RIP3-Dependent Accumulation of Mitochondrial Superoxide Anions in TNF-α-Induced Necroptosis

Jiyoung Lee, Sunmi Lee, Seongchun Min, Sang Won Kang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Excessive production of reactive oxygen species (ROS) is a key phenomenon in tumor necrosis factor (TNF)-α-induced cell death. However, the role of ROS in necroptosis remains mostly elusive. In this study, we show that TNF-α induces the mitochondrial accumulation of superoxide anions, not H2O2, in cancer cells undergoing necroptosis. TNF-α-induced mitochondrial superoxide anions production is strictly RIP3 expression-dependent. Unexpectedly, TNF-α stimulates NADPH oxidase (NOX), not mitochondrial energy metabolism, to activate superoxide production in the RIP3-positive cancer cells. In parallel, mitochondrial superoxide-metabolizing enzymes, such as manganese-superoxide dismutase (SOD2) and peroxiredoxin III, are not involved in the superoxide accumulation. Mitochondrial-targeted superoxide scavengers and a NOX inhibitor eliminate the accumulated superoxide without affecting TNF-α-induced necroptosis. Therefore, our study provides the first evidence that mitochondrial superoxide accumulation is a consequence of necroptosis.

Original languageEnglish
Pages (from-to)193-201
Number of pages9
JournalMolecules and Cells
Issue number4
StatePublished - 30 Apr 2022

Bibliographical note

Publisher Copyright:
© The Korean Society for Molecular and Cellular Biology.


  • NADPH oxidase
  • necroptosis
  • superoxide anion
  • tumor necrosis factor-α


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