The critical organelle in cells that drives ferroptosis
Our new paper reports that the endoplasmic reticulum is the key site in cells that drives ferroptosis.
In our new paper, we found that the endoplasmic reticulum is crucial for driving a specific type of cell death known as ferroptosis.
Here is our paper, published today in Nature Chemical Biology. A free viewable version:
and the regular version:
https://www.nature.com/articles/s41589-022-01249-3
Ferroptosis is a type of cell death driven by oxidative damage, specifically peroxidation, of lipids within the membranes of cells. We first proposed this form of cell death in a 2012 Cell paper from my lab:
Although we knew that lipids get peroxidized during ferroptosis, and this peroxidation is critical to drive the resulting cell death, it has been unclear where these lipids are located within cells. There have been proposals that various organelles within cells are the key sites for lipid peroxidation:
This is a key question to answer to understand how lipid peroxidation actually causes cell death, and also to be able therapeutically modulate ferroptosis in various diseases.
In a longstanding collaboration with Keith Woerpel’s lab at NYU and Wei Min’s lab at Columbia, we used a variety of methods to determine where these lipids needs to be peroxidized to drive cell death.
First, we examined the subcellular location of a compound named ferrostatin, which we had identified many years ago as a fairly direct inhibitor of ferroptosis. This compound acts by directly blocking lipid peroxidation, so identifying its subcellular localization tells us where lipid peroxidation is necessary in order for cell death to occur.
We found that this compound localizes to three major sites within cells — mitochondria, lysosomes, and the endoplasmic reticulum.
However, we found that the mitochondria and lysosomes were not needed for its protective effect, leaving only the endoplasmic reticulum as a critical necessary site of lipid peroxidation during ferroptosis.
Next, we examined the subcellular localization of polyunsaturated fatty acids (PUFAs), which are key lipids that control ferroptosis sensitivity. We found that these PUFAs localize to lipid droplets and the endoplasmic reticulum, but that the lipid droplets were not needed for their ability to control ferroptosis, again leaving the endoplasmic reticulum as the key site.
Third, we examined the subcellular localization of FINO2, an endoperoxide compound discovered in Keith Woerpel’s lab that can fairly directly trigger lipid peroxidation and ferroptosis:
https://pubs.acs.org/doi/abs/10.1021/acschembio.5b00900
Examining the subcellular localization of this compound allowed us to determine where lipid peroxidation is sufficient to trigger ferroptosis.
We found that FINO2 was localized to the endoplasmic reticulum, again highlighting the central role of the endoplasmic reticulum in driving ferroptosis.
Finally, we imaged the appearance of lipid peroxidation within cells using a fluorescent sensor. We found that lipid peroxidation occurred first and most extensively in the endoplasmic reticulum, and only once the cells were dying or dead, we could detect some lipid peroxidation in the plasma membrane of cels. This highlighted again that the endoplasmic reticulum is the crucial site within cells that is both necessary and sufficient to trigger ferroptosis.
These findings now allow us to take a more targeted approach to controlling ferroptosis, by examining in the future how we can induce and inhibit lipid peroxidation with the endoplasmic reticulum.
Here are some additional commentaries and articles about our new paper:
I am grateful to the entire team that worked on this, especially our collaborators Keith Woerpel and Wei Min and they labmembers, and my MD-PHD student Niki von Krusenstiern.
