Cell: Polyamines Buffer Reactive Iron and Limit Ferroptosis

Cell has published a study showing that polyamines bind reactive iron

On August 14, Cell published a study of cellular polyamines. When researchers depleted polyamines in cultured cells, the amount of labile, chemically reactive iron increased. At the same time, the cells became more dependent on GPX4, an enzyme that reduces oxidized membrane lipids.

Cells need iron, but its chemically reactive fraction initiates chain reactions that oxidize membrane lipids. The accumulation of these oxidized lipids leads to ferroptosis, an iron-dependent form of cell death caused by membrane damage.

Polyamines include spermidine and spermine. Cells maintain them at high concentrations and regulate those concentrations closely. Ankur Jain's team set out to determine why cells need such a large pool and conducted a genome-wide CRISPR screen. In a large population of cultured cells, the researchers disrupted genes one at a time and examined which losses became especially harmful after polyamine depletion.

The screen identified GPX4. When polyamines were depleted, either genetic loss of this enzyme or its inhibition with drugs killed the cells. Adding spermidine or compounds that inhibit ferroptosis restored cell viability. These results linked the cellular polyamine pool to protection of the membrane from oxidation.

The authors investigated iron as the cause of this dependence on GPX4. Polyamine depletion increased cellular levels of ferritin, an iron-storage protein, while a fluorescent dye detected more reactive iron. Deferoxamine, which binds iron, restored cell viability during GPX4 inhibition. At the same time, the total amount of iron decreased. These experiments indicate that existing iron was redistributed into a more reactive pool.

Polyamine depletion also increased ferritin levels in organoids, which are miniature models of the mouse intestine grown from cells. In living cells, two fluorescent sensors whose brightness changes with the concentrations of the substances they detect showed an inverse relationship: as polyamine levels fell, the reactive iron signal increased.

The authors propose a model in which polyamines keep some iron in a less reactive state. Under this model, the polyamine pool changes iron availability, which in turn determines how strongly the membrane depends on protection by GPX4.