Necroptosis is a type of highly regulated necrotic cell death which is characterized by translocation of the MLKL protein to the plasma membrane. This results in loss of plasma membrane integrity, release of intracellular contents, and an inflammatory response. Although extensive efforts have been dedicated to understanding the protein machinery involved in necroptosis, which contributes to numerous inflammatory pathologies, relatively little research has focused on understanding the roles of specific lipids in the membrane-related changes which are essential to necroptosis. We investigated global changes in lipid composition during necroptosis using an untargeted LC-MS-based approach. Among our findings, we revealed a striking accumulation saturated very long chain fatty acids, which contain ≥20 carbons in their acyl chain, during necroptosis. We discovered that preventing very long chain fatty acid biosynthesis prevents membrane permeabilization and ameliorates necroptotic cell death. We therefore believe that these lipids are functionally involved in the membrane-related changes that occur during necroptosis. We investigated the effects of very long chain fatty acids in biological and artificial membranes, and used molecular dynamics simulations to provide insights into their effects on membrane properties. We are currently investigating the role of these lipids as substrates for protein acylation, which we suspect may play a role in targeting proteins to the plasma membrane during necroptosis, using “clickable” very long chain fatty acid probes.<br/>

Very long chain fatty acids play a functional role during necroptosis

2019 Fall National Meeting

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