Anti-death properties of TNF against metabolic poisoning: Mitochondrial stabilization by MnSOD

Annadora J. Bruce-Keller, James W. Geddes, Pamela E. Knapp, Robert W. McFall, Jeffrey N. Keller, Frederick W. Holtsberg, Sampath Parthasarathy, Sheldon M. Steiner, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

The cytokine tumor necrosis factor (TNF) is toxic to some mitotic cells, but protects cultured neurons from a variety of insults by mechanisms that are unclear. Pretreatment of neurons or astrocytes with TNF caused significant increases in MnSOD activity, and also significantly attenuated 3- nitropropionic acid (3-NP) induced superoxide accumulation and loss of mitochondrial transmembrane potential. In oligodendrocytes, however, MnSOD activity was not increased, and 3-NP toxicity was unaffected by TNF. Genetically engineered PC6 cells that overexpress MnSOD also were resistant to 3-NP-induced damage. TNF pretreatment and MnSOD overexpression prevented 3-NP induced apoptosis, and shifted the mode of death from necrosis to apoptosis in response to high levels of 3-NP. Mitochondria isolated from either MnSOD overexpressing PC6 cells or TNF-treated neurons maintained resistance to 3-NP-induced loss of transmembrane potential and calcium homeostasis, and showed attenuated release of caspase activators. Overall, these results indicate that MnSOD activity directly stabilizes mitochondrial transmembrane potential and calcium buffering ability, thereby increasing the threshold for lethal injury. Additional studies showed that levels of oxidative stress and striatal lesion size following 3-NP administration in vivo are increased in mice lacking TNF receptors.

Original languageEnglish (US)
Pages (from-to)53-71
Number of pages19
JournalJournal of Neuroimmunology
Volume93
Issue number1-2
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

Keywords

  • Calcium homeostasis
  • Caspase
  • Cytokines
  • Free radicals
  • Inflammation

ASJC Scopus subject areas

  • Immunology
  • Clinical Neurology
  • Immunology and Allergy
  • Neurology

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