Pro-ferroptotic lipids as key control points for caveola formation and disassembly
Yeping Wu, Ye‐Wheen Lim, Kerrie‐Ann McMahon, Nick Martel, James Rae, Harriet P. Lo, Ya Gao, Vikas A. Tillu, Elin Larsson, Richard Lundmark, Daniel S. Levic, Michel Bagnat, Junxian Lim, David P. Fairlie, Albert Pol, Brett M. Collins, Nicholas Ariotti, Thomas E. Hall, Robert G. Parton
Abstract
Caveolae are specialized plasma membrane domains with a unique lipid composition. Lipid peroxidation has recently been implicated in triggering caveola disassembly, releasing cavin proteins to regulate oxidative-stress-associated cellular processes, particularly ferroptosis. Here, we investigated how specific lipids influence caveola formation and their response to oxidative stress. A targeted screening of pro-ferroptotic enzymes identified ACSL4, a key enzyme in synthesizing polyunsaturated fatty acid (PUFA)-linked phospholipids, and ether phospholipid biosynthesis enzymes as critical regulators of caveola formation. Membrane-incorporated omega-6 PUFAs promoted caveola formation, while their displacement by omega-3 PUFAs or monounsaturated fatty acids disrupted this process. Importantly, oxidation of omega-6 PUFA chains in phosphatidylethanolamine (PE) triggered caveola disassembly during lipid peroxidation, potentially by affecting cavin-membrane interactions. These findings unveil a new model for caveola formation and signaling, linking caveola dynamics to ferroptosis with pro-ferroptotic lipids as essential caveolar components and key control points for caveola disassembly under oxidative stress.