Science1 publisher2 min readPublished
Blocking iron's route into mitochondria made high cysteine harmless to cells
A Rockefeller group reports in Nature Metabolism that free cysteine pulls iron out of ferritin and into mitochondria, while glutathione, built on the same reactive sulfur group, leaves the stored iron alone.
The Scientist · Science desk
What happened
- A Nature Metabolism paper reports that excess cysteine pries iron out of ferritin, the complex that normally keeps the metal locked away, and that the freed iron piles up in mitochondria and kills the cell.
- A genome-wide CRISPR screen looked for gene losses that let cells survive high cysteine, and it returned SLC25A28, which imports iron into mitochondria, plus receptor proteins that break ferritin down.
- Follow-up experiments showed cysteine reacting directly with the iron held inside ferritin and converting it into a form able to escape the protein shell.
- Glutathione could not do the same thing, even though it carries the identical reactive sulfur-containing group that makes cysteine so chemically active.
- Cysteine is the only one of the 20 amino acids cells use to build proteins that becomes acutely toxic when it is present in excess.
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Why it matters
- capability Because two separate steps on the same route each abolished the toxicity when blocked, a lab can now raise or lower a cell's tolerance for cysteine by moving iron, without altering its redox chemistry.
- constraint With no cell lines or concentrations in the published account, the result cannot be converted into an intake threshold for an animal, let alone a person.
- decision Anyone weighing cysteine supplementation now has the study author's own caution to set against the trials suggesting a benefit.
- precedent If glutathione synthesis is partly an iron-containment step, studies that manipulate glutathione and read out oxidative damage have a second variable they are expected to measure.
A knockout screen of this kind selects for absence. Disable one gene per cell, raise cysteine to a level that kills, then sequence whatever still grows, and the genes that come back are the ones the cell needed in order to die. In the Rockefeller screen the hits sat on a single route into the mitochondrion: SLC25A28, which imports iron, and the receptor proteins that break ferritin down [3].
The comparison with glutathione is the informative part. Both molecules carry the same reactive sulfur group [5]. Only cysteine turned ferritin's stored iron into a form that could escape the shell [4]. If reactive sulfur alone were doing the damage, glutathione should have done it too, since cells hold glutathione at much higher concentrations than free cysteine [10].
Then two interruptions. Blocking the release of iron from ferritin removed the toxicity of high cysteine, and blocking iron's transport into mitochondria removed it as well [6]. Inside the mitochondria, the freed iron built up and damaged iron-sulfur proteins [7]. Cysteine is one of the ingredients cells use to build iron-sulfur clusters in the first place [8].
Kivanc Birsoy, who heads the Laboratory of Metabolic Regulation and Genetics at Rockefeller, says the result answers an evolutionary question about why cells spend energy packaging cysteine into glutathione [14]. "If cells had relied on cysteine instead, it would have been catastrophic for mitochondria. We now know that keeping free cysteine low was nature's way of protecting the cell's energy generator," Birsoy said [11]. Toshitaka Nakamura, a postdoctoral fellow in the lab, said that "understanding why cells keep cysteine low would provide the long-awaited evolutionary explanation for why they chose glutathione as their main antioxidant" [13].
The work is in cultured cells. The published account of the study does not state which cell lines or what cysteine concentrations were used, so nothing here sets a number for intake in an animal or a person. The toxicity has a floor as well as a ceiling: cells with too little cysteine lose their glutathione and die of that [9], and cells with far too much die of iron reaching their mitochondria [1].
That floor leaves the supplement question open, and Birsoy raised it himself. "There are some studies suggesting cysteine supplementation might be beneficial," he said. "This should be taken with a grain of salt precisely because of how toxic high cysteine is to cells" [12].
What to watch
- Whether the ferritin-to-mitochondria route holds in whole animals as well as in cultured cells.
- Whether the paper's own figures report the cysteine concentrations at which cells began to die.
- Whether other labs test glutathione's role in keeping iron locked inside ferritin alongside its role as an antioxidant.