Researchers at the VIB-KU Leuven Center for Cancer Biology have made a groundbreaking discovery regarding the initiation of ferroptosis, a unique form of cell death driven by lipid oxidation and iron. By uncovering the critical interaction between the endoplasmic reticulum (ER) and mitochondria, they have identified how these cellular compartments act as central ignition points for this process.

In a recent study published in Nature Cell Biology, Professor Patrizia Agostinis and her team shed light on the role of ER-mitochondria contact sites (EMCSs) in triggering a cascade that ultimately leads to the death of cancer cells.

Understanding Ferroptosis

Ferroptosis is characterized by the oxidation of specific fats, known as phospholipids (PLs), in cell membranes due to the inhibition of the cell's defense system. This lipid peroxidation is a key feature of ferroptosis, leading to damage in the cell's outer layer and subsequent cell death. Although a recent discovery, ferroptosis has been associated with various diseases, including neurodegenerative disorders and cancer.

Despite its significance, the exact location within the cell where PL peroxidation initiates has remained unknown.

Key Findings

Professor Patrizia Agostinis and her team utilized super-resolution live imaging to observe the spatiotemporal events triggered by ferroptosis at the inter-organelle level. They discovered that EMCSs are the first cellular membranes susceptible to lipid peroxidation, playing a crucial role in spreading damaging lipids to mitochondria. This process leads to an increase in reactive oxygen species (ROS) production and fragmentation of mitochondria, amplifying cellular damage.

Maria Livia Sassano, the study's first author, highlighted the role of EMCSs as functional command centers for initiating and propagating lipid peroxidation, providing valuable insights into the mechanisms of ferroptosis.

Implications for Cancer Treatment

By disrupting the physical link between the endoplasmic reticulum and mitochondria, researchers were able to reduce the accumulation of harmful lipid peroxides, shielding cells from ferroptosis. On the other hand, enhancing ER-mitochondria connections intensified lipid peroxidation and accelerated cell death.

The study suggests that boosting EMCSs could be a promising strategy to enhance the vulnerability of aggressive tumors, such as triple-negative breast cancer (TNBC), to ferroptosis. Tumors with more EMCSs are particularly susceptible to this form of cell death, while those lacking in ER-mitochondria contact can be sensitized to ferroptosis by promoting closer interaction between these organelles.

Professor Patrizia Agostinis emphasized the potential of targeting these cellular hotspots to enhance ferroptosis vulnerability in resistant tumors and reduce lipid peroxidation in neurodegenerative diseases.

Source: News-Medical