoxide anion radical, produced during mitochondrial respiration,
is involved in the generation of several potentially
damaging reactive oxygen species including peroxynitrite. To
examine directly the role of superoxide and peroxynitrite in
neuronal apoptosis, we generated neural cell lines and transgenic
mice that overexpress human mitochondrial manganese
superoxide dismutase (MnSOD). In cultured pheochromocytoma
PC6 cells, overexpression of mitochondria-localized
MnSOD prevented apoptosis induced by Fe21, amyloid
b-peptide (Ab), and nitric oxide-generating agents. Accumulations
of peroxynitrite, nitrated proteins, and the membrane lipid
peroxidation product 4-hydroxynonenal (HNE) after exposure to
the apoptotic insults were markedly attenuated in cells expressing
MnSOD.
Received Aug. 25, 1997; revised Oct. 30, 1997; accepted Nov. 4, 1997.
This work was supported by National Institutes of Health Grants NS29001,
NS35253, and AG05119 to M.P.M. and by the Kentucky Spinal Cord and Head
Injury Research Trust. We thank J. Begley and W. Fu for technical assistance and G.
Waeg for providing HNE antibody.
Correspondence should be addressed to Dr. Mark P. Mattson, 211 Sanders-Brown
Building, University of Kentucky, Lexington, KY 40536-0230.
Copyright © 1998 Society for Neuroscience 0270-6474/98/180687-11$05.00/0
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