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

This is the authors' abstract. We don't add key points for this paper.

factor (TNF)--induced cell death. However, the role of ROS in necroptosis remains mostly elusive. In this study, we show that TNF- induces the mitochondrial accumulation of superoxide anions, not H 2 O 2 , in cancer cells undergoing necroptosis. TNF-induced mitochondrial superoxide anions production is strictly RIP3 expression-dependent. Unexpectedly, TNF- stimulates NADPH oxidase (NOX), not mitochondrial energy metabolism, to activate superoxide production in the RIP3positive cancer cells. In parallel, mitochondrial superoxidemetabolizing 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--induced necroptosis. Therefore, our study provides the first evidence that mitochondrial superoxide accumulation is a consequence of necroptosis.