Necroptosis: is there a role for mitochondria?

Once thought to be a random process of cell death, necrosis can proceed via a defined molecular mechanism and is integral to physiological and pathological states. In particular a form of necrosis called necroptosis has been the subject of intense investigation. Necroptosis is initiated by tumor necrosis factor-α (TNFα), which leads to the activation of the kinase receptor-interacting protein 1 (RIP1). RIP1 then binds with and activates RIP3 to form the necrosome. RIP3 in turn interacts with and activates the pseudokinase mixed lineage kinase domain-like (MLKL). This complex has then been proposed to induce necrotic death via the induction of mitochondrial dysfunction, with a variety of mechanisms being put forth including: production of mitochondrial reactive oxygen species (ROS), activation of the mitochondrial phosphatase PGAM5, or induction of mitochondrial permeability transition (MPT). However, recent evidence suggests that none of these are involved in necroptosis, and that mitochondria may in fact be dispensable for this process. Therefore, the purpose of this perspective is to discuss the current understanding of necroptosis, and more specifically, what role if any do mitochondria play in this mechanism of cell death.