TNF-α-induced ROS production triggering apoptosis is directly linked to Romo1 and Bcl-XL

Abstract

Reactive oxygen species (ROS) produced by tumor necrosis factor-α (TNF-α) have an important function in cell death by activating c-Jun N-terminal kinase. However, the exact mechanism of mitochondrial ROS production, after TNF-α stimulation, is not clearly understood. In this study, we determined that ROS modulator 1 (Romo1) and B-cell lymphoma-extra large (Bcl-X L) are directly associated with TNF-α-induced ROS production. In response to TNF-α, TNF complex II, which consists of receptor-interacting protein 1, TNF receptor-associated protein with death domain, TNF receptor-associated factor 2, Fas-associated death domain protein, and pro-caspase-8, binds to the C-terminus of Romo1 located in the mitochondria. Concurrently, Romo1 recruits Bcl-X L to reduce the mitochondrial membrane potential, resulting in ROS production and apoptotic cell death. On the basis of these results, we suggest that Romo1 is a molecular bridge between TNF-α signaling and the mitochondria for ROS production that triggers TNF-α-mediated apoptosis, as well as a novel target in the development of anti-inflammatory agents that block the origin of ROS production. © 2010 Macmillan Publishers Limited. All rights reserved.