University of Veterinary Medicine Vienna Membrane Lipid Reshaping Underlies Oxidative Stress Sensing by the Mitochondrial Proteins UCP1 and ANT1 Oxidative stress and ROS are important players in the pathogenesis of numerous diseases. In addition to directly altering proteins, ROS also affects lipids with negative intrinsic curvature such as phosphatidylethanolamine (PE), producing PE adducts and lysolipids. The formation of PE adducts potentiates the protonophoric activity of mitochondrial uncoupling proteins, but the molecular mechanism remains unclear. Here, we linked the ROS-mediated change in lipid shape to the mechanical properties of the membrane and the function of uncoupling protein 1 (UCP1) and adenine nucleotide translocase 1 (ANT1). We show that the increase in the protonophoric activity of both proteins occurs due to the decrease in bending modulus in lipid bilayers in the presence of lysophosphatidylcholines (OPC and MPC) and PE adducts. Moreover, MD simulations showed that modified PEs and lysolipids change the lateral pressure profile of the membrane in the same direction and by the similar amplitude, indicating that modified PEs act as lipids with positive intrinsic curvature. Both results indicate that oxidative stress decreases stored curvature elastic stress (SCES) in the lipid bilayer membrane. We demonstrated that UCP1 and ANT1 sense SCES and proposed a novel regulatory mechanism for the function of these proteins. The new findings should draw the attention of the scientific community to this important and unexplored area of redox biochemistry. en TEXT article Keywords: Force-Field; Spontaneous Curvature; Atp Synthase; Fatty-Acids; Phosphatidylethanolamine; Mechanism; Validation; Proton; Shape; Phospholipids 2023 2023 Jovanović, Olga (University of Veterinary Medicine Vienna) Pohl, Elena E (University of Veterinary Medicine Vienna) Bashkirov, Pavel V. (Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow / Scientific Research Institute of System Biology and Medicine, Moscow ) Vazdar, Mario (University of Chemistry and Technology, Prague) Žuna, Kristina (University of Veterinary Medicine Vienna) Chekashkina, Ksenia (Federal Research and Clinical Center of Physical-Chemical Medicine / A.N. Frumkin Institute of Physical Chemistry and Electrochemistry) Škulj, Sanja (University of Zagreb) MDPI