RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis

The Grim RIPper Cells can undergo regulated cell death through distinct processes known as apoptosis and necrosis. Regulation of apoptosis is better understood than that of necrosis. In a screen for gene products that participate in control of necrosis in cells treated with TNF (tumor necrosis factor), D.-W. Zhang et al. (p. 332 ; published online 4 June) identified a protein kinase, RIP3. In cells treated with TNF and a caspase inhibitor that inhibits apoptosis, seven metabolic enzymes interacted with RIP3, some of which are associated with mitochondria. Generation of reactive oxygen species was necessary for TNF-induced necrosis, and depletion of RIP3 reduced the generation of reactive oxygen species. Thus, RIP3 may participate in the mechanisms that link energy metabolism with mechanisms of cell death.