Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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RIP3-Dependent Accumulation of Mitochondrial Superoxide Anions in TNF-α-Induced Necroptosis

  • Lee, Jiyoung (Department of Life Science, College of Natural Science, Ewha Womans University) ;
  • Lee, Sunmi (Department of Life Science, College of Natural Science, Ewha Womans University) ;
  • Min, Seongchun (Department of Life Science, College of Natural Science, Ewha Womans University) ;
  • Kang, Sang Won (Department of Life Science, College of Natural Science, Ewha Womans University)
  • Received : 2021.11.10
  • Accepted : 2021.12.10
  • Published : 2022.04.30
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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.

Keywords

Acknowledgement

We thank Prof. Yun Soo Bae (Ewha Womans University) for sharing APX-115 reagent. This study was supported by grants from the National Research Foundation of Korea (2018R1A2B3006323 and 2017M3A9B6073098). S.M. was also supported by grants from the National Research Foundation of Korea (2019R1I1A1A01057557) and the RP-Grant (2019-2020) of Ewha Womans University.

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