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

The cytokine tumor necrosis factor (TNF) is toxic to some mitotic cells, bu t protects cultured neurons from a variety of insults by mechanisms that ar e unclear. Pretreatment of neurons or astrocytes with TNF caused significan t increases in MnSOD activity, and also significantly attenuated 3-nitropro pionic acid (3-NP) induced superoxide accumulation and loss of mitochondria l transmembrane potential. In oligodendrocytes, however, MnSOD activity was not increased, and 3-NP toxicity was unaffected by TNF. Genetically engine ered PC6 cells that overexpress MnSOD also were resistant to 3-NP-induced d amage. TNF pretreatment and MnSOD overexpression prevented 3-NP induced apo ptosis, and shifted the mode of death from necrosis to apoptosis in respons e to high levels of 3-NP. Mitochondria isolated from either MnSOD overexpre ssing PC6 cells or TNF-treated neurons maintained resistance to 3-NP-induce d loss of transmembrane potential and calcium homeostasis, and showed atten uated release of caspase activators. Overall, these results indicate that M nSOD activity directly stabilizes mitochondrial transmembrane potential and calcium buffering ability, thereby increasing the threshold for lethal inj ury. Additional studies showed that levels of oxidative stress;md striatal lesion size following 3-NP administration in vivo are increased in mice lac king TNF receptors. (C) 1999 Elsevier Science B.V. All rights reserved.