Cysteine, despite its importance for the synthesis of glutathione (GSH), is one of the few amino acids with direct toxicity even at physiological concentrations. Conversely, cysteine dietary restriction has been reliably shown to increase both average and maximum lifespan. Ray mentioned cysteine in quite a few of his articles and interviews, and his explanation of cysteine;s toxicity revolved mostly around its role as a reductant and goitrogen. However, there seems to be another toxicity mechanism and the study below finally shines light on it. Namely, iron overload, which Ray also warned against, and believed that iron overload is one of the key drivers of aging and diseases. The study below demonstrates that cysteine sequesters iron from ferritin and this allows iron to accumulate in very high concentrations inside the mitochondria, where it not only leads to lipid peroxidation and formation of reactive oxygen species (ROS), but also directly causes cell death. When either the release of iron from ferritin or its cellular uptake is blocked, cysteine is no longer toxic.
https://www.nature.com/articles/s42255-026-01616-7
https://www.rockefeller.edu/news/40469-cysteine-toxic-glutathione/
“…Cysteine is one of the main building blocks that cells use to make proteins. But this amino acid is a double-edged sword—too much cysteine is toxic to the cell. Cells therefore keep free cysteine levels to a minimum, converting most of the amino acid into the antioxidant glutathione. Now, a new paper explains why cysteine is so toxic at high concentrations. The findings, published in Nature Metabolism, show that cysteine can pry iron from ferritin, the protein complex that normally keeps the metal safely locked away, flooding the cell with iron that accumulates in the mitochondria, leading to cell death. These results resolve a longstanding question in basic biology, and offer the first comprehensive explanation for why cells may have evolved to expend significant energy packaging cysteine into glutathione.”
“…On the other hand, too much cysteine is just as toxic. In fact, cysteine is the only one of the 20 protein-building amino acids that becomes acutely toxic when present in excess. “There are some studies suggesting cysteine supplementation might be beneficial,” Birsoy says. “This should be taken with a grain of salt precisely because of how toxic high cysteine is to cells.”
“…Ferritin normally keeps iron safely locked away, while SLC25A28 transports available iron into mitochondria. Finding SLC25A28 at the center of their genetic screen led the researchers to ask whether excess cysteine was somehow freeing iron from ferritin and sending it into mitochondria. A series of experiments confirmed that cysteine can react directly with iron stored in ferritin, changing it into a form that can escape. Glutathione, despite sharing cysteine’s reactive sulfur-containing group, could not. And when the researchers blocked either the release of iron from ferritin or its transport into mitochondria, high levels of cysteine were no longer toxic—a deft demonstration that its impact on iron’s movement is what explains its toxicity.”
