Cells use a little-known molecule to protect themselves from iron overload

Iron is essential. Our cells need it to produce energy, carry oxygen throughout the body, and power countless chemical reactions that sustain life. But this metal has a dark side. When too much of it is left free inside cells, it can trigger destructive reactions that break down DNA, proteins, and even cell membranes.Now, MIT associate professor of biology and Whitehead Institute for Biomedical Research member Ankur Jain; MIT assistant professor of biology and Koch Institute for Integrative Cancer Research member Whitney Henry; and Pushkal Sharma PhD ’26 have discovered that cells rely on an unexpected protector against this threat: small molecules called polyamines.The researchers’ detailed findings, published Aug. 14 in the journal Cell, reveal that polyamines act like storage lockers for iron, safely holding the metal in a non-reactive state until cells need it.These findings solve a decades-old mystery about why cells maintain such extraordinarily high levels of polyamines and uncover a previously unknown defense mechanism that protects cells from toxic iron overload.This work could also help scientists develop better cancer treatments, by allowing iron overload to trigger cancer cell death. It could also offer new clues about diseases like early-onset Parkinson’s disease, in which mutations affect polyamine levels within neurons.The Jain Lab studies RNA, the intermediary between DNA and the tiny molecular machines called proteins that perform most of the essential tasks inside cells. The lab is particularly interested in how RNA folds, misfolds, and sometimes clumps inside cells.Jain and Sharma first began studying polyamines because these molecules bind to RNA and help shape its structure. However, they suspected that polyamines must be playing other roles inside cells: they’re among the most abundant small molecules within cells, present at levels comparable to ATP, the molecule cells use as their energy currency.“We’ve known that without polyamines, cells stop growing and dividing,” Jain says. “But their best-known function only requires a small fraction of the polyamine levels cells actually have.”To uncover polyamines’ hidden function inside cells, the researchers used a large-scale genetic approach that allows them to screen the entire genome at once, rather than testing genes one-by-one, in order to find out which cellular processes are impacted when polyamine levels are changed within cells.The screen revealed that when cells have reduced levels of polyamines, a protein called GPX4 becomes essential for survival. GPX4 is known to prevent harmful chemical reactions that damage the fatty molecules that make up cell membranes. The team also found that cells with lower polyamine levels have higher amounts of another protein that acts as an iron sponge and keeps the metal in a mineralized form. Together, these findings led the researchers to hypothesize that polyamines might be helping keep iron in a safe, non-reactive state within cells.To test this idea, they developed a new fluorescent sensor that would allow them to measure chemically reactive iron inside living cells. The new sensor causes living cells to glow based on the amount of chemically reactive iron they contain, allowing researchers to track any changes under a microscope in real-time.The team paired the new iron sensor with another sensor they had previously developed that measures polyamine levels within cells. By employing them simultaneously, they observed a striking pattern: As polyamine levels dropped within cells, the amount of chemically reactive iron went up, offering new evidence that polyamines play a key role in preventing toxic iron build up inside cells.Beyond answering a fundamental biological question, these findings could have implications for cancer treatment. Cancer cells often rely on high polyamine levels to support their rapid growth and division. However, cancer drugs designed to lower polyamine levels to stop cell division have had limited success.“We saw that when polyamine levels fall, cells rely on GPX4 to protect themselves from iron toxicity,” says Sharma, who is also the first author of the study. “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 discovery may also have implications beyond cancer. Mutations in genes that help move polyamines around cells are linked to a rare form of early-onset Parkinson’s disease, and scientists have long observed unusually high levels of iron in the brains of Parkinson’s patients. While it is still unclear whether excess iron directly contributes to neuron death in Parkinson’s, the discovery that polyamines help buffer reactive iron inside cells offers a possible explanation for this link and opens new directions for future investigation.In addition, the researchers expect the new iron sensor to be a valuable tool for other scientists. By allowing them to track chemically reactive iron inside living cells, it could power new discoveries in aging, cancer, and neurodegeneration.“There are a lot of promising future directions for this work,” Jain says. “It’s exciting to think about how these tools and findings could help answer further questions about disease pathways and potentially help design better therapies.”This work is supported by grants from the National Institutes of Health, Bumpus Foundation, and Pew Charitable Trusts. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.