Necroptosis is a type of highly regulated necrotic cell death. It is characterized by the permeabilization of the plasma membrane via mixed-lineage kinase-like protein (MLKL) and release of intracellular contents at early stages of the process. This permeabilization facilities the leakage of cytosolic material to extracellular environment, which causes cell death; at the organismal level, this leakage causes an inflammatory response in the surrounding tissues. Given this critical role of membranes during necroptosis, little research has focused on understanding the roles of lipids in the membrane-related changes during this process. To identify novel lipid players of necroptosis, we employed untargeted lipidomics and showed that saturated very long chain fatty acids (VLCFAs) accumulated via activated biosynthesis in necroptosis. Depleting the levels of VLCFAs resulted in reduced necroptotic cell death and membrane permeabilization whereas increasing VLCFA levels induced membrane permeabilization, showing that VLCFAs are functionally involved in necroptosis. We used atomistic Molecular Dynamics simulations to investigate the microscopic origin of these observations and showed that it is the interdigitation of C24 FA between the individual leaflets that results in disorder and, consequently, membrane disruption. In parallel, we also showed that saturated VLCFAs can also be incorporated into numerous membrane proteins during necroptosis, including MLKL and phosphoMLKL, key for membrane permeabilization, during necroptosis. Our results point to convergent mechanisms of membrane disruption, including targeting of proteins to cellular membranes by fatty acylation and permeabilization via bilayer disruption during necroptosis. Our current efforts are towards the identification of the pathways that result in the activation of VLCFA biosynthesis and the acyltransferases that can process these specific lipids during necroptosis.

Noncanonical Roles of Lipids in Necroptosis

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