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ARTICLE

Mitochondrial Manganese Superoxide Dismutase Prevents Neural Apoptosis and Reduces Ischemic Brain Injury: Suppression of Peroxynitrite Production, Lipid Peroxidation, and Mitochondrial Dysfunction

Jeffrey N. Keller, Mark S. Kindy, Fredrick W. Holtsberg, Daret K. St. Clair, Hsiu-Chuan Yen, Arriane Germeyer, Sheldon M. Steiner, Annadora J. Bruce-Keller, James B. Hutchins and Mark P. Mattson
Journal of Neuroscience 15 January 1998, 18 (2) 687-697; DOI: https://doi.org/10.1523/JNEUROSCI.18-02-00687.1998
Jeffrey N. Keller
1Molecular and Cell Biology Division, Department of Biological Sciences,
2Sanders-Brown Research Center on Aging,
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Mark S. Kindy
2Sanders-Brown Research Center on Aging,
3Department of Biochemistry,
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Fredrick W. Holtsberg
1Molecular and Cell Biology Division, Department of Biological Sciences,
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Daret K. St. Clair
4Department of Toxicology,
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Hsiu-Chuan Yen
4Department of Toxicology,
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Arriane Germeyer
2Sanders-Brown Research Center on Aging,
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Sheldon M. Steiner
1Molecular and Cell Biology Division, Department of Biological Sciences,
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Annadora J. Bruce-Keller
2Sanders-Brown Research Center on Aging,
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James B. Hutchins
6Department of Anatomy, University of Mississippi Medical Center, Jackson, Mississippi 39216
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Mark P. Mattson
2Sanders-Brown Research Center on Aging,
5Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, and
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Abstract

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 Fe2+, amyloid β-peptide (Aβ), 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. Glutathione peroxidase activity levels were increased in cells overexpressing MnSOD, suggesting a compensatory response to increased H2O2 levels. The peroxynitrite scavenger uric acid and the antioxidants propyl gallate and glutathione prevented apoptosis induced by each apoptotic insult, suggesting central roles for peroxynitrite and membrane lipid peroxidation in oxidative stress-induced apoptosis. Apoptotic insults decreased mitochondrial transmembrane potential and energy charge in control cells but not in cells overexpressing MnSOD, and cyclosporin A and caspase inhibitors protected cells against apoptosis, demonstrating roles for mitochondrial alterations and caspase activation in the apoptotic process. Membrane lipid peroxidation, protein nitration, and neuronal death after focal cerebral ischemia were significantly reduced in transgenic mice overexpressing human MnSOD. The data suggest that mitochondrial superoxide accumulation and consequent peroxynitrite production and mitochondrial dysfunction play pivotal roles in neuronal apoptosis induced by diverse insults in cell culture and in vivo.

  • Alzheimer’s disease
  • amyloid β-peptide
  • cyclosporin A
  • hydroxynonenal
  • middle cerebral artery occlusion
  • nitric oxide
  • superoxide anion radical
  • transgenic
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The Journal of Neuroscience: 18 (2)
Journal of Neuroscience
Vol. 18, Issue 2
15 Jan 1998
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Mitochondrial Manganese Superoxide Dismutase Prevents Neural Apoptosis and Reduces Ischemic Brain Injury: Suppression of Peroxynitrite Production, Lipid Peroxidation, and Mitochondrial Dysfunction
Jeffrey N. Keller, Mark S. Kindy, Fredrick W. Holtsberg, Daret K. St. Clair, Hsiu-Chuan Yen, Arriane Germeyer, Sheldon M. Steiner, Annadora J. Bruce-Keller, James B. Hutchins, Mark P. Mattson
Journal of Neuroscience 15 January 1998, 18 (2) 687-697; DOI: 10.1523/JNEUROSCI.18-02-00687.1998

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Mitochondrial Manganese Superoxide Dismutase Prevents Neural Apoptosis and Reduces Ischemic Brain Injury: Suppression of Peroxynitrite Production, Lipid Peroxidation, and Mitochondrial Dysfunction
Jeffrey N. Keller, Mark S. Kindy, Fredrick W. Holtsberg, Daret K. St. Clair, Hsiu-Chuan Yen, Arriane Germeyer, Sheldon M. Steiner, Annadora J. Bruce-Keller, James B. Hutchins, Mark P. Mattson
Journal of Neuroscience 15 January 1998, 18 (2) 687-697; DOI: 10.1523/JNEUROSCI.18-02-00687.1998
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Keywords

  • Alzheimer’s disease
  • amyloid β-peptide
  • cyclosporin A
  • hydroxynonenal
  • middle cerebral artery occlusion
  • nitric oxide
  • superoxide anion radical
  • transgenic

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