Jeong Hye Jin, Min Sein, Villalon Lucas A, Jeong Keunhong, Chung Jean K
Department of Physics and Chemistry, Korea Military Academy, Seoul 01805, South Korea.
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
JACS Au. 2025 Aug 15;5(9):4337-4345. doi: 10.1021/jacsau.5c00696. eCollection 2025 Sep 22.
Lipid peroxidation (LPO) of cellular membranes is a near-universal indicator of aging and disease, yet the mechanistic link between the LPO and disease remains elusive. In this study, we demonstrate that efficient LPO in model membranes is accomplished through synergy between selective enzymatic oxidation by lipoxygenase (LOX) and nonspecific oxidation by reactive oxygen species (ROS). Through fluorescence-based oxidation kinetic measurements, we show that soluble ROS alone fails to induce significant oxidation under physiologically relevant conditions. However, enzymatic oxidation enhances the ROS-driven LPO by altering membrane permeability. Strikingly, this process drives the macroscopic clustering of the membrane-bound protein KRAS on giant unilamellar vesicles (GUVs), revealing potential functional consequences. If this mechanism extends to living cells, it could reshape our understanding of oxidative stress in disease. Our findings represent an essential step toward advancing an integrated understanding of oxidative membrane biology, encompassing both enzymatic oxidation and oxidation by ROS.
细胞膜的脂质过氧化（LPO）是衰老和疾病几乎通用的指标，然而LPO与疾病之间的机制联系仍不清楚。在本研究中，我们证明模型膜中的高效LPO是通过脂氧合酶（LOX）的选择性酶促氧化与活性氧（ROS）的非特异性氧化之间的协同作用实现的。通过基于荧光的氧化动力学测量，我们表明在生理相关条件下，单独的可溶性ROS不能诱导显著的氧化。然而，酶促氧化通过改变膜通透性增强了ROS驱动的LPO。令人惊讶的是，这一过程驱动了巨型单层囊泡（GUV）上膜结合蛋白KRAS的宏观聚集，揭示了潜在的功能后果。如果这种机制扩展到活细胞，可能会重塑我们对疾病中氧化应激的理解。我们的发现是朝着推进对氧化膜生物学的综合理解迈出的重要一步，包括酶促氧化和ROS氧化。
