Researchers identify cellular hotspots that trigger ferroptosis

Researchers at the VIB-KU Leuven Center for Cancer Biology have uncovered how a unique interaction between two cellular compartments, namely the endoplasmic reticulum (ER) and mitochondria, can act as a central ignition point for ferroptosis, a form of cell death driven by lipid oxidation and iron. In a study published in Nature Cell Biology, the team of Professor Patrizia Agostinis highlights the role of ER-mitochondria contact sites (EMCSs) in setting off a cascade that leads to the death of cancer cells.

Ferroptosis is a type of cell death that happens when certain fats (called phospholipids, or PLs) in cell membranes get damaged by oxidation, as a consequence of the blockade of the cell's main defense system. This damage is known as lipid peroxidation and it's a key feature of ferroptosis. Once lipid peroxidation starts, it quickly spreads to the cell's outer layer, damaging the main barrier and leading to cell death. Ferroptosis is a recently discovered way that causes cell death, and it has been linked to the development and progression of various diseases, like neurodegenerative disorders and cancer. However, to date, where inside the cell PL peroxidation begins remains unknown.

In a study led by Professor Patrizia Agostinis of the VIB-KU Leuven Center for Cancer Biology, super-resolution live imaging was used to chart spatiotemporal events triggered by ferroptosis at the inter-organelle level. The research team tracked the precise moment PL peroxides form and spread within the cell. They found that the first cellular membranes susceptible to lipid peroxidation are the endoplasmic reticulum-mitochondrial contact sites (EMCSs). EMCSs not only expand rapidly in response to lipid peroxidation, but also play a key role in spreading the damaging lipids to mitochondria. In turn, this causes an increase in the production of reactive oxygen species (ROS) and fragmentation of these energy-producing organelles, which amplifies cellular damage.

Maria Livia Sassano, first author of the study: "Our findings show that EMCSs, because of their specific lipid landscape, act as functional command centers for initiating and propagating lipid peroxidation in cells undergoing ferroptosis. An exciting discovery because we now understand what initiates ferroptosis and how we can potentially control it."

Boosting ferroptosis to defeat cancer cells

Having discovered the role of EMCSs in ferroptosis, the researchers found that disrupting the physical link between the endoplasmic reticulum and mitochondria significantly reduced the accumulation of harmful lipid peroxides. This "untethering" effect effectively shields cells from undergoing ferroptosis. Conversely, enhancing and stabilizing the ER-mitochondria connections intensifies PL peroxidation and accelerates cell death

Building on these findings, the study shows that boosting EMCSs could be an effective strategy to enhance the vulnerability to ferroptosis of aggressive tumors, like triple-negative breast cancer (TNBC). TNBC tumors don't all react the same way to treatment, inducing ferroptosis. Those that naturally have more EMCSs are particularly vulnerable to ferroptosis, while TNBC in which the ER and mitochondria aren't in good contact, are more difficult to kill, but can be sensitized by forcing these organelles to come in close vicinity. Playing into this advantage, scientists can increase the tumor's susceptibility to lipid damage, effectively tipping the balance toward this type of cell death.

"Our findings may have relevant implications for TNBC, hormone-resistant cancers that are much harder to treat than other breast cancer types, since the 'EMCS status' could serve as a biomarker of the vulnerability of these tumors to treatments that induce ferroptosis" explains Professor Patrizia Agostinis of the VIB-KU Leuven Center for Cancer Biology. "On a more general note, with this new fundamental knowledge, we can begin to design strategies that specifically target and modulate these cellular hotspots. By doing so, we hope to enhance ferroptosis vulnerability, especially in those tumors that are resistant to current therapies, while on the other hand, to reduce lipid peroxidation and cell death in neurodegenerative diseases"