Abstract
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 language | English |
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Pages (from-to) | 193-201 |
Number of pages | 9 |
Journal | Molecules and Cells |
Volume | 45 |
Issue number | 4 |
DOIs | |
State | Published - 30 Apr 2022 |
Bibliographical note
Publisher Copyright:© The Korean Society for Molecular and Cellular Biology.
Keywords
- NADPH oxidase
- necroptosis
- superoxide anion
- tumor necrosis factor-α