“Death is my Heir”—Ferroptosis Connects Cancer Pharmacogenomics and Ischemia- Reperfusion Injury  Wulf Tonnus, Andreas Linkermann  Cell Chemical Biology  Volume 23, Issue 2, Pages 202-203 (February 2016) DOI: 10.1016/j.chembiol.2016.02.005 Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 1 A Speculative Model of an NADPH Abundance Gradient That Defines the Risk of Ferroptosis and Directs the Progression of Synchronized Regulated Necrosis An isolated, severely injured cell may undergo an NADPH-depleting form of regulated necrosis, such as ferroptosis, necroptosis, mitochondrial permeability transition-mediated regulated necrosis (MPT-RN), parthanatos, or oxytosis (Vanden Berghe et al., 2014), and succumb to this cell death. In vivo, in a functional syncytium such as a renal tubule that is interconnected through the epithelial cell layer by gap junctions and other pores that allow a free diffusion of NADPH from one cell to the next, a low NADPH concentration in one cell will negatively affect the NADPH concentration of the neighboring cell. The white arrows indicate the putative flow of NADPH toward the areas of lower cytosolic concentration. Shimida et al. demonstrate that low NADPH levels are a biomarker for the sensitivity of a particular cell to undergo ferroptosis. For the first time, this computational study now suggests a speculative model of how the observation of synchronized regulated necrosis may be explained. GPX4, glutathione peroxidase 4; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; NADK, NAD+-kinase. Cell Chemical Biology 2016 23, 202-203DOI: (10.1016/j.chembiol.2016.02.005) Copyright © 2016 Elsevier Ltd Terms and Conditions