Altered mitochondrial calcium handling and cell death by necroptosis: An emerging paradigm

The classical necroptosis signaling is mediated by death receptors (DRs) that work in synergy with traditional caspase inhibitory signals. Currently, potential therapeutic molecules are in various phases of clinical trials for a spectrum of pathological conditions associated with necroptosis. However, a non-classical model of necroptosis has also emerged over the last decade with a relatively unexplored molecular mechanism. Although in vitro studies and preclinical models have shown its close association with mitochondrial dysfunction (mito-dysfunction), contradictory reports have emerged which complicate its definitiveness. Though impaired mitochondrial calcium ([Ca2+]m) handling is established in necrotic cell death, how this interplay regulates necroptosis is yet to be elucidated. Taking these questions into consideration, we have discussed various molecular aspects of necroptosis with the emerging role of mito-dysfunction. Based on the central role of altered [Ca2+]m handling in mito-dysfunction mediated necroptosis, we have provided a comprehensive molecular insight into this emerging paradigm. Potential reasons for the contradictory findings regarding the role of mito-dysfunction in necroptosis in general and mitochondrial-dependent necroptosis in specific are discussed. We also provide insights into the current understanding of how [Ca2+]m can be a critical determinant in deciding the cell fate under certain pathological conditions, while under others it may be dispensable. Lastly, we have highlighted the key molecular targets which have a direct implication for therapeutic intervention in conditions that are associated with impaired [Ca2+]m handling and cell death by necroptosis.