Manganese superoxide dismutase protects from TNF-α-induced apoptosis by increasing the steady-state production of H2O2

Jaya Dasgupta*, Sita Subbaram, Kip M. Connor, Ana M. Rodriguez, Oren Tirosh, Joseph S. Beckman, David Jourd'Heuil, J. Andrés Melendez

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Manganese superoxide dismutase (SOD2) has been well established to be essential for protection from a variety of apoptotic stimuli. Here we demonstrate that the antiapoptotic effects of SOD2 are attributed to its ability to generate H2O2 and that its efficient removal resensitizes cells to tumor necrosis factor (TNF)-α-induced apoptosis. SOD2 overexpression in HT-1080 cells leads to a decrease in the fluorescence of the superoxide-sensitive fluorophore, dihydroethidium, and a concomitant increase in oxidation of the H2O2-sensitive dye, dichlorodihydrofluorescein diacetate (DCFDA). The rate of aminotriazole- inhibited catalase activity also was increased when SOD2 is overexpressed and reflects a 1.6-fold increase in the steady-state production of H 2O2. The increase in H2O2 was associated with decreased sensitivity to TNF-α-mediated apoptosis, as measured by monitoring the loss of mitochondrial membrane potential (MMP), caspase activation, poly-ADP ribose polymerase (PARP) cleavage, and accumulation of hypodiploid DNA content. Both the increase in H2O2 and resistance to TNF-mediated apoptosis were reversed by coexpression of catalase. The lipid hydroperoxide scavengers, β-hydroxytoluene and trolox, and the iron chelator, desferroxamine, showed partial recovery of TNF-induced apoptosis. These findings indicate that increases in the intracellular steady-state production of H2O2 by SOD2 can block the activation of key processes fundamental to the process of programmed cell death.

Original languageAmerican English
Pages (from-to)1295-1305
Number of pages11
JournalAntioxidants and Redox Signaling
Volume8
Issue number7-8
DOIs
StatePublished - Jul 2006

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