Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand
Reactive oxygen species are proposed to act as mediators in a variety of signalling pathways, including regulated cell death. Disruption of redox homeostasis is commonly observed during cell death, but it is difficult to determine if this is a cause or a consequence of cellular demise. We are investigating redox changes during receptor-mediated cell death, with more recent focus on TNF-mediated necroptosis. The key effector protein in necroptosis is the mixed lineage kinase-domain like (MLKL) pseudokinase. The biochemical mechanisms involved in mediating MLKL function are still poorly understood, but MLKL is phosphorylated and undergoes an oxidative oligomerization early in the process. These events are associated with other redox changes in the cells, and a dramatic alteration in mitochondrial metabolism. We are attempting to piece together the sequence of events in necroptosis signalling and their biological significance.