Abstract
Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.
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Acknowledgements
The authors thank L. Magtanong, D. Pratt and members of the Dixon and Olzmann labs for discussion and comments on the manuscript. This work is supported by the National Institutes of Health (R01GM122923 to S.J.D. and R01GM112948 to J.A.O.) and the American Cancer Society (RSG-21-017-01 to S.J.D. and RSG-19-192-01 to J.A.O.). J.A.O. is a Chan Zuckerberg Biohub Investigator and is also supported by a Bakar Fellows Spark Award.
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S.J.D. is a co-founder of Prothegen and a member of the scientific advisory board for Hillstream BioPharma. S.J.D. holds patents related to ferroptosis. J.A.O. is a member of the scientific advisory board for Vicinitas Therapeutics and holds patents related to ferroptosis.
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Glossary
- Caveolae
-
Small invaginations of the plasma membrane enriched for certain lipids and proteins.
- Endocytosis
-
The process of taking up materials from outside the cells into intracellular vesicles called endosomes. Endosomes can then transport materials within the cell to other compartments such as the lysosome.
- Ether lipid
-
A class of phospholipid where one of the two fatty acyl chains is bound to the glycerol backbone by an ether bond rather than the more common ester bond. Ether lipids may contribute importantly to the execution of ferroptosis in some cells.
- Ferritinophagy
-
The catabolism of iron-laden ferritin nanocages in the autophagolysosome to release free iron atoms.
- Fe–S clusters
-
Iron–sulfur clusters are essential enzyme cofactors. Several different configurations of iron and sulfur atoms yield distinct types of clusters.
- Integrated stress response
-
A gene expression programme that can help the cell respond to a shortage of individual amino acids by increasing the expression of membrane transporters and other metabolic enzymes that restore homeostasis.
- Lipolysis
-
The enzymatic breakdown of triacylglycerol to glycerol and free fatty acids mediated by a series of lipases recruited to the lipid droplet surface.
- Lipophagy
-
The breakdown of the lipid droplet, or a portion of the lipid droplet, through its delivery to the lysosome by a selective autophagic pathway.
- Membrane contact sites
-
Regions of close proximity between two organelles that are often stabilized by protein tethers. These sites typically function as sites for the exchange of lipids and metabolites.
- Monounsaturated fatty acids
-
(MUFAs). Fatty acid molecules that contain a single carbon–carbon double bond.
- Necroptosis and pyroptosis
-
Two forms of non-apoptotic cell death that are biochemically distinct from each other and from ferroptosis.
- Polyunsaturated fatty acid
-
(PUFA). Fatty acid molecule that contains multiple carbon–carbon double bonds, making it more sensitive to oxidative damage.
- Reactive oxygen species
-
(ROS). An umbrella term for a number of small oxygen radicals and species that contain oxygen and which can easily form radical-containing species. Oxygen radicals that may initiate lipid peroxidation, leading to ferroptosis, include the hydroperoxyl radical (the conjugate acid of superoxide) and the hydroxyl radical, which itself can be formed from the Fenton reaction between hydrogen peroxide and iron.
- Selenoprotein
-
One of a small number of proteins in mammalian cells that incorporate the unusual selenium-containing amino acid selenocysteine. Typically, these proteins are involved in some aspect of redox regulation in the cell.
- Stimulator of interferon genes
-
(STING). A protein that can sense DNA in the cytosol and orchestrate a downstream immune response by binding to other signalling proteins.
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Dixon, S.J., Olzmann, J.A. The cell biology of ferroptosis. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00703-5
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DOI: https://doi.org/10.1038/s41580-024-00703-5
