Spatial regulation of phospholipid peroxidation by endoplasmic reticulum-mitochondria contact sites: implications for neuronal ferroptosis in Alzheimer’s disease

Ferroptosis-related alterations have been reported in Alzheimer’s disease (AD), but where neuronal phospholipid peroxidation begins and how it propagates between organelles remain unclear. Endoplasmic reticulum-mitochondria contact sites coordinate phospholipid exchange and influence local redox processes, potentially regulating the spatial distribution of this damage. Evidence from non-AD experimental systems implicates contact-associated membranes in early phospholipid peroxidation. Specific contact-associated pathways can also transfer lipid radicals from mitochondria to the endoplasmic reticulum, alleviating mitochondrial oxidative damage. AD models have separately shown alterations in contact structures and membrane lipid composition, while postmortem human brain tissue also exhibits contact-associated phenotypes. However, these observations have not been directly linked causally to the spatiotemporal dynamics of phospholipid peroxidation and ferroptotic outcomes within the same AD-relevant neuronal system. Based on this evidence, we propose a working hypothesis requiring validation. AD-associated contact remodeling may alter the local supply of oxidizable phospholipids and the interorganelle distribution of lipid radicals, thereby influencing neuronal phospholipid peroxidation and ferroptosis susceptibility. This hypothesis can be tested in AD-relevant neuronal models by jointly measuring contact structures, lipid exchange flux, and the subcellular location and temporal sequence of phospholipid peroxidation. These measurements should be combined with pathway-specific interventions and ferroptosis rescue experiments. If these causal relationships are validated, this framework could provide a mechanistic basis for identifying neuronal membrane lipid oxidation biomarkers and preclinically evaluating candidate contact-site-associated intervention targets.