While lipid peroxidation (LPO) is a hallmark of cellular damage and disease, the precise mechanisms by which environmental factors like metal ions modulate this process are not fully elucidated. This study investigates the effects of Mg 2+ , Ca 2+ , and Mn 2+ on the LPO kinetics of two distinct model membrane systems: pure 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) vesicles and anionic vesicles containing 30% 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS). Using fluorescence-based oxidation kinetic measurements, we systematically analyzed LPO under three distinct conditions to differentiate the underlying mechanisms: enzymatic oxidation driven by lipoxygenase (LOX), non-enzymatic oxidation induced by a reactive oxygen species (ROS) generating system, and a combined condition to simulate synergistic effects. We observed that Mg 2+ and Ca 2+ consistently and significantly accelerated LPO in DOPS-containing vesicles across all three oxidative conditions. Importantly, this effect was not observed in neutral DOPC vesicles, suggesting a pivotal role for the negatively charged DOPS headgroups in mediating the metal-ion-induced LPO. In contrast, Mn 2+ appeared to inhibit oxidation in both membrane systems. These findings provide a clear mechanism for how Mg 2+ and Ca 2+ accelerate LPO in anionic membranes, while also highlighting the unique behavior of Mn 2+ . Our work offers a crucial step toward understanding the complex interplay between metal homeostasis, membrane composition, and oxidative stress, which is essential for elucidating the etiology of various diseases.
Cho et al. (Sun,) studied this question.