Scientists Discover How Cells Keep Iron From Turning Toxic

Iron keeps cells alive, but too much chemically reactive iron turns destructive, damaging DNA, proteins and cell membranes. Researchers at the Whitehead Institute have identified an unexpected defense: small molecules called polyamines. Published in the journal Cell, the study shows polyamines can bind iron and hold it in a non-reactive state until cells need it.

The discovery came from Whitehead Institute Member Ankur Jain, also an associate professor of biology at the Massachusetts Institute of Technology (MIT), former postdoc Whitney Henry, and graduate student Pushkal Sharma. Jain's lab mainly studies RNA, the molecule that carries DNA's instructions to build proteins, and the team first studied polyamines because they bind RNA. Polyamines are among the most abundant small molecules in cells, reaching levels comparable to ATP, the cell's main energy source.

A genome-wide genetic screen found that cells with reduced polyamine levels became highly dependent on a protein called GPX4, which protects cell membranes from damaging chemical reactions. Those cells also made more of another protein that stores iron in a mineralized form. The researchers then built a fluorescent sensor that makes living cells glow according to their reactive-iron content, paired it with an existing polyamine sensor, and found that as polyamine levels fell, reactive iron rose.

The discovery may help explain why cancer drugs that lower polyamine levels, explored because cancer cells keep polyamine levels high to fuel rapid growth, have had limited success so far. "Combining drugs that lower polyamine levels with those that block GPX4 might be more effective for killing cancer cells than targeting either pathway alone," says Sharma, the study's first author.

The results may also be relevant to early-onset Parkinson's disease. Mutations in genes that transport polyamines within cells have been linked to a rare form of the condition, and unusually high iron levels have long been observed in the brains of people with Parkinson's.