Polyamines Protect Cells from Toxic Iron Buildup

Iron is necessary for life. Cells use it to produce energy, carry oxygen, and drive countless chemical reactions. But when too much iron sits unbound inside a cell, it can trigger reactions that damage DNA, proteins, and cell membranes. A team from Whitehead Institute has now  identified an unexpected safeguard against this danger: small molecules called polyamines. Their findings, published in Cell, show that polyamines act like storage lockers for iron, holding the metal in a non-reactive state until cells need it. The discovery answers a decades-old question about why cells maintain such high polyamine levels and reveals a previously unknown defense against iron overload. 

The Jain Lab studies RNA and how it folds, misfolds, and clumps inside cells. Ankar Jain and team began examining polyamines because the molecules bind RNA and help shape its structure, but they suspected polyamines served other purposes, since they exist at levels comparable to ATP, the cell’s energy currency. “We’ve known that without polyamines, cells stop growing and dividing,” Jain noted. “But their best-known function only requires a small fraction of the polyamine levels cells actually have.” 

To find polyamines’ hidden role, the team ran a genome-wide genetic screen and found that when polyamine levels drop, a protein called GPX4, which prevents damage to membrane fats, becomes essential for survival. Cells with lower polyamine levels also had more of a protein that mineralizes and contains iron. This led the researchers to test whether polyamines keep iron in a safe form. Using a newly developed fluorescent sensor that tracks chemically reactive iron in living cells, paired with an existing polyamine sensor, they saw that as polyamine levels fell, reactive iron rose.

The findings may aid cancer treatment. Cancer cells depend on high polyamine levels to grow, but drugs lowering those levels have had limited success alone. “We saw that when polyamine levels fall, cells rely on GPX4 to protect themselves from iron toxicity,” first author Pushkal Sharma explained. “This could mean that combining drugs that lower polyamine levels with those that block GPX4 might be more effective for killing cancer cells than targeting either pathway alone.”

The work may also inform early-onset Parkinson’s disease, where mutations affecting polyamine transport are linked to elevated brain iron levels, though a direct causal role remains unclear. Jain notes the new sensor could help other researchers studying aging, cancer, and neurodegeneration, adding, “There are a lot of promising future directions for this work.”