A recent study investigates the critical role of endoplasmic reticulum-mitochondria contact sites (EMCSs) in phospholipid peroxidation (PLox) and ferroptosis, a form of cell death associated with lipid oxidation.

The research emphasizes the significance of EMCS remodeling in propagating lipid peroxidation signals, highlighting potential intervention points for regulating ferroptosis.

Using high-resolution live cell imaging and oxidative phospholipidomics, the study reveals that EMCSs serve as primary sites for early PLox during the onset of ferroptosis.

Upon induction of ferroptosis with agents such as RSL3 and IKE, EMCSs rapidly expand, significantly decreasing the distance between the endoplasmic reticulum and mitochondria, which indicates enhanced tethering between these organelles.

These EMCSs are essential for transporting key phospholipids from the endoplasmic reticulum to mitochondria, which is crucial for maintaining cellular and organelle functions.

The process of PLox initiates at the EMCSs and subsequently spreads to the mitochondria, leading to mitochondrial damage and ultimately cell death.

Blocking PLox with ferrostatin-1 (Fer-1) prevents the expansion of EMCSs, suggesting a causal relationship between lipid oxidation and the dynamics of EMCS.

Ferroptosis is driven by oxidized polyunsaturated fatty acid-containing phosphatidylethanolamine (PE), and the enzyme glutathione peroxidase 4 (GPX4) can mitigate this process by reducing hydroperoxyl lipids.

Experimental results indicate that EMCSs are critical for mitochondrial calcium uptake, suggesting their role in cellular signaling during ferroptosis.

Overall, the findings suggest that targeting the dynamics of EMCSs could represent a promising strategy for mitigating diseases associated with ferroptosis.